American J Hematol - 2023 - Shimony - Acute Myeloid Leukemia 2023 Update On Diagnosis Risk Stratification and Management

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Received: 18 October 2022 Revised: 1 December 2022 Accepted: 15 December 2022
DOI: 10.1002/ajh.26822
ANNUAL CLINICAL UPDATES IN

HEMATOLOGICAL MALIGNANCIES
Acute myeloid leukemia: 2023 update on diagnosis,

risk-stratification, and management
Shai Shimony 1,2 | Maximilian Stahl 1 | Richard M. Stone 1

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
2
Rabin Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
Correspondence
Richard M. Stone, MD, Dana-Farber Cancer Abstract
Institute, 450 Brookline Ave, Boston, MA
Disease overview: Acute myeloid leukemia (AML) is a frequently fatal bone marrow
02215, USA.
Email: richard_stone@dfci.harvard.edu stem cell cancer characterized by unbridled proliferation of malignant marrow stem
cells with associated infection, anemia, and bleeding. An improved understanding of
pathophysiology, improvements in measurement technology and at least 10 recently
approved therapies have led to revamping the diagnostic, prognostic, and therapeutic
landscape of AML.
Diagnosis: One updated and one new classification system were published in 2022,
both emphasizing the integration of molecular analysis into daily practice. Differences
between the International Consensus Classification and major revisions from the pre-
vious 2016 WHO system provide both challenges and opportunities for care and clin-
ical research.
Risk assessment and monitoring: The European Leukemia Net 2022 risk classifica-
tion integrates knowledge from novel molecular findings and recent trial results, as
well as emphasizing dynamic risk based on serial measurable residual disease assess-
ment. However, how to leverage our burgeoning ability to measure a small number of
potentially malignant myeloid cells into therapeutic decision making is controversial.
Risk adapted therapy: The diagnostic and therapeutic complexity plus the availability
of newly approved agents requires a nuanced therapeutic algorithm which should
integrate patient goals of care, comorbidities, and disease characteristics including
the specific mutational profile of the patient's AML. The framework we suggest only
represents the beginning of the discussion.
1 | I N T RO DU CT I O N age at diagnosis of 68 years.3 The estimated 5-year OS is 30%4 and

differs greatly between various age groups, reaching 50% in younger
Acute myeloid leukemia (AML) is a heterogenous disease that arises patients but is less than 10% in patients older than age 60.5 How-
1,2
from uncontrolled proliferation of clonal hematopoietic cells. It is ever, such statistics, based mainly on older trials, could be improving
the most common form of acute leukemia in adults, with a median with the FDA approval of 11 new drugs or combinations since
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SHIMONY ET AL. 503
20176–19 (Table 1). Furthermore, new molecular insights regarding with favorable response and improved survival.54–56 AML with BCR::
AML evolution, progression, and resistance mechanisms have ABL1 was added as a formal AML defining lesion, with requirement of
greatly affected our diagnosis, classification, and monitoring of blasts ≥20% and not ≥10%, to differentiate from CML in accelerated
patients with AML.2,40,41 phase.
The WHO and ICC classifications employ different blast thresh-
olds to define AML in certain situations. While there is no minimum
1.1 | Representative case threshold in the WHO criteria for AML with defining genetic abnor-
malities (with the exception 20% required for AML with BCR::ABL1
A 67-year-old man with past medical history of hypertension and and AML with CEBPA bZIP mutation), the ICC requires at least 10%
dyslipidemia presents with marked fatigue. Complete blood count blasts in the bone marrow or peripheral blood for defining AML with
is notable for pancytopenia with Hg of 7.5 g/dL, white blood cell recurrent genetic abnormalities (with the exception of ≥20% in AML
count of 2.3 109 cells/μL, and platelet count of 27 109 cells/μL. with BCR::ABL1). For all other AML subgroups, the 20% blasts thresh-
Bone marrow biopsy demonstrates 22% myeloblasts, normal old was retained by the WHO. However, the ICC introduced a new
karyotype by cytogenetics, and a BCOR deletion mutation category of (MDS)/AML with 10%–19% blasts in the bone marrow or
(c.3395_3396delGG p.V1132fs) with variant allele frequency peripheral blood, in recognition of the similarities in biology and prog-
of 42%. nosis between these patients and those with ≥20% myeloblasts.57–60
How would this patient be diagnosed based on the recently pub- The definition of AML with myelodysplasia related changes
lished WHO and ICC classification system? (MRC) was not included in in either classification system. Instead, both
WHO and ICC introduced categories with molecular and cytogenetic
abnormalities that define functional secondary ontogeny and are asso-
2 | U P D A T E S I N DI A G N O S I S ciated with poor prognosis.61 However, while the WHO defined these
categories as AML myelodysplasia-related (AML-MR) that included a
40 41
One updated and one new AML classification system were pub- prior history of MDS or MDS/MPN, the ICC instead defined prior
lished in 2022, both utilizing novel findings in AML pathophysiology MDS or MDS/MPN as a qualifier to the diagnosis of AML. In addition,
and emphasizing the integration of molecular analysis into daily prac- which molecular and cytogenetic abnormalities considered MDS-
tice in AML. We will discuss major revisions from the previous 2016 defining lesions slightly differ between the two classifications. For
42
WHO edition classification and highlight some similarities and dif- example, a RUNX1 mutation is included as myelodysplasia-defining in
ferences between the classification systems. the ICC definition, whereas it does not qualify as a myelodysplasia
The 2016 WHO criteria defined AML as presence of 20% blasts defining lesion in the WHO 2022 criteria, (Figure 1 and Table 2).
in the bone marrow or peripheral blood, any evidence of extramedul- Both classification systems incorporated special consideration for
lary myeloblasts (myeloid sarcoma), or presence of AML defining prior cytotoxic exposure and genetic predisposition. In the WHO clas-
genetic abnormalities PML::RARA, RUNX1::RUNX1T1, and CBFB:: sification, those were reclassified under a new diagnostic category
MYH11 irrespective of blast percentage.42 called secondary myeloid neoplasms encompassing myeloid neo-
Of note, Acute promyelocytic leukemia (APL), usually associated plasms arising after cytotoxic therapeutics or which possess a defined
with a PML::RARA translocation, is a unique clinicopathological AML germline predisposition. In the ICC classification, these were not
entity that comprise 5%–10% of AML diagnoses.43,44 APL is treated defined as a separate group but as added qualifiers to AML diagnosis
with combinations including all trans retinoic acid (ATRA) and arsenic (Figure 1). With recent advances in molecular diagnosis and analysis,
trioxide (ATO), with or without additional chemotherapy and has more individuals with myeloid malignancies (even those who present
excellent prognosis as compared to other non-APL AML at advanced ages) than previously are now recognized to have an
subtypes.45–51 In this review, we will not discuss APL management; inherited germline predisposition.62 Thus, it has been advocated that
AML will refer to non-APL AML. any MDS and any AML patient with certain molecular/cytogenetic
Both new classifications broaden the genetic abnormalities that lesions, a syndromic presentation or a suggestive family history
define specific AML groups. NPM1 is now recognized by both WHO undergo a genetic analysis of unaffected tissue to assess for a germ-
and ICC as an AML-defining mutation, due to the rarity of NPM1 line predisposition.63 The finding of a germline predisposition may
mutations in MDS and the rapid progression seen in most patients affect the patient's treatment, such as donor selection for AlloSCT or
previously defined as MDS with NPM1 mutation.52,53 The WHO now decision regarding the appropriate conditioning regimen. In addition,
delineates CEBPA mutated AML as an entity including biallelic CEPBA it may also effect the monitoring and evaluation of family members.64
mutation or a monoallelic in-frame basic leucine zipper region (bZIP) For example, germline mutations in DDX41 are the most common
mutated gene. The ICC definition of CEBPA mutated AML only genetic predisposition mutations in MDS and AML.65,66 The occur-
requires the presence of the bZIP alteration. This is due to the discov- rence of AML is generally thought to involve a second “hit” in DDX41
ery that the in-frame mutations in the bZIP C-terminus region have in the background of a germline mutation in this gene.67 AML with
distinct clinical and molecular characteristics: younger age, higher DDX41 germline mutations have unique clinical characteristics: more
white blood cell counts, and enrichment in co-mutations of GATA2 common in males, usually present in the 7th decade, low peripheral
and NPM1. The presence of a bZIP in-frame mutation is associated blood leukocyte and bone marrow blast counts, and are associated
TABLE 1 Drugs and/or combinations recently approved by the FDA for AML with selected trials evaluating off-label indication.
504
Drug Mechanism Approved indication FDA approval date Approved regimen Selected trials in non-labeled setting
Enasidenib10 IDH2 inhibitor R/R IDH2 mutated Jan 08, 2017 Monotherapy • HMA + ena versus HMA in IDH2 mutated ND-AML20
AML • Ena + ven for IDH2 mutated AML (NCT04092179)21
• Ena + intensive induction chemotherapy for IDH2 mutated
ND-AML (NCT02632708,22 NCT03839771)
• ASTX727 + ven + ena for IDH2 mutated R/R AML
(NCT04774393)
Midostaurin6 FLT3 inhibitor ND FLT3 mutated Apr 28, 2017 with “7 + 3” and • Midostaurin as maintenance therapy post AlloSCT23
AML HIDAC • Crenolanib versus Midostaurin added to induction
consolidation chemotherapy for FLT3 mutated ND-AML (NCT03258931)
Ivosidenib8,9,15 IDH1 inhibitor R/R IDH1 mutated R/R—Jul 20, 2018 R/R—Monotherapy • Ivo + intensive induction chemotherapy for IDH1 mutated
AML ND—Combination ND-AML (NCT02632708,22 NCT03839771)
ND IDH1 mutated ND therapy with • ASTX727 + ven + ivo for IDH1 mutated R/R AML
AML age Monotherapy –May azacitidine or (NCT04774393)
≥75 years/ 02, 2019 monotherapy • Ivo + ven ± aza in AML (NCT03471260)24
comorbidities, not Combination—May • CPX351 + ivo for IDH1 mutated R/R AML
fit for intensive 25, 2022 (NCT04493164)
chemotherapy
CPX3517 Liposomal ND t-AML or AML- Aug 03, 2017 Monotherapy for • CPX351 in patients with t-AML or AML-MRC
daunorubicin and MRC induction and age <60 years (NCT04269213)
cytarabine consolidation • CPX351 + ven, ivo or midostaurin in ND-AML patients
(NCT04075747)
• CPX351 with quizartinib in FLT3 mutated AML
(NCT04128748)
• Low dose CPX351 + ven in ND-AML (NCT04038437)
• CPX351 + ven in R/R AML (NCT03629171)
GO13,25,26 CD33-directed ND CD33-positive Sep 01, 2017 ND—combinationa • GO + Ven in R/R CD33 positive AML (NCT04070768)
antibody drug AML with intensive • GO + CPX351 in AML (NCT03904251, NCT03878927)
conjugate chemotherapy • GO + CLAG-M for ND (NCT03531918)27 or GO + CLAG
R/R CD33 positive R/R—monotherapy for R/R AML (NCT04050280)
adults
Venetoclax11,17,18,28 BCL2 inhibitor ND-AML Nov 21, 2018 combination + • FLAG-IDA + ven in ND-AML29 or ND and R/R AML30
age ≥75 years/ azacitidine, • “7 + 3” + ven in AML31 (NCT03709758)32
comorbidities, not decitabine or LDAC • Clad + ven + LDAC/aza in ND-AML33
fit for intensive • Cladribine + ida + ara-C + ven in ND-AML34
chemotherapy • HMA + ven + FLT3i35 in AML
• Ven in combination with reduced intensity conditioning for
AlloSCT36
• HMA + Ven as maintenance therapy post AlloSCT
(“VIALE-T", NCT04161885) or post chemotherapy
(“VIALE-M", NCT04102020)
SHIMONY ET AL.
TABLE 1 (Continued)
Drug Mechanism Approved indication FDA approval date Approved regimen Selected trials in non-labeled setting
Glasdegib16 Hedgehog pathway ND-AML age Nov 21, 2018 In combination with • CPX351+ Glasdegib in t-AML or AML-MR
SHIMONY ET AL.
inhibitor ≥75 years / LDAC (NCT04231851)

comorbidities, not • “7 + 3” with versus without glasdegib in ND-AML
fit for intensive (NCT03416179)
chemotherapy
Gilteritinib12 FLT3 inhibitor R/R FLT3 mutated Nov 21, 2018 Monotherapy • Gilteritinib + ven in R/R FLT3 mutated AML37
AML • Gilteritinib + ven + HMA in FLT3 mutated AML: (with
azacitidine),38 (with ASTX727—NCT05010122)
• CPX351 + gilteritinib in FLT3 mutated R/R AML
(NCT05024552)
• Gilteritinib + Atezolizumab in R/R FLT3 mutated AML
(NCT03730012)
• Gilteritinib versus Midostaurin added to “7 + 3” in FLT3
mutated ND-AML (NCT04027309, NCT03836209)
CC48614 Oral DNMT inhibitor ND-AML patients Sep 01, 2020 Monotherapy • CC486 as maintenance post AlloSCT,23 (NCT04173533)
aged 55 ≥ as post- • CC486 + ven as maintenance after conventional
intensive induction chemotherapy (NCT04102020)
therapy in patient • CC486 + ven in AML (NCT04887857, NCT05287568)
who achieved
remission
Olutasidenib19,39 IDH1 inhibitor R/R IDH1 mutated Dec 01, 2022 Monotherapy
AML
a
Approved as single agent in patients with ND-AML as well, but rarely used as monotherapy.
Abbreviations: “7+3”, daunorubicin and cytarabine; AML, acute myeloid leukemia; AML-MRC, acute myeloid leukemia with myelodysplastic related changes; ara-C, cytarabine; CD, cluster of differentiation;
clad, cladribine; CLAG, cladribine, cytarabine, and G-CSF, granulocyte stimulating factor; CLAG-M, CLAG chemotherapy with mitoxantrone; DNMT, DNA methyltransferase; Ena, enasidenib; FLAG-IDA,
fludarabine, cytarabine, G-CSF, idarubicine; FLT3, fms related tyrosine kinase 3; FLT3i, FLT3 inhibitor; GO, gemtuzumab ozogamicin; HIDAC, high dose cytarabine; AlloSCT, allogeneic stem cell transplantation;
HMA, hypomethylating agents; ida, idarubicin; IDH, isocitrate dehydrogenase; ivo, ivosidenib; LDAC, low dose cytarabine; ND, newly diagnosed; R/R, relapse or refractory; t-AML, therapy related AML; ven,
venetoclax.
505
506 SHIMONY ET AL.
F I G U R E 1 Comparison between WHO 5th versus ICC AML definitions. *with the exception ≥20% required for AML with BCR::ABL1 and
AML with CEBPA by the WHO and ≥20% in AML with BCR::ABL1. Colors reflect similar subgroups between classifications.AML, acute myeloid
leukemia; MDS, myelodysplastic syndrome; ICC, international consensus classification; MPN, myelodysplastic neoplasm; WHO, World Health
Organization.
with high chemo-responsiveness with an overall favorable prognosis needed for patients who are treated with less-intensive therapies
compared to matched patients with wild-type DDX41.68 including venetoclax-based regimens. The major changes in the
While advances in AML diagnosis could aid in optimizing the best ELN 2022 risk criteria as compared to ELN 2017 criteria 71 are
therapy for each subgroup, two novel classification systems challenge noted below:
communication between health care professionals, especially patholo-
gists, treating clinicians, and patients. However, it will remain the clini- • FLT3-ITD allelic ratio (AR) is no longer incorporated into the risk
cian's responsibility to integrate all data to arrive at a therapeutic classification. Thus, patients with FLT3-ITD mutated AML are
decision. The advantage of the ICC defined category of MDS/AML is considered in the intermediate group, irrespective of their AR or
that it should lead to a wider spectrum of trials from which a patient presence of NPM1 mutation. The main reasons for change are
and physician may choose, and thus is favored by the authors. lack of standardization in AR measuring assays, the effect of
Although the ICC recommends a 3–5-days turnaround time for molec- midostaurin on FLT3-ITD mutated AML6,72 and integration of
ular tests, we recognize that this goal is aspirational for many centers. MRD into decision making.73,74
However, waiting a week to make a therapeutic decision for almost all • AML with myelodysplasia-related gene mutations (as delineated by
AML patients is considered advisable and safe.69 ICC) is now defined as adverse risk. This includes the presence of a
Case continues: pathologic variant in one or more of ASXL1, BCOR, EZH2, RUNX1,
Our patient would be classified as AML with myelodysplasia- SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2 genes. Although typically
related gene mutation by the ICC and AML-MR by the WHO associated with antecedent hematological malignancy or dysplastic
classification. marrow elements, these mutations confer adverse risk, even in
What is this patient's prognosis? clinical and morphological de novo AML.2,61
• NPM1 mutated AML with adverse cytogenetic abnormalities will
be classified as adverse risk. This is based on meta-analysis that
3 | U P D A T E S I N RI SK ST R A T I F I C A T I O N evaluated additional cytogenetic abnormalities in patients with
NPM1 mutated AML.75 The exact role of additional molecular
A new European leukemia network (ELN) 2022 guidelines which abnormalities (other than FLT3 ITD) in patients with NPM1
include an update to the 2017 risk classification was recently pub- mutated AML is not yet defined.
lished (Table 3).70 The new 2022 risk classification • The favorable prognosis in CEPBA mutant AML is due to the in-
integrates knowledge from novel molecular findings and recent frame mutations affecting the bZIP region, irrespective of whether
trial results, as well as emphasizing dynamic risk based on mono- or bi-allelic mutations are present.54–56
response assessment, such as measurable residual disease (MRD) • Additional disease-defining cytogenetic abnormalities are now con-
negativity. However, the guidelines are largely based on sidered as adverse risk—t(3q26.2;v) involving the MECOM gene
intensively treated patients, so future adjustments may be and t(8;16)(p11;p13) associated with KAT6A::CREBBP, as they were
SHIMONY ET AL. 507
T A B L E 2 Major differences between WHO 5th AML and the ICC AML classifications. Major differences are bolded and highlighted in the
right column.
Major differences in new AML Classification systems
WHO 5TH AML classification ICC AML classification (ELN 2022) Main differences
Structure
Two groups Hierarchical diagnosis of AML with recurrent 2 groups definition (WHO) versus
1. AML defined by genetic abnormalities genetic abnormalities =>mutated TP53 hierarchical order (ICC)
2. AML defined by differentiation: requires (VAF > 10%) => AML with myelodysplasia
exclusion of AML with defined genetic related gene mutations => AML with
alterations, MPAL, myeloid neoplasm myelodysplasia-related cytogenetic abnormalities
pCT and history of proven MPN. => AML NOS
Blast threshold (bone marrow or peripheral blood)
AML defined by genetic abnormalities does AML with recurrent genetic abnormalities requires Different blasts thresholds. New
not require any blast threshold (except 10% blasts (except AML with BCR::ABL1 requires definition of MDS/AML in ICC
for AML with BCR::ABL1 and AML with 20%). Other subtypes are defined as MDS/AML criteria.
biallelic/single bZIP mutations in CEPBA (blasts 10%–19%) or AML (blasts ≥20%).
mutation which require 20%). AML
defined by differentiation requires 20%
blasts.
AML-MR versus AML with myelodysplasia related gene mutations/cytogenetic abnormalities (formerly known as AML-MRC)
Cytogenetic: del(5q)/t(5q); 7/del(7q)/(t7q); Cytogenetic: del(5q)/t(5q)/add(5q); 7/del(7q); +8; Modest difference in molecular
del(11q); del(12p)/t(12p); 13/del(13q); del(12p)/t(12p)/add(12p); iso(17q), 17/add and cytogenetic definitions.
del(17p)/t(17p)/iso(17q); idic(X)(q13) or (17p) or del(17p); del(20q); idic(X)(q13) or Significance and interpretation of
Complex karyotype (≥ 3 abnormalities). Complex Karyotype (≥3 abnormalities) prior MDS diagnosis
Molecular: ASXL1, BCOR, EZH2, SF3B1, Molecular: ASXL1, BCOR, EZH2, SF3B1, SRSF2,
SRSF2, STAG2, UAKF2, and ZRSR2. STAG2, U2AF1, ZRSR2, and RUNX1.
Prior history of MDS or MDS/MPN Prior history of MDS or MDS/MPN accounts as a
accounts for AML-MR qualifier and not a separate group
Prior History of MDS or MDS/MPN, prior cytotoxic therapy, germline disposition
New Definition of secondary myeloid Diagnostic qualifiers in addition to AML group Different categorization of clinical
neoplasm (separate from AML defined • Therapy related or pathological characteristics
groups above) • Progression from MDS or MDS/MPN
• Myeloid neoplasms post cytotoxic • Germline predisposition
therapy (pCT).
• Myeloid neoplasms associated with
germline predisposition
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 cytotoxic therapy; WHO, World Health Organization.
also shown to be associated with dismal long-term overall survival, 3.1 | MRD measurement and monitoring
76,77
although AlloSCT may be useful.
• Hyperdiploid karyotypes with multiple trisomies (or polysomies) MRD is a biomarker that can be used for prognostic, predictive, moni-
are no longer considered as complex karyotypes and are toring, and response assessment in AML. Our ability to measure and
excluded from the adverse risk group, as patients with only interpretate MRD has improved dramatically with novel and more
numerical cytogenetic changes and no structural abnormalities accessible technologies. The two most established technologies to
have better survival outcome compared to patients with three evaluate MRD are multiparameter flow cytometry (MFC) and
or more cytogenetic changes with structural abnormalities. 78 real-time quantitative PCR (RT-qPCR) each of which can detect one
malignant cell in 10.4 While the former may be accessible for most
Case continued: patients with AML, the latter requires the knowledge of specific diag-
Our patient would be classified as adverse risk based on the nostic cytogenetic abnormalities or mutations and is validated only in
updated 2022 ELN risk classification because of the BCOR mutation patients with CBF or NPM1 mutations. MRD can also be measured
(whereas based on ELN 2017 classification he would have been clas- (down to a level of about 1/106) via several next generation sequenc-
sified as intermediate risk). ing (NGS) techniques79 with varying degrees of sensitivity and with
How do we define his response to treatment? Can we integrate the digital droplet PCR (ddPCR),80 although these two measurements are
use of MRD as prognostic and/or predictive tool for his management? still considered investigational. The ELN published recommendations
508 SHIMONY ET AL.
TABLE 3 ELN 2022 risk classification negativity versus those who did not.81 MRD measured by RT-qPCR with
Risk Category Genetic abnormality a threshold of 0.1% was found to be an independent prognostic factor
in 346 NPM1 mutated patients82 when measured after two cycles of
Favorable t(8;21)(q22;q22.1)/RUNX1::RUNX1T1a
intensive chemotherapy (MRD positivity HR for death: 4.38; 95% CI,
inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::
MYH11a 2.57–7.47; p < .001). Similarly, MRD was prognostic when performed by
NGS panel with a cut-off ≥0.02 for positivity among 430 intensively
Mutated NPM1 without FLT3-ITDb
treated patients with AML who achieved CR after 2 cycles of chemo-
bZIP in-frame mutated CEBPAc
therapy.83 Patients with persistent MRD positivity, excluding mutations
Intermediate FLT-ITD (irrespective of allelic ratio or NPM1
in DNMT3A, TET2, and ASXL1, which are often present in clonal hemato-
mutation)
poiesis, had higher 4-year relapse rates (55.4% vs. 31.9%; hazard ratio,
t(9;11)(p21.3;q23.3)/MLLT3::KMT2Ad
2.14; p < .001) as well as worse 4-year overall survival (41.9% vs. 66.1%;
Cytogenetic and/or molecular abnormalities not
classified as favorable or adverse hazard ratio for death, 2.06; p < .001). In addition, NGS contributed addi-
tive prognostic value compared to MFC-MRD, with patients who were
Adverse t(6;9)(p23;q34.1)/DEK::NUP214
negative by both had the lowest rate of relapse (73% when both were
t(v;11q23.3)/KMT2A rearranged (excluding
KMT2A-PTD) positive, 50% when either MFC-MRD or NGS-MRD were negative
and 27% when both were negative, p < .001).
t(9;22)(q34.1;q11.2)/BCR::ABL1
While the data are relatively limited, the value of MRD as a prog-
(8;16)(p11;p13)/KAT6A::CREBBP
nostic marker in non-intensively treated patients has also been demon-
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2,
MECOM(EVI1) strated. Among patients who were treated with azacytidine and
venetoclax in the VIALE-A trial, patients who achieved composite com-
t(3q26.2;v)/MECOM(EVI1)-rearranged
plete remission (cCR defined as complete response [CR] or complete
5 or del(5q); 7; 17/abn(17p)
responses with incomplete count recovery [CRi]) and MFC-MRD nega-
Complex karyotype (change in definition)e;
tivity (<0.1%) versus cCR without MRD negativity had longer duration
Monosomal Karyotype
of response (DOR), event free survival (EFS), and overall survival (OS).
Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1,
SRSF2, STAG2, U2AF1, or ZRSR2f The median DOR, EFS, and OS were not reached in patients with MRD
Mutated TP53 (Variant Allele Frequency ≥10%) negativity with 12-month estimates for DOR, EFS, and OS in this group
of 81.2%, 83.2%, and 94.0%. In patients with MRD positivity, the
Note: Changes from ELN 2017 risk classification are bolded.
median DOR, EFS, and OS were 9.7, 10.6, and 18.7 months, corre-
Abbreviation: ELN, European leukemia network.
a
Presence of KIT or FLT3 mutations does not alter risk category. sponding to 12-month DOR, EFS, and OS estimates of 46.6%, 45.4%,
b
AML with NPM1 and adverse risk cytogenetic abnormalities is defined as and 67.9% respectively. MRD negativity by MFC was independently
adverse risk. predictive for OS (HR 0.285; 95% CI 0.159–0.510; p < .001).84
c
Only in-frame mutations affecting the basic leucine zipper (bZIP) region
NGS-MRD was also evaluated as a prognostic marker in the pre-
of CEBPA, irrespective whether they occur as monoallelic or biallelic
mutations, have been associated with favorable outcome. transplant setting. Initial results from the PRE-MEASURE study were pre-
d
The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, sented at ASCO 2022. Blood samples were obtained from the CIBMTR
concurrent adverse-risk gene mutations. biobank; pre-AlloSCT MRD was measured by ultra-deep anchored multi-
e
Complex karyotype ≥ three unrelated chromosome abnormalities in the
plex PCR-based NGS-MRD for FLT3, NPM1, IDH1/2 and KIT with error-
absence of other class-defining recurring genetic abnormalities; excludes
hyperdiploid karyotypes with three or more trisomies (or polysomies)
corrected variant calling. Among 448 patients treated with AML who
without structural abnormalities. achieved CR and proceeded with AlloSCT, pre-AlloSCT negativity was
f
AML with NPM1 and one of these adverse molecular abnormalities do associated with improved OS, RFS and lower relapse rates (p < .0001 for
not alter risk category currently. all). Regarding specific mutations—FLT3-ITD and NPM1 MRD negativity
Source: Modified from Döhner et al. ELN 2022 recommendations,
were also associated with improved OS and RFS (p < .001).85
tab. 6).70
The current ELN MRD guidelines recommend using qPCR for
patients with NPM1 or CBF mutated AML (despite varying sensitivi-
in 2021 based on available evidence concerning the standardization ties, ddPCR or NGS-MRD may be alternatively used). For all others,
of MFC-MRD and RT-qPCR MRD thresholds, MRD response defini- MFC-MRD, ideally established at diagnosis to define the patient-
tion, and use of MRD in clinical decision making.74 While a highly specific leukemia associated immunophenotype (LAIP), may be used
commendable effort, their conclusions, particularly those surrounding (with error-corrected NGS-MRD used adjunctively in some cases).
therapeutic choice based on MRD findings, remain controversial. Measurement at diagnosis should ideally be from bone marrow aspi-
The prognostic value of MRD is well-established, both in patients rate but can be done from peripheral blood in patients with NPM1 or
treated with intensive chemotherapy, as well as in patients treated with CBF mutated AML with ≥20% peripheral blasts. The first post-
lower intensity therapies. In a systematic review and meta-analysis of treatment MRD should be measured in the marrow after two cycles
MRD as prognostic tool in AML among 11,151 patients, the average OS of therapy (those with NPM1 and CBF mutant AML may have periph-
HR for achieving MRD negativity was 0.36 (95% [CI], 0.33–0.39) and eral blood assessment). An end-of-treatment MRD measurement from
the 5 year OS was 68% versus 34% among patients who achieved MRD marrow aspirate is also recommended. To assess for recurrence
SHIMONY ET AL. 509
before morphological relapse in NPM1 or CBF mutant AML, assess- when the end of treatment NPM1 or CBF AML qPCR is less than 2%,
ments via blood every 4–6 weeks or bone marrow every 3 months only values above that level are considered positive.74,88,90,91 The incor-
are recommended. The MFC-MRD monitoring frequency should be poration of MRD as an endpoint also created new definitions for time
similar, but data supporting such intervals are lacking leading the panel to event outcomes other than OS, such as event free survival (EFS),
to define this as an exploratory recommendation. relapse free survival (RFS), or cumulative incidence of relapse (CIR).
Even though a relapse by flow without a clinical relapse carries Those are now designated with lowercase MRD and reflect MRD posi-
86
the same adverse prognosis as a morphological relapse, there are no tivity as an event. For proper interpretation of a given study, the MRD
clear-cut data supporting the clinical value (e.g., mortality reduction) technique and sensitivity should be provided.
of intensive screening with any technique. We have not routinely Case continues:
adopted such a strategy. Finally, the sensitivity of any technique is Our patient is considered as intensive induction chemotherapy
critical. In patients without a useful molecular genetic diagnostic candidate based on fitness.
mutation, we routinely employ flow cytometry, using “different from What is the best initial therapy for this patient?
normal” MRD technology, which generally uses a 0.02% cut-off.87 For
detection of NPM1 mutations or CBF translocations, we use PCR
measurement, as previously mentioned.82,88 4 | UP D A TE S I N T RE A T M E NT S A N D
Moreover, the use of MRD as a predictive tool which could aid in C O M B I N A T I ON TH E R A P I E S
therapeutic decisions is even less established, with one prospective trial
demonstrating the predictive value of MRD measurement in patients 4.1 | General considerations.
with RUNX1::RUNX1T1 AML for decision on AlloSCT after the second
consolidation (see “updates in post remission therapy”).89 In addition, A patient may be deemed “fit” for intensive chemotherapy based on
MRD negativity is not a sine qua non for cure, as relapse can occur in young age and no major co-morbidities. It is perhaps easier to delin-
up to 30% of patients with MRD negativity82,83 and not all patients eate who should not receive intensive chemotherapy than who should
with MRD positive disease will relapse, especially those with low level definitively be subject to a long hospitalization with a significant risk
PCR-MRD in patients with NPM1 or CBF mutations.90,91 Thus, in our of treatment-related mortality. At this time, age over 75 is thought to
clinical practice, we use MRD as adjunct data among many others and be a relative contraindication to intensive chemotherapy, especially
not as a sole parameter to base our decisions. based on the known availability of effective less intensive chemother-
apy. Secondly, the FDA has agreed on a set of fairly stringent criteria
(poor hepatic, renal, cardiac, pulmonary function) that make a patient
3.2 | Response and outcomes evaluation unfit for intensive chemotherapy. The criteria, suggested by Ferrara
et al,93 are commonly incorporated into eligibility criteria and were
The main change in response definition in ELN 2022 was the integra- validated in a large cohort of patients for predicting shorter term mor-
tion of MRD status. The criteria for CR, CRi, partial response (PR), and tality after intensive chemotherapy treatment in AML.94 However,
marrow leukemia free state (MLFS) have not changed from the ELN even a “fit” patient (of any age) might not be “appropriate” for inten-
2017. A new definition was added: CR with partial hematological sive chemotherapy, such as those with adverse risk biology, if the
recovery (CRh) which includes bone marrow blasts <5%, absence of overall outcomes, even with somewhat high initial response rates, are
peripheral blasts, or extramedullary disease and partial count recovery expected be so low that a less intensive approach is likely to be at
with ANC ≥500/μL and platelets ≥50 000/μL. CRh was used as post least no worse. The relatively high CR rates in adverse risk patients
hoc analysis required by the FDA for enasidenib approval10 and after- may be due in part to a reduction in treatment-related morality (TRM)
wards used in other clinical trials, but the exact role of CRh in predict- with intensive induction chemotherapy over time.95
92
ing survival is yet to be defined. In addition, due to integration of The general approach to cure in AML is to achieve CR to reduce
MRD to disease response evaluation, if MRD negative response was the leukemia burden by several orders of magnitude and then admin-
achieved, all CR subtypes (i.e., CR, Cri, and CRh) can be marked with ister post remission therapy, which could be chemotherapy and/or
MRD evaluation as well, (i.e., CRMRD-, CRiMRD-, and CRhMRD-). alloSCT. The choice of the most appropriate induction and post-
The definition of relapse remains bone marrow leukemia blasts remission therapy is based on multiple parameters, including patient
≥5%, any reappearance of peripheral leukemic blasts in two samples comorbidities, past medical history including prior myeloid disease
1 week apart or new extra-medullary disease. A new definition of MRD and/or cytotoxic chemotherapy exposure, AML cytogenetic and
failure or relapse is based on one of the following, if repeated within molecular risk profile, possibly post-therapy MRD status, as well as
4 weeks to validate the results in a second consecutive sample from the donor availability and patients' goals of care.71
same tissue source, preferably bone marrow: conversion from MRD
negativity to positivity by any method or copy number increase by
quantitative PCR by a factor of 10. The cut-off for MFC-MRD negativ- 4.2 | Update on Induction therapy
ity is <0.1% for CD45-expressing cells using either LAIP or different-
from-normal immunophenotype. MRD negativity by qPCR is defined as The backbone of intensive chemotherapy is anthracycline and cytara-
cycling threshold (Ct) ≥40 in ≥2 of 3 replicates. Due to low relapse risk bine based therapy,96,97 most commonly as “7 + 3” regimen using
510 SHIMONY ET AL.
F I G U R E 2 Treatment Algorithm for Newly diagnosed patients with AML fit for intensive therapy. White - FDA approved treatments; yellow -
investigational therapies. AlloSCT, allogeneic stem cell transplantation; AML, acute myeloid leukemia; AML-MRD, acute myeloid leukemia with
myelodysplasia related changes (ELN 2017 definition); CBF, core binding factor; CK, complex karyotype; ELN, European Leukemia Network;
FLT3i, FLT3 inhibitors; GO, gemtuzumab ozogamycin; HMA, hypomethylating agents; MRD, measurable residual disease; ND, newly diagnosed;
tAML, therapy related AML; Ven, venetoclax.
daunorubicin at a dose of 60–90 mg/m2 for 3 days and cytarabine at with AML when GO was added to 7 + 3 or FLAG-IDA versus no GO
a dose of 100–200 mg/m2 for 7 days.98–101 However, other induction addition.25 The benefit was confined to patients with favorable and
regimens are in use including CLAG-M,102 G-CLAM,103 IA,104 intermediate cytogenetics (6 years OS of 76 vs. 55% [OR 0.47, CI
FLAG-IDA,105 and lomustine-IA.106 Whether any of these are “better” 95% 0.31–0.74] and 39 versus 34% [OR 0.84, CI 95% 0.75–0.95]
than 3 + 7 alone is unclear, though the addition of either lomus- respectively). It should be noted, however, that OS of patients with
tine,106 a nucleoside analog107 or treatment with FLAG-IDA108 have CBF-AML not receiving GO in the meta-analysis was particularly low
each been suggested to be superior to 3 + 7 in prospective random- with a 5-year OS survival of 55%. An OS advantage with GO addition
ized trials; the latter was deemed too toxic for general use.109 More- was not seen in any of the individual trials included in the meta-analy-
over, several drugs were recently approved for patients with newly sis. These issues, plus the marrow and hepatoxicity of GO, have
diagnosed AML who are fit for intensive chemotherapy (Table 1 and caused many to question the routine addition of GO to induction
Figure 2). Regarding the dose of daunorubicin, in two large- therapy. In the ALFA0701 trial, which was included in the meta-analy-
randomized trials, 90 versus 45 mg/m2 improved survival among sis, the administration of fractionated dose of 3 mg/m2 on days 1, 4,
99 100
younger and older patients, as well as in patients with specific and 7 was associated with equal benefit and less toxicity13 compared
mutations (NPM1, FLT3, and DNMT3A).98 However, there was no ben- with other more compressed dosing schedules. A post hoc analysis of
2
efit in term of survival among 1206 patients with AML when 90 mg/m the ALFA0701 trial demonstrated a benefit for the addition of GO in
was compared to 60 mg/m2 (although all patients received a second favorable and intermediate risk groups per ELN 2017 risk criteria.110
2
course of daunorubicin 50 mg/m , which could potentially reduce the Additional positive trials included in the meta-analysis (AML-MRC15
beneficial effects of 90 mg/m2 vs. 60 mg/m2).101 and NCRI-AML16) employed a single 3 mg/m2 GO dose on the first
day of induction111,112 and in each subsequent cycle. The AMLSG
09-09 trial was a phase III randomized study not included in the meta-
4.2.1 | Gemtuzumab ozogamycin analysis, which evaluated the addition of GO to idarubicin, cytarabine,
etoposide, and all-trans-retinoic acid in patients with NPM1 positive-
Gemtuzumab ozogamicin (GO) is a CD33 monoclonal antibody conju- AML.113 EFS was not statistically different between the GO arm and
gated to calicheamicin. In an individual patient meta-analysis of ran- the standard arm (HR 0.83, CI 95% 0.65–1.04, p = .1), with higher
domized control trials, improved survival was seen among patients rates of early deaths in the GO arm (10.3% vs. 5.7%, p = .05 and 20%
SHIMONY ET AL. 511
in patients age ≥70 years) due to a higher rate of infections. Subgroup to receive either CPX351 or 7 + 3.7 Patients either had t-AML, prior
analysis revealed a significant EFS improvement in the GO arm in MDS/CMML or AML-MRC. Both CR rates and the median OS were
females, patients younger ≤70 years, and non-FLT3 internal tandem higher among patients treated with CPX351 versus 7 + 3 37% versus
duplication (ITD) patients. The impact of GO addition was also benefi- 26% (p = .02) and 9.3 months versus 6 months; HR for death 0.7,
cial in achieving an MRD negative state defined as a 3-log reduction 95% CI 0.6–0.9 respectively. The median times to platelet (≥50 000/
measured by quantitative RT-PCR (56% vs. 41%, p = .01) which trans- μL) and absolute neutrophil counts (≥500/μL) recovery were longer
lated into lower relapse rates in the GO arm versus standard therapy with CPX351 versus 7 + 3 (35 vs. 29 and 36.5 days vs. 29 days,
(4-year cumulative incidence relapse rates 29.3% vs. 45.7% respec- respectively), with similar infection rates (93%) in each arm but higher
tively. p = .009).13 Overall, it seems that the addition of GO to stan- rates of bleeding were seen in the CPX-351 arm (all cause—74.5%
dard AML therapy is beneficial mainly in patients with favorable and vs. 59.6%; grade 3–5 11.8% vs. 8.6%). Early mortality in the CPX351
possibly intermediate risk ND-AML. As the absolute value of the ben- group versus 7 + 3 was numerically lower, both at 30-days (5.9%
efit of adding GO to induction chemo in intermediate risk patients is vs. 10.6% p = .15) and 60-days (13.7% vs. 21.2% p = .097). Longer
small and many of these patients receive SCT in CR1 (and would be follow-up demonstrated that the survival benefit was maintained
subject to a higher risk of sinusoidal obstruction syndrome (SOS) due (median OS 9.3 vs. 6 months, HR 0.7, CI 95% 0.55–0.91), especially
114
to prior GO exposure ) many US clinicians reserve the use of GO in among patients who received a transplant but had been previously
induction for those with favorable risk cytogenetics. treated with CPX 351 (52% vs. 23%, HR 0.51, CI 95% 0.3–
0.9),119,120 perhaps suggesting (though it was not measured) that
CPX-351 lead to remission at lower MRD levels than 3 + 7. Real
4.2.2 | FLT3 inhibitors world evidence also demonstrated the efficacy of CPX351 among
188 patients with 24.5% under the age of 60.121 While the FDA
Midostaurin, a type I (active in patients with FLT3-ITD and FLT3-TKD approved CPX-31 for patients of any age with AML-MRC, the ran-
mutations) first generation FLT3 inhibitor, was approved for patients domized trial was limited to patients aged 60–75 years, a group
6
with FLT3 mutations, based on the results from the RATIFY trial that expected to be enriched for AML with adverse biology, which could
demonstrated improved survival among patients aged 18–59 with potentially benefit from less intensive therapy. A recent retrospective
FLT3 mutated AML treated with 7 + 3 + midostaurin versus 7 + 3 comparison compared outcomes of 217 patients who received
alone. The FDA approved the combination of 7 + 3 + midostaurin for CPX351 versus 437 patients who received HMA + Venetoclax.122
all patients with FLT3 mutated AML deemed eligible for intensive che- The OS rates were comparable between groups (13 months for CPX-
motherapy based in part on data supporting improved outcomes ver- 351 vs. 11 months for HMA + venetoclax; HR, 0.88; 95% confidence
sus historical cohorts in patients aged 60–70 (median OS 22.7 interval, 0.71–1.08; p = .22), even after adjusting for different base-
vs. 8.4 months, HR for death 0.47, 95% CI 0.33–0.67, p < .01).115,116 line characteristics and with a sensitivity analysis including only
In addition, in a post-hoc analysis of the RATIFY trial, improved sur- patients who were eligible for the CPX351 randomized trial. In con-
vival with midostaurin was seen across all ELN 2017 risk groups incor- trast, the rates of infection (51% vs. 20%, p < .0001), febrile neutrope-
porating FLT3-ITD allelic ratio and NPM1 mutational status.72 nia (90% vs. 54%, p < .0001), and length of hospitalization (41 vs.
Resistance was associated with either loss of FLT3-ITD with acquisi- 15 days, p = .0004) were higher among patients treated with CPX351
tion of mutations in signaling pathways, persistence of FLT-ITD clones, versus HMA + venetoclax, which questions the exact role of CPX351
or other mechanisms.117 Several more potent FLT3 inhibitors are in this population. Moreover, with the recent WHO and ICC defini-
being evaluated in the upfront setting. Results from the phase III tions of myelodysplastic neoplasms and AML-MR, the validity of CPX-
QUANTUM FIRST trial were first presented at the EHA 2022 con- 351 in patients who are deemed fit in the AML-MR category but
gress. The QUANTUM FIRST trial demonstrated improved OS among would not have been eligible for the CPX versus “3 + 7” trial is not
patients up to 75 years of age with ND FLT3-ITD (as the drug is not clear. There may be subgroups for whom venetoclax plus HMA or
active in those with FLT3-TKD mutations) mutated AML treated with 7 CPX-351 is better. Although prospective randomized trials are not yet
+ 3 + quizartinib versus 7 + 3 (median 32 vs. 15 months, HR 0.78, available, as patients with monocytic subtypes of AML fare relatively
95% CI 0.62–0.98, p = .03). 118
There was a slightly higher rate of fatal poorly with azacitidine + venetoclax,123 they may be best served by
events in the quizartinib arm (11.3 vs. 9.7%). In addition, ongoing trials CPX-351. Conversely, chemo-unresponsive subtypes of AML, such as
are also evaluating the 7 + 3 + midostaurin versus 7 + 3 with the those with TP53 mutations should receive aza/ven or protocol
more potent FLT3 inhibitors gilteritinib (HOVON 156—NCT04027309, therapy,124 although among patients with adverse-risk of cytogenetics
PreECOG—NCT03836209) or crenolanib (NCT03258931). and mutated TP53, the addition of venetoclax to azacitidine improved
responses but not overall survival.125
4.2.3 | CPX351
4.2.4 | Venetoclax combination therapies
CPX351, a liposomal formulation of daunorubicin and cytarabine, was
approved in 2017 for t-AML or AML-MRC. Approval was based on Venetoclax, a BH3 mimetic that selectively inhibits the pro-apoptotic
the phase 3 trial in which 309 patients aged 60–75 were randomized BCL2 protein and induces apoptosis in acute myeloid leukemia
512 SHIMONY ET AL.
cells,126 was approved in combination with HMA or LDAC for patients 4.3 | Updates in post remission therapy
not fit for induction with intensive chemotherapy for newly diagnosed
(ND) AML patients age ≥ 75 or in those who are ineligible for inten- After remission is achieved, post-induction therapy is necessary for a
sive chemotherapy.11,17 However, several phase I-II trials are evaluat- reasonable chance for a favorable long-term outcome and possibly
ing the efficacy and safety of venetoclax with fludarabine, cytarabine, cure. Generally, patients with ELN favorable risk score should receive
idarubicin, and G-CSF (FLAG-IDA) or daunorubicin plus cytarabine in 3–4 cycles of high dose chemotherapy, whereas patients within the
the upfront setting. Among 45 patients with ND-AML, FLAG-IDA intermediate or adverse risk are recommended to proceed with
with venetoclax yielded in composite CR rates of 89%, with 93% of AlloSCT.41 This is mainly based on the risk of death from relapse or
CR patients achieving MRD negativity with an estimated 2-year OS of refractory disease (high in those with non-favorable subtypes) possi-
76%.29 The CAVEAT trial demonstrated CR/CRi rates of 72% in bly overcoming the risk of TRM associated with alloSCT. Although
51 patients older than 60 with a 7-day venetoclax pre-phase followed most patients with CBF-AML usually do not proceed with AlloSCT
by 5 + 2 and venetoclax for additional 7 days. The CR/CRi rates were while in CR, as mentioned earlier the benefit of AlloSCT was demon-
very high (97%) among patients with de-novo AML versus 43% in strated in a prospective trial evaluating the predictive value of MRD
patients with Secondary AML.127 Among 33 patients aged 18–60 positivity in patients with RUNX1::RUNX1T1 AML after the second
with ND-AML, venetoclax combination with 7 + 3 yielded in compos- consolidation. Patients who had positive MRD (defined by qPCR with
ite CR rates of 91% with 97% MRD negativity, and 1 year estimated less than 3-log reduction) were offered to proceed with AlloSCT and
OS of 97%31 . In an additional phase I trial evaluating 7 + 3 with had lower relapse rates, improved disease free survival, and OS when
venetoclax, all 11 evaluated patients achieved CR, most (78%) with treated with AlloSCT versus continuation of chemotherapy.89
32
MRD negative CR. Venetoclax combined with cladribine, idarubicin, While most agree that adverse risk AML patients have the best
and cytarabine in 50 patients with ND AML resulted in 94% compos- chance for long-term survival if an allogeneic is done during CR1, an
ite complete response, 85% at the level of MRD negativity with a analysis based on MRC trials in the UK suggests that the optimal strat-
1 year OS rate of 85%.34 While these early results are encouraging, egy in intermediate risk patients is to transplant only in CR2, thereby
these regimens are highly myelosuppressive with risk for prolonged saving many (especially those with MRD negativity and a relatively
cytopenia and infections. Thus, until we have a longer follow-up and low chance of relapse) from unnecessary SCT-associated morbidity
matched control trials, intensive chemotherapy with venetoclax in the and mortality.130 On the contrary, a large meta-analysis of prospective
upfront setting should be evaluated only in the contest of clinical clinical trials evaluating AlloSCT at CR1 versus non-AlloSCT treat-
trials. ments demonstrated OS advantage both in intermediate risk
(HR 0.83, 95% CI 0.74–0.93) as well as in adverse risk (HR 0.73,
0.59–0.90) groups.131 Our approach is to transplant all adverse and
4.2.5 | IDH inhibitors intermediate patients at CR1 who have an available donor and no
contraindication. With the ability to safely conduct haploidentical
Isocitrate dehydrogenase (IDH) mutations occur in 15%–20% of AlloSCT, almost all patients have a donor.132
2,128
patients in AML. IDH mutations result in the formation of a Post-transplant maintenance therapy may contribute to pro-
neomorphic reaction product R-2-hydroxyglutarate, an oncometa- longed survival. In a meta-analysis of five randomized controlled trials,
bolite which leads to epigenetic alterations and impaired hemato- maintenance therapy versus no therapy post alloSCT was associated
poietic differentiation similar to those observed when TET2 is with improved OS.133 Of note, only the use of sorafenib, a first-
129
mutated. The IDH1 and IDH2 inhibitors ivosidenib and enaside- generation type II TKI (active in patients with FLT3-ITD mutations) was
nib were approved as monotherapy for patients with R/R IDH associated with improved OS in the maintenance trials included in the
mutated AML; ivosidenib was approved in the frontline setting for analysis.134–138 Additional post-alloSCT maintenance therapies, such as
unfit patients, either as monotherapy or combined with azacitidine HMA plus venetoclax (“VIALE-T"; NCT04161885) or the second gener-
(see “non-intensive therapy for newly diagnosed patients”). Both ation TKI Gilteritinib in FLT3 mutant patients (NCT 02997202) are now
IDH inhibitors were evaluated in a phase 1 trial in combination with being evaluated in the setting of phase III clinical trials.
7 + 3 in 151 “fit” patients with IDH mutated AML. The CR/CRi/ For patients with intermediate or adverse risk AML by cytogenet-
CRp rates were 77% with addition of ivosidenib and 74% with ena- ics, who cannot proceed with alloSCT, maintenance therapy with
sidenib.22 39% and 23% of patients achieved mIDH1/2clearance by CC-486 (“oral azacitidine”) can be administered. CC-486 is an oral
ddPCR respectively. Overall, the combination was tolerable with hypomethylating agent that was FDA approved as post-induction
low rates of differentiation syndrome or significant QT prolonga- therapy, based on the results of the phase 3 QUAZAR AML-001
tion. Prior to the routine adoption of IDH inhibitors plus intensive trial.14 The trial enrolled patients aged 55–86 with newly diagnosed
chemotherapy in the upfront setting, we await the results from AML who received intensive chemotherapy, achieved complete remis-
HOVON 150, a phase 3 trial evaluating the benefit of adding IDH sion and were not candidates for alloSCT. Patients received either
inhibitor to 7 + 3 in fit patients with ND IDH mutated AML CC-486 for 14 days in 28-day cycles (n = 238) or placebo (n = 234).
(NCT03839771). The median OS and RFS were better in the CC4-486 versus placebo
SHIMONY ET AL. 513
F I G U R E 3 Treatment Algorithm for Newly diagnosed patients with AML unfit for intensive therapy. White - FDA approved treatments;
yellow - investigational therapies. AlloSCT, allogeneic stem cell transplantation; AML, acute myeloid leukemia; ELN, European Leukemia Network;
FLT3i, FLT3 inhibitors; HMA, hypomethylating agents; IDH, isocitrate dehydrogenase; IDHi, IDH inhibitor; MRD, measurable residual disease;
ND, newly diagnosed; Ven, venetoclax.
group (24.7 vs. 13.8 months, and 10.2 vs. 4.8 months, respectively which revolutionized the treatment paradigm in AML in patients who
p < .001 for both). There were higher rates of side effects, such as are not fit for intensive chemotherapy induction (Table 1 and
gastrointestinal (50–65% vs. 10%–24%), neutropenia (44% vs. 26%), Figure 3) and promoted prolonged survival.
and infections (17% vs. 8%) in the CC-486 arm. Adverse events led to
drug interruption in 43% of patients. Ad hoc analysis demonstrated
improved OS and RFS irrespective of MRD status at first remission, 4.4.1 | Venetoclax combination therapies
with conversion rates to MRD negativity in 25% of patients receiving
CC-486.139 However, alloSCT is more accessible in recent years due As mentioned previously, venetoclax combinations with hypomethy-
to use of more tolerated reduced intensity conditioning140 as well as lating agents (HMA) or low dose cytarabine (LDAC) were found to be
larger pool of donors due to improved outcomes with haploidentical very effective and approved for older patients with AML. In the phase
alloSCT.141,142 Moreover, the use of alloSCT is more common in older III VIALE-A trial, azacitidine added to venetoclax improved responses
143 144
patients and associated with less morbidity and TRM. Thus, the and overall survival (OS) versus azacitidine alone in patients >75 years
use of CC-486 may be limited to those few patients who are deemed old or those with significant comorbidities (composite CR 66.4%
fit for intensive therapy but not for transplant. vs. 28.3%, p < .001; median OS 14.7 vs. 9.7 months, HR 0.66, 95% CI
0.52–0.85, p < .001).28 In the VIALE-C trial, venetoclax was added to
LDAC versus LDAC monotherapy. The trial failed to achieve the pri-
4.4 | Non-intensive therapy for newly diagnosed mary OS endpoint (median OS 7.2. vs 4.1 months, HR 0.75 95% CI
patients 0.52–1.07 p = .11).18 This was partially due to diminished power
(fewer patients were enrolled compared to VIALE-A [431 vs. 211]), as
Just a few years ago, our ability to treat older patients who are not fit well as inclusion of patients who received HMA as prior therapy in
for intensive therapy was limited to mainly supportive care and was the VIALE-C trial. However, in a post hoc analysis with 6 months addi-
associated with a dismal prognosis. While decitabine or azacytidine tional follow-up, an OS advantage was seen (8.4 vs. 4.1 months, HR
were commonly used in older patients, it was never clear whether 0.7, 95% CI 0.5–0.98, p = .04). These regimens are now considered
145,146
these single agents were better than other available therapies. standard of care for older patients or patients who are not deemed fit
Several drugs and combination therapies, especially the addition of for intensive chemotherapy, although a subgroup analysis in patients
venetoclax to low dose chemo, were recently approved for this group, younger than age 75 who were eligible for the trial based on
514 SHIMONY ET AL.
significant comorbidity did not show a benefit for the doublet over AML. The question of whether to use azacitidine with either veneto-
azacitidine. As noted earlier, the role of HMA/venetoclax relative to clax or ivosidenib remains open, especially when considering that
intensive induction in younger patients without co-morbidities most patients would relapse and ivosidenib can also serve as a sal-
remains unclear. The ability to achieve high rates of short-term CR vage therapy in these patients. However, since ivosidenib plus vene-
and MRD negative responses at acceptable toxicity with HMA and toclax was less toxic hematologically than HMA/venetoclax based
venetoclax may allow AlloSCT to be performed in patients eligible for on a rapid neutrophil recovery time, some suggest that the former
that procedure and potentially could lead to even better long-term therapy might be more appropriate for a relatively more frail patient.
outcomes.147,148 The response to venetoclax and HMA combination Although not approved for patients with IDH2 mutated ND-AML,
is heterogeneous, with decreased response rates in several morpho- combination therapy of the IDH2 inhibitor enasidenib with azacitidine
logic, cytogenetic, and molecular subgroups.28,123,149 For example, the was recently evaluated in the phase II AG221-AML-005 randomized
duration of response varies greatly, being only a few months in trial.20 101 patients were assigned in 2:1 ratio to azacitidine with
high-risk TP53 mutated AML and in those with monocytic differentia- (n = 68) or without (n = 33) enasidenib. The median age was 75 and
tion.123,149,150 Venetoclax may also be synergistic with other thera- the CR rates were 54% versus 12% (p < .0001) in azacitidine + enasi-
pies, such as other low dose chemotherapy, targeted therapy, and denib versus azacitidine alone. Twelve (18%) patients in the enaside-
151
immunotherapy. For example, Kadia et al reported on the results of nib group experienced differentiation syndrome and were treated
venetoclax combined with low dose chemotherapy (LDAC combined with corticosteroids. The median overall survival was similar between
with cladribine, alternating with azacitidine) in older patients (age groups (22 months), which may partially be attributed to the favorable
≥60 years) or those deemed unfit for intensive chemotherapy.33 The outcomes in patients with IDH2 mutation irrespective of treatment
composite CR rates was 93%, with 84% of remitting patients achiev- strategy, as these patients also experience prolonged survival with
ing MRD negativity. With a median follow-up time of 22 months, the other therapies which could be given a salvage, such as azacitidine +
median OS and disease-free survival were not reached, with an esti- venetoclax.149
mated 24-month OS of 63.5% (95% CI 52%–78%). It should be noted,
however, that patients aged 60 or older, even if they were eligible for
intensive chemotherapy were included, which may have accounted in 4.4.3 | Glasdegib
part for the impressive results.
The hedgehog pathway, a critical embryonic signaling pathway, is over-
expressed in myeloid leukemia cells.153 Based on this observation, the
4.4.2 | IDH inhibitors hedgehog pathway inhibitor glasdegib was evaluated in combination
with LDAC compared to LDAC alone, in patients with ND AML
As previously mentioned, The IDH1 inhibitor ivosidenib was FDA deemed not fit for intensive chemotherapy, based on age ≥75 or having
approved as oral monotherapy in patients with IDH1 mutated AML, significant comorbidities (BRIGHT AML 1003 study).16 Glasdegib was
9
both in ND patients not eligible for intensive therapy, as well as in given orally 100 mg/day in 28 days cycles and LDAC was administrated
the R/R setting.8 The phase III AGILE trial evaluated the addition of subcutaneously for 10 days at the start of each cycle. The complete
ivosidenib to azacitidine versus azacitidine in patients with ND remission rates and median OS were 17% versus 2.3% (p < .05) and 8.8
IDH1-mutated AML older than 75 or with comorbidities. 15
Patients versus 4.9 months (HR 0.51, 80% CI 0.39–0.67, p = .0004) in the glas-
were randomly assigned to azacitidine for 7 days in 28-day cycles degib + LDAC versus LDAC alone respectively. This trial led to the
(n = 74) versus azacitidine and ivosidenib 500 mg once daily FDA approval of LDAC + Glasdegib in ND patients unfit for intensive
(n = 74). The primary efficacy endpoint, EFS, was superior in chemotherapy. A post hoc analysis demonstrated a survival benefit irre-
patients randomized to ivosidenib plus azacitidine compared with spective of response status.112 Although no direct comparison was per-
azacitidine alone (HR 0.16, CI 95% 0.16–0.69). The median overall formed, due to the similarity of the populations evaluated in the
survival was higher in patients who received ivosidenib (24 months VIALE-A and VIALE-C trials and with better results shown with veneto-
vs. 7.9 months, HR 0.44, 95% CI 0.27–0.73). Based on these results, clax combination, glasdegib is not widely used in patients with ND
the FDA approved this combination for patients with ND IDH1 AML deemed unfit for intensive chemotherapy. The efficacy of glasde-
mutated AML aged 75 and above or with comorbidities. The major gib with LDAC in the R/R setting was evaluated in a small retrospective
limitation is the lack of comparison with the current standard of care study that demonstrated composite CR (CR + CRp) rates of 21% with
therapy for IDH1 mutant AML in older adults, namely HMA with a median OS of 3.9 months.154 Thus, the role of glasdegib in the treat-
venetoclax, who fare quite well with the “older” combination ther- ment algorithm for newly diagnosed older adult setting is not yet deter-
apy. In a combined analysis of data from the VIALE-A28 and the mined, as other alternatives seem more appealing.
phase Ib trial of HMA+ VEN,11 patients with IDH1 mutated AML
benefit from addition of venetoclax to azacitidine versus azacitidine
alone (median OS 15.2 vs. 2.2. HR 0.19 95% CI 0.08–0.44).152 4.4.4 | Gilteritinib
Nonetheless, the number of patients in this analysis with IDH1
mutations was low (33 in the VIALE-A and 11 in the phase-Ib trial) Gilteritinib is a type 1 second-generation inhibitor, more potent and
and the favorable prognosis was largely driven by IDH2-mutated specific than midostaurin.155,156 Gilteritinib is approved for patients
SHIMONY ET AL. 515
F I G U R E 4 Treatment algorithm for patients with relapsed or refractory AML. White - FDA approved treatments; yellow - investigational
therapies. AlloSCT, allogeneic stem cell transplantation; AML, acute myeloid leukemia; CK, complex karyotype; DLI, donor lymphocyte infusion;
FLT3i, FLT3 inhibitors; GO, gemtuzumab ozogamycin; HMA, hypomethylating agents; IDH isocitrate dehydrogenase; MRD, measurable residual
disease; R/R, relapse or refractory; Ven, venetoclax.
with R/R FLT3 mutated AML12 (see R/R AML). Gilteritinib was also cytometry (1% myeloblasts). While awaiting SCT, he experienced a
evaluated in combination with other therapies in the upfront setting. clinical relapse, proven by marrow exam, after peripheral blasts were
In the phase III randomized LACEWING trial, patients with ND FLT3 detected. Molecular panel at relapse demonstrated acquisition of a
mutated AML deemed not eligible for intensive chemotherapy were TP53 mutation (VAF of 20%) that was not demonstrated at
randomized to azacitidine (n = 49) versus azacitidine with gilteritinib diagnosis.
(n = 74).157 The median OS was similar between groups (9.8 months What therapies are available or in development for relapsed AML?
vs. 8.9 months, HR 0.92, 95% CI 0.529–1.585, p = .75) although
higher composite CR rates were seen with azacitidine + gilteritinib
versus azacitidine (58% vs. 26.5%, p < .001). Adverse event rates were 4.5 | Relapsed and refractory (R/R) AML
similar between groups. Of note, almost half (44%) of patients in the
AZA arm were treated subsequently with a FLT3 inhibitor versus 20% Relapsed or refractory AML remains a therapeutic challenge, with
in the gilteritinib plus azacitidine arm, which might have contributed 5-year survival being only 10%.158,159 Several factors including age,
to the perceived lack of success of this combination in FLT3 mutant duration from first complete remission (CR1), initial cytogenetics and
AML in ND older adults. At present, such patients should receive previous alloSCT are prognostic factors in the relapsed setting.160 The
venetoclax plus azacitidine, although so-called triplet combinations general paradigm in R/R AML, at least in patients who are willing to
(FLT3inhibtor/HMA/Venetoclax) are under investigation. For exam- accept more therapy for a relatively small chance of good long-term
ple, in a phase II trial evaluating the triplet therapy of venetoclax, deci- outcomes, is attempt to achieve a second remission161,162 and to con-
tabine, and FLT3 inhibitors (sorafenib, gilteritinib, or midostaurin) in solidate with alloSCT in CR2,163 although an abstract presented at the
ND unfit patients as well as R/R patients, CR rates were 75% and plenary session of the American Society of Hematology meeting in
35
2-year OS was 80% among ND patients. As the data is immature 2022 suggested that allogeneic stem cell transplantation at the time
and from a single-arm studies, triplet combination therapies should be of relapse without salvage chemotherapy may be a superior strat-
used with caution, and preferably within the context of clinical trial. egy.164 In patients who received an alloSCT in CR1, the options also
Case continued: include manipulation of the immune system in order to stimulate graft
The patient received 3 + 7 induction therapy and achieved a versus leukemia effect via tapering graft versus host disease
complete remission. After a single cycle of modified high dose cytar- prophylaxis,165 administering donor T-cells Infusion (DLI),166 addition
abine, his marrow was MRD positive by multiparameter flow of immune checkpoint inhibitors167 or a second alloSCT.168 Several
TABLE 4 Selected investigational drugs for acute myeloid leukemia.
516
Early efficacy
Target Drug Regimens Population outcomes Ongoing trials
183
Menin SNDX-5613 (revumenib) Monotherapy R/R MLL rearranged 44% composite CR Phase I-II AUGMENT-101, NCT04065399
184 or mutated NPM1
KO-539 (ziftomenib) Monotherapy 25% CR rates Phase I-II KOMET-001, NCT04067336
AML
CD 47 Magrolimab Magrolimab + HMA185,186 ND-AML (enriched ORR 69%, 50% Phase III, TP53 mutated AML ENHANCE-2, NCT04778397
for TP53 and high CR/CRi
risk)
TP53 mutated AML ORR 49%, CR 33%,
median OS
10.8 months
Magrolimab + HMA + ven.187 ND + R/R AML CR/CRi 94% in ND Phase III, ND-AML ENHANCE-3, NCT05079230
CR/CRi 63% in ven
naïve; 27% in ven
failure
TIM-3 Sabatolimab (MBG453) Sabatolimab+ HMA188 ND-AML unfit for ORR 40%. ORR 54% Phase Ib, NCT03066648
intensive in RUNX1/ASXL1/
chemotherapy TP53 mutated AML
Sabatolimab+ HMA + ven189 ND-AML unfit for CR/CRi 67% Phase II, NCT04150029
intensive
chemotherapy
E-selectin Uproleselan190 “7 + 3” + Uproleselan ND-AML ≥60 years CR/CRi—72% Phase III ongoing, NCT03701308
fit for intensive
therapy
MEC + uproleselan R/R AML fit for 41% composite CR Phase III ongoing, NCT03616470
intensive therapy median OS
8.8 months
CD123 Tagrasofusp191 Tagrasofusp + HMA ND-AML not fit for ND-AML—20% Phase I, NCT03113643
intensive therapy, CR/CRi
Tagrasofusp HMA + Ven BPDCN, R/R-AML ND-AML—89%
CR/CRi.
IMGN632 IMGN632 +/ HMA +/ ven192 R/R AML IMGN632 + HMA Phase Ib/II in both ND and R/R AML, NCT04086264
+ Ven 55% ORR,
composite CR 31%
Flotetuzumab (DART CD123/CD3) monotherapy193 Refractory or early CR/CRh/CRi—30%. 2nd generation MGD024 Phase I in R/R AML, NCT05362773
relapse (<6 mo)
AML
Abbreviations: 7 + 3, cytarabine plus daunorubicin; AML, acute myeloid leukemia; CD, cluster of differentiation; CR, complete response; CRh, complete response with partial count recovery; CRi, complete
response with incomplete count recovery; DART, dual affinity retargeting proteins; HMA, hypomethylating agent; MEC, mitoxantrone, etoposide, and cytarabine; ND, newly diagnosed; ORR, overall response
rate; OS, overall survival; R/R, relapse or refractory; ven, venetoclax.
SHIMONY ET AL.
SHIMONY ET AL. 517
targeted therapies for patients with specific mutations were approved patients attained MRD negativity. The 24-month OS was 67% and
in recent years for patients with R/R AML (Table 1 and Figure 4). 50% in the ND and R/R AML groups respectively. Although promising,
these results should be verified in a larger cohort and compared to
standard of care therapy for these patients.
4.5.1 | Gilteritinib Olutasidenib is a selective IDH1 inhibitor just approved for R/R
IDH1 mutated AML based on the results of a phase I-II trial.19,39 In
As mentioned, Gilteritinib is a potent FLT3 inhibitor that inhibits both the phase I portion of the trial, 78 patients with AML (n = 65;
ITD and TKD versions of the enzyme.169 Gilteritinib was approved as 17 newly diagnosed and 48 R/R) or intermediate, high, or very high
monotherapy for patients with R/R FLT3-mutated AML based on the risk MDS (n = 13, 7 treatment naïve and 6 R/R) per IPSS-R received
results of the ADMIRAL trial.12 Patients with R/R FLT3 mutated AML olutasidenib as monotherapy (n = 32) or in combination with azaciti-
were randomized to either gilteritinib monotherapy (120 mg daily, dine (n = 46). Among patients with AML who received olutasidenib
n = 247) or salvage chemotherapy (n = 124). The median overall sur- monotherapy, the overall response rate was 1/4 (25%) and 9/24
vival in the gilteritinib group was significantly longer than that in the (32%) patients with newly diagnosed and R/R disease respectively.
chemotherapy group (9.3 months vs. 5.6 months; HR 0.64; 95% CI The median OS in patients with R/R AML was 8.7 months (CI 95%
0.49 to 0.83; p < .001) and side effects were less common in the gil- 2.5-not reached) with monotherapy and 12.1 months (CI 95% 4.2-not
teritinib group versus chemotherapy. In a follow-up analysis at reached) with combination therapy. The rate of differentiation syn-
24 months, among the 40 patients in the gilteritinib arm who received drome was 13%, similar to that seen with other IDH inhibitors.174
AlloSCT and were treated with gilteritinib as post-AlloSCT mainte- According to the FDA's approval summary, the CR + CRh rate among
nance, the cumulative relapse rates were 0% and 18.6% among 147 patients with R/R IDH1 mutated AML was 35% (51/147)39 and
patients who achieved CR/CRh or composite CR, respectively, which 29/86 (34%) transfusion dependent patients became RBC and platelet
may suggest a role for gilteritinib as post AlloSCT in the advanced dis- transfusion independent. Both approved IDH1 inhibitors will seldom
ease maintenance.170 Of note, only 12% of patients in the AMDIRAL be used as single agents in the newly diagnosed setting since either
study had prior FLT3 inhibitor exposure. However, the benefit of gil- HMA + venetoclax or HMA + Ivosidenib are considered optimal.
teritinib in patients with prior exposure to FLT3 inhibitor was demon- Moreover, the best treatment of patients with R/R IDH1 mutant AML
strated both in a post hoc analysis of the ADMIRAL and the phase I-II is uncertain as there is no data on what partners to employ with ivosi-
CHRYSALLIS trial,171 as well in real world data.172,173 In a phase Ib-II denib or olutasidenib, let alone comparisons between the two agents,
trial gilteritinib was combined with venetoclax in 61 patients (56 with given the ubiquitous prior receipt of the aforementioned initial combi-
FLT3 mutation) with R/R AML,37 with 64% of patients having received nation therapies.
prior FLT3 inhibitor therapy. The modified composite CR rates (CR The IDH2 inhibitor enasidenib was FDA approved for patients with
+ CRi + CRp + MLFS) was 75%, with 36% of them MLFS. Molecular IDH2-mutated R/R AML based on the results of phase 2 single arm
remission by FLT3 PCR was achieved in 60% of patients and the study.10 However, the phase III trial IDHENTIFY in patients with IDH2
median OS was 10 months. Grade 3–4 cytopenias were common mutated R/R AML treated with enasidenib versus SOC failed to meet
(80%) and adverse events prompted venetoclax and gilteritinib dose its primary endpoint of OS improvement.175 In a post hoc analysis of
interruptions in 51% and 48% respectively. A triplet therapy with IDHENTIFY evaluating patients who were treated with enasidenib ver-
HMA, venetoclax and gilteritinib is being explored in the FLT3 mutant sus lower intensity therapies (LDAC, HMA or best supportive care, but
relapse setting yielding high response rates (ORR of 67%—CR + CRi not HMA plus venetoclax), enasidenib was associated with improved
+ MLFS and median OS of 10.5 months); however, myelosuppression CR rates and OS (1 year OS 41 vs. 26%, HR 0.74 95% CI 0.56–
required a dose reduction in gilteritinib to 80 mg daily for further 9.97).176 Combination therapy with enasidenib was also evaluated in a
38
studies. Whereas the initial results suggest a high degree of myelo- small case series in the R/R setting, either as doublet with azacitidine or
suppression with either gilteritinib plus venetoclax or gilteritinib plus triplet therapy with venetoclax as well, with composite (CR + CRi) rates
venetoclax and azacitidine in relapsed AML, these regimens could of 58% and potential benefit with the addition of venetoclax (1 year
serve as a bridge to transplant, with long term use seen as unlikely, at OS 67% vs. 20%, HR 0.26, 95% CI 0.09–0.97, p = .08).177
least without significant dose modifications.
4.5.3 | Gemtuzumab ozogamycin

4.5.2 | IDH inhibitors
As mentioned, GO is a CD33 monoclonal antibody conjugated to cali-
As mentioned, the IDH1 inhibitor ivosidenib was approved as mono- cheamicin. It was also approved for patients with R/R AML, mainly
therapy for patients with IDH1 mutated R/R AML.8 Recently, Lacho- based on the results from the phase II MYELOFRANCE-1 trial, which
wiez et al. presented data from a phase Ib-II trial in patients with IDH1 demonstrated 26% CR rates with a median RFS of 11 months.26 Due
mutated MDS (n = 9), ND-AML (n = 14), or R/R AML (n = 8) who to its modest efficacy, as well as association with higher risk of
were treated with venetoclax and ivosidenib ±azacitidine.24 The SOS114 in patients which optimally would proceed with AlloSCT, the
response rates were high (composite CR rate 87%); 63% of AML use of GO in this setting is limited.
518 SHIMONY ET AL.
T A B L E 5 Selected unresolved challenges in acute myeloid combined with intensive chemotherapy to improve outcomes for R/R
leukemia management. patients. In a phase Ib/II trial, DiNardo et al reported results of FLAG-
Diagnosis IDA plus venetoclax regimen in patients with R/R AML. The compos-
• Should patients with TP53 MDS/AML be considered as a sole ite CR rates were 61%–75%, and 1 year OS estimate of 68%.30
unique entity and addressed differently from other AML? AlloSCT was crucial for long-term survival, with a landmark analysis in
Measurable residual disease use the R/R group demonstrating improved survival among patients con-
• What is the optimal method to measure MRD and what are the solidated with alloSCT versus chemotherapy alone (median OS not
crucial time points during therapy that would influence our reached vs. 7 months, p = .009). As expected, patients with R/R AML
decision analysis?
harboring TP53 mutation had a dismal prognosis (OS 7 months). As
• Develop a potent MRD eraser therapy such as blinatumomab these combinations are highly myelosuppressive, all patients received
in ALL
anti-bacterial quinolone, anti-fungal, and anti-viral therapy prophylaxis
• Does MRD have a predictive value pre-transplant, that is– does
and the length of venetoclax was amended during trial from 14 to
eradicating MRD positivity leads to improved outcomes?
• Should additional treatment be administered with the goal of 7 days. Real-world data of FLAG-IDA and venetoclax demonstrated
eradicating MRD prior to transplant if patients are in a invasive bacteremia in half of the patients and fungal infection in one-
morphologic remission and allogeneic stem cell transplant is third of the patients.179 The high risk for infections requires vigilant
ready to be conducted?
monitoring and prompt treatment when early signs of such problems
• Can MRD negativity pre-transplant negate the deleterious
are observed. Although not approved for in R/R AML, venetoclax with
prognostic value of baseline characteristics (e.g should patients
with adverse risk genetic at diagnosis who achieves MRD HMA was evaluated in this setting in real-world studies, with
negativity defer transplant?) response rates of 31%–60%.180,181 Given the limitations of indirect
Upfront therapy comparison, response rates seem higher with HMA and venetoclax in
• What is the optimal upfront therapy for patients who can R/R AML compared to HMA alone (16% CRi182), but overall survival is
tolerate intensive chemotherapy? similar (6.1–6.8 months vs. 6.7 months, respectively).
• What is the optimal frontline therapy in younger or older
Case continued:
patients who can tolerate intensive chemotherapy?
Due to dismal prognosis with current approved therapies and
• Should targeted agents (FLT3 and IDH1/2 inhibitors) be
administered concurrently with HMA + venetoclax or should TP53 mutated R/R AML, additional investigational therapies were
they be used at time of disease progression? sought for our patient.
TP53 mutated disease
• Develop more potent therapies for TP53 mutated AML
• What is the role of transplant in TP53 mutated patients? 5 | S E L E C T E D I N V E S TI G A T I O N A L
• Are there subsets of TP53 mutated AML which are curable by
THERAPIES
current therapies (e.g. single TP53 mutated with low VAF and
absence of LOH and complex karyotype)?
• Should patients with TP53 mutated AML be treated with a Despite marked improvements in AML management, the outcomes
prolonged maintenance therapy? are still unsatisfactory, especially in patients with high-risk disease.
Relapse/refractory patients Numerous trials are evaluating targeted therapies or immunotherapies
• What is the optimal therapy after HMA plus venetoclax failure? as monotherapies or in combination. Though most of these therapies
Maintenance are still under investigation without description of long-term out-
• Who should be treated with maintenance therapy after intensive comes, a few have shown promising early responses, even in challeng-
chemotherapy? ing population as patients with TP53 mutated AML or MLL rearranged
• Can venetoclax based therapy be stopped in patients who have AML (Table 4).
achieved a deep molecular response? Mixed-lineage leukemia (MLL) translocations involving the lysine
• Who should be treated with maintenance therapy post-alloSCT histone methyltransferase KMT2A at chromosome 11q23 are found
and what therapy should be used? in 5%–10% of adults with AML194 and as stated by the recent ELN
Abbreviations: AlloSCT, allogeneic stem cell transplantation; AML, acute confer an adverse prognosis, except for the t(9;11)(p21.3;q23.3)/
myeloid leukemia; HMA, hypomethylating agents; IDH, isocitrate MLLT3::KMT2A translocation, which is categorized as intermediate
dehydrogenase; MDS, myelodysplastic syndrome; MRD, measurable risk.41 These rearrangements are characterized by increased expres-
residual disease.
sion of homeobox (HOX) genes, which are also dysregulated in NPM1
mutated AML and are associated with self-renewal of hematopoietic
4.5.4 | Venetoclax + Salvage chemo stem cells.195 The scaffold protein menin, which is encoded by the
MEN1 gene, binds to KMT2A and is crucial for its function.196 Several
The typically chosen intensive chemotherapy-only regimens for R/R early phase trials are currently evaluating small-molecule inhibitors
include mitoxantrone/etoposide/cytarabine, high dose cytarabine that interfere with the KMT2A-menin interaction: SNDX 5613 which
alone, cytarabine/clofarabine, or fludarabine/idarubicin/cytarabine/ demonstrated composite CR rates of 44% among 45 patients with
G-CSF. None is clearly better than another.178 Venetoclax was also mutated NPM1 or MLL rearranged AML (AUGMENT 101)183; and
SHIMONY ET AL. 519
KO539 (KOMET1), which demonstrated efficacy in a smaller number relapse.193 Among the 30 patients treated at the recommended phase
of patients.184 dose, the complete remission (CR)/CR with partial hematological
Uproleselan (GM-1271) is an E-selectin inhibitor that was found recovery (CRh) rate was 26.7%. The most frequent adverse events
to disrupt vascular niche mediated chemoresistance.197 A phase I/II were grade 1–2 infusion-related reactions and cytokine release syn-
study demonstrated efficacy among patients with R/R AML treated drome (CRS). A 10-gene immune signature predicted response to
with MEC regimen combined with uproleselan. The composite remis- flotetuzumab with an immune-infiltrated IFN-γ–dominant tumor
sion rates were 41% with 35% CR, and the median OS was microenvironment being associated with improved response to ther-
8.8 months. In addition, there was a significant decrease in the rates apy. It should be noted, however, that flotetuzumab development
of oral mucositis, which often complicates the MEC regimen.190 A was discontinued with the focus now being a second generation
phase II/III and a phase III trial are now evaluating the addition of DART named MGD024,202 which is of longer half-life for ease of
uproleselan to chemotherapy, both in patients with ND-AML older administration and expected to be associated with fewer CNS
than 60 years (NCT03701308) and in patients with R/R AML events. One issue with all these approaches is that AML blasts do
(NCT03616470) respectively. not have either a truly leukemia specific or a dispensable antigen
CD47 is a “do not eat me,” antiphagocytic signal that is overex- such as CD19 on B cells so useful in the ALL context. Both CD33
pressed by cancer cells to enable the immune evasion of phagocytosis and CD123 are abundantly expressed on AML blasts but are also
by macrophages.198 Magrolimab is an anti-CD-47 monoclonal anti- present on normal hematopoietic stem and progenitor cells which
body with anti-leukemic activity.199 The use of azacitidine with could result in significant myelotoxicity. One creative approach to
magrolimab was evaluated in a phase Ib trial in ND-AML patients unfit allow CAR T cell persistence without the unwanted prolonged mye-
for intensive therapy, enriched in TP53 mutations (83%). Results were loablation effect is to genetically edit out the CAR target antigen
encouraging with 65% achieving responses and 45% achieving from a donor allograft using CRISPR/Cas9 technology and then give
CR. The responses were particularly encouraging among patients har- CAR T cells directed against this now “leukemia specific” antigen
boring TP53 mutations with 71% responses and 45% complete post allo-SCT.203 It remains to be seen whether such an approach
responses. In an expansion cohort of 72 TP53 mutated patients 48.6% will be successful in clinical trials.
responses rate including a 33.3% CR rate was described. The median Case continued:
estimated OS was 10.8 months (CI 95% 6.8–12.8). As there is hemoly- Our patient was enrolled in a phase I-II trial with azacitidine,
sis associated with CD47 due to the expression of this epitope on venetoclax, and the anti-CD47 magrolimab.
RBCs, a ramp-up dosing approach is required as is close monitoring of
anemia. Early results from phase Ib trial evaluating safety and efficacy
of an azacitidine, venetoclax, and magrolimab triplet demonstrated 6 | CHOOS ING A TRE A T M ENT STRAT EG Y
94% response rates and 81% CR rates in ND-AML, 63% CR or CRi
rates in R/R patients naïve to prior venetoclax, and 27% in patients One of the more crucial decisions in AML is whether the patient is
with prior venetoclax failure.187 The encouraging results seen with deemed eligible for intensive regimen therapy and will they benefit
magrolimab have led to several phase III trials: azacitidine + veneto- from such a therapy (for example, patients with mutated TP53 may
clax with magrolimab versus placebo in ND-AML patients not fit for not benefit from intensive chemotherapy regimen). This decision is
intensive therapy (ENHANCE 3, NCT05079230); and magrolimab + based on patient age, comorbidities, goals of care, as disease charac-
azacitidine versus venetoclax + azacitidine or intensive chemotherapy teristics. It is also based on the physician's common practice and expe-
in patients with TP53 mutated AML (ENHANCE 2, NCT04778397). rience. There are several tools to assess the treatment related
MBG453 (Sabatolimab) is a humanized antibody that targets mortality (TRM) that may be associated with intensive chemotherapy;
TIM3, which serves as an inhibitory checkpoint on both immune and however, none can really adjust for all the many variables in the deci-
leukemic cells, but not on normal hematopoietic stem cells. A phase Ib sion. Rather, we suggest some principles in making the choice for the
in patients with AML and high risk MDS demonstrated 41.2% of patient.
response rates in patients with ND-AML.188 An ongoing phase II trial
is evaluating the safety and efficacy of sabatolimab plus azacitidine + 1. The most common cause of death in AML is relapse or refractory
venetoclax in patients with AML unfit for intensive chemotherapy disease.
(STIMULUS-AML1, NCT04150029). 2. Age by itself should not be the only determinant for treatment
Other immune therapies under development include bispecific intensity.
antibodies and chimeric antigen receptor (CART) cells directed against 3. A comprehensive evaluation of comorbidities should be completed
a multitude of different antigens including CD123, CD33, and when deciding upon treatment strategy. Transient comorbidities
CD70.200,201 The clinically advanced among these immunotherapeutic that are result of AML should not be a contraindication to receive
approaches is flotetuzumab which is a bispecific DART antibody- intensive chemotherapy.
based molecule to CD3ε on T cells and CD123 on AML blasts. Flote- 4. In older patients, geriatric assessment should be pursued and
tuzumab was tested in a multicenter, open-label phase 1/2 trial in should be taken in consideration of the optimal treatment that fit
88 AML patients with either primary induction failure or early our patient. Although there is no standardization of type of
520 SHIMONY ET AL.
assessment,204 a geriatric assessment can reveal vulnerabilities CONFLIC T OF INT ER E ST

that are not detected in routine clinical practice205 and predicts Richard M. Stone reports grants and personal fees from Abbvie, per-
206,207
morbidity and mortality. The prognostic value of geriatric sonal fees from Actinium, grants and personal fees from Agios, per-
assessment was also seen in older patients treated with lower sonal fees from Argenx, grants from Arog, personal fees from Astellas,
intensity regimens208 as well as intensive chemotherapy, and can personal fees from AstraZeneca, personal fees from Biolinerx, per-
aid in predicting non-fatal toxicities during induction.209 In a ran- sonal fees from Celgene, personal fees from Daiichi-Sankyo, personal
domized trial, standard oncological consultation with additional fees from Elevate, personal fees from Gemoab, personal fees from
geriatrician consultation versus without was associated with higher Janssen, personal fees from Jazz, personal fees from Macrogenics,
rates of end-of-life and goals of care discussion, in addition to grants and personal fees from Novartis, personal fees from Otsuka,
being valued by 63%–88% of clinicians as beneficial.210 personal fees from Pfizer, personal fees from Hoffman LaRoche, per-
5. Goals of care should be discussed early and guide decision on best sonal fees from Stemline, personal fees from Syndax, personal fees
treatment for the patient. from Syntrix, personal fees from Syros, personal fees from Takeda,
6. A consideration should be made if the patient is eligible for from Trovagene, outside the submitted work. Maximilian Stahl reports
alloSCT. This can affect the decision on the initial therapy, as a consulting and personal fees from Curtis Oncology, Haymarket Media,
bridge to transplant or as a definitive therapy. Boston Consulting; Membership on advisory board of Novartis,
7. Certain AML subtypes may have differential response to different Kymera. Shai Shimony do not have COI to declare.
therapy modalities (i.e., TP53 mutated AML are poorly responsive
to chemotherapy, patients with monocytic differentiation may be DATA AVAILABILITY STAT EMEN T
less responsive to HMA plus venetoclax, etc). Not applicable.
Finally, we note that the provocative new classifications sys- OR CID

tems in AML should not be seen as a hindrance to therapeutic Shai Shimony https://orcid.org/0000-0001-7245-9652
advances, but rather as stimulus to more thoughtful and creative Maximilian Stahl https://orcid.org/0000-0002-1299-5901
trial designs. The NCCN and ELN 2022 guidelines are a highly valu- Richard M. Stone https://orcid.org/0000-0002-7526-2633
able efforts that represent consensus that will aid critical decision-
making. Too many options in the former and too dogmatic instruc- RE FE RE NCE S
tions based on limited data in some cases (particularly about the 1. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N
value of “erasing” MRD) in the latter are minor criticisms. We have Engl J Med. 2015;373(12):1136-1152.
2. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classifica-
provided algorithms that should be considered only to be the con-
tion and prognosis in acute myeloid leukemia. N Engl J Med. 2016;
sensus of the authors. Figures 2–4 are meant to provide a frame- 374(23):2209-2221.
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10968652, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26822 by Nat Prov Indonesia, Wiley Online Library on [04/03/2023].

ANNUAL CLINICAL UPDATES IN

Acute myeloid leukemia: 2023 update on diagnosis,

Shai Shimony 1,2 | Maximilian Stahl 1 | Richard M. Stone 1

1 | I N T RO DU CT I O N age at diagnosis of 68 years.3 The estimated 5-year OS is 30%4 and

502 wileyonlinelibrary.com/journal/ajh Am J Hematol. 2023;98:502–526.

inhibitor ≥75 years / LDAC (NCT04231851)

Major differences in new AML Classification systems

4.5.3 | Gemtuzumab ozogamycin

assessment,204 a geriatric assessment can reveal vulnerabilities CONFLIC T OF INT ER E ST

Finally, we note that the provocative new classifications sys- OR CID

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