Abstract

The acute myeloid leukemia (AML) treatment landscape has changed substantially since 2017. New targeted drugs have emerged, including venetoclax to target B-cell lymphoma 2, midostaurin and gilteritinib to target FLT3, and ivosidenib and enasidenib to target mutant isocitrate dehydrogenase 1 and 2, respectively. Other additions include reapproval of gemtuzumab ozogomycin to target CD33, glasdegib to target the hedgehog pathway, and a liposomal formulation of daunorubicin and cytarabine (CPX-351). Genomically heterogeneous AML has a tendency to evolve, particularly under selective treatment pressure. For decades, treatment decisions have largely centered around chemotherapy drug intensity. Physicians now have access to an increasing number of drugs with novel mechanisms of action and distinctive side-effect profiles. Key issues faced by hematologists in this era of new drugs include (1) the timely identification of actionable mutations at diagnosis and at relapse; (2) deciding which drug to use among several therapeutic options; and (3) increasing awareness of how to anticipate, mitigate, and manage common complications associated with these new agents. This article will use 3 case presentations to discuss some of the new treatment challenges encountered in AML management, with the goal of providing practical guidance to aid the practicing physician.

REFERENCES

REFERENCES
1.
Kantarjian
H
,
Ravandi
F
,
O’Brien
S
, et al
.
Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia
.
Blood
.
2010
;
116
(
22
):
4422
-
4429
.
2.
Döhner
H
,
Estey
E
,
Grimwade
D
, et al
.
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel
.
Blood
.
2017
;
129
(
4
):
424
-
447
.
3.
Prassek
VV
,
Rothenberg-Thurley
M
,
Sauerland
MC
, et al
.
Genetics of acute myeloid leukemia in the elderly: mutation spectrum and clinical impact in intensively treated patients aged 75 years or older
.
Haematologica
.
2018
;
103
(
11
):
1853
-
1861
.
4.
Burnett
AK
,
Milligan
D
,
Prentice
AG
, et al
.
A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment
.
Cancer
.
2007
;
109
(
6
):
1114
-
1124
.
5.
Kantarjian
HM
,
Thomas
XG
,
Dmoszynska
A
, et al
.
Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia
.
J Clin Oncol
.
2012
;
30
(
21
):
2670
-
2677
.
6.
Cortes
JE
,
Heidel
FH
,
Hellmann
A
, et al
.
Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome
.
Leukemia
.
2019
;
33
(
2
):
379
-
389
.
7.
DiNardo
CD
,
Pratz
KW
,
Letai
A
, et al
.
Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study
.
Lancet Oncol
.
2018
;
19
(
2
):
216
-
228
.
8.
Wei
AH
,
Strickland
SA
Jr.
,
Hou
JZ
, et al
.
Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study
.
J Clin Oncol
.
2019
;
37
(
15
):
1277
-
1284
.
9.
Strickland
SA
,
Chyla
B
,
Popovic
R
, et al
.
Cytogenetic and molecular drivers of outcome with venetoclax-based combination therapies in treatment-naive elderly patients with acute myeloid leukemia (AML) [abstract]
.
Clin Lymphoma Myeloma Leuk
.
2018
;
18
(
suppl 1
). Abstract
S202
.
10.
Montesinos
P
,
Lorenzo
I
,
Martín
G
, et al
.
Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model
.
Haematologica
.
2008
;
93
(
1
):
67
-
74
.
11.
Agarwal
SK
,
DiNardo
CD
,
Potluri
J
, et al
.
Management of venetoclax-posaconazole interaction in acute myeloid leukemia patients: evaluation of dose adjustments
.
Clin Ther
.
2017
;
39
(
2
):
359
-
367
.
12.
Prata
PH
,
Bally
C
,
Prebet
T
, et al
.
NPM1 mutation is not associated with prolonged complete remission in acute myeloid leukemia patients treated with hypomethylating agents
.
Haematologica
.
2018
;
103
(
10
):
e455
-
e457
.
13.
Papaemmanuil
E
,
Gerstung
M
,
Bullinger
L
, et al
.
Genomic classification and prognosis in acute myeloid leukemia
.
N Engl J Med
.
2016
;
374
(
23
):
2209
-
2221
.
14.
Stone
RM
,
Mandrekar
SJ
,
Sanford
BL
, et al
.
Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation
.
N Engl J Med
.
2017
;
377
(
5
):
454
-
464
.
15.
Schlenk
RF
,
Kayser
S
,
Bullinger
L
, et al;
German-Austrian AML Study Group
.
Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation
.
Blood
.
2014
;
124
(
23
):
3441
-
3449
.
16.
Sakaguchi
M
,
Yamaguchi
H
,
Najima
Y
, et al
.
Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia
.
Blood Adv
.
2018
;
2
(
20
):
2744
-
2754
.
17.
Iland
HJ
,
Bradstock
K
,
Supple
SG
, et al;
Australasian Leukaemia and Lymphoma Group
.
All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4)
.
Blood
.
2012
;
120
(
8
):
1570
-
1580
,
quiz 1752
.
18.
Callens
C
,
Chevret
S
,
Cayuela
JM
, et al;
European APL Group
.
Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group
.
Leukemia
.
2005
;
19
(
7
):
1153
-
1160
.
19.
Hills
RK
,
Castaigne
S
,
Appelbaum
FR
, et al
.
Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials
.
Lancet Oncol
.
2014
;
15
(
9
):
986
-
996
.
20.
Castaigne
S
,
Pautas
C
,
Terré
C
, et al;
Acute Leukemia French Association
.
Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study
.
Lancet
.
2012
;
379
(
9825
):
1508
-
1516
.
21.
Renneville
A
,
Abdelali
RB
,
Chevret
S
, et al
.
Clinical impact of gene mutations and lesions detected by SNP-array karyotyping in acute myeloid leukemia patients in the context of gemtuzumab ozogamicin treatment: results of the ALFA-0701 trial
.
Oncotarget
.
2014
;
5
(
4
):
916
-
932
.
22.
Lambert
J
,
Lambert
J
,
Nibourel
O
, et al
.
MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin
.
Oncotarget
.
2014
;
5
(
15
):
6280
-
6288
.
23.
Olombel
G
,
Guerin
E
,
Guy
J
, et al
.
The level of blast CD33 expression positively impacts the effect of gemtuzumab ozogamicin in patients with acute myeloid leukemia
.
Blood
.
2016
;
127
(
17
):
2157
-
2160
.
24.
Kottaridis
PD
,
Gale
RE
,
Langabeer
SE
,
Frew
ME
,
Bowen
DT
,
Linch
DC
.
Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors
.
Blood
.
2002
;
100
(
7
):
2393
-
2398
.
25.
Schmalbrock
LK
,
Cocciardi
S
,
Dolnik
A
, et al
.
Clonal evolution of FLT3-ITD positive AML in patients treated with midostaurin in combination with chemotherapy within the Ratify (CALGB 10603) and AMLSG 16-10 trials [abstract]
.
Blood
.
2017
;
130
(
suppl 1
). Abstract
182
.
26.
Cortes
JE
,
Khaled
S
,
Martinelli
G
, et al
.
Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial
.
Lancet Oncol
.
2019
;
20
(
7
):
984
-
997
.
27.
Perl
AE
,
Martinelli
G
,
Cortes
JE
, et al
.
Gilteritinib significantly prolongs overall survival in patients with FLT3-mutate relapsed/refractory acute myeloid leukemia: results from the phase 3 Admiral trial [abstract]
.
Cancer Res
.
2019
;
79
(
suppl 13
).
Abstract CT184
.
28.
Perl
AE
,
Altman
JK
,
Cortes
JE
, et al
.
Final results of the chrysalis trial: a first-in-human phase 1/2 dose-escalation, dose-expansion study of gilteritinib (ASP2215) in patients with relapsed/refractory acute myeloid leukemia (R/R AML) [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract
1069
.
29.
Levis
MJ
,
Perl
AE
,
Altman
JK
, et al
.
Evaluation of the impact of minimal residual disease, FLT3 allelic ratio, and FLT3 mutation status on overall survival in FLT3 mutation-positive patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) in the Chrysalis phase 1/2 study [abstract]
.
Blood
.
2017
;
130
(
suppl 1
). Abstract
2705
.
30.
Wang
ES
,
Tallman
MS
,
Stone
RM
, et al
.
Low relapse rate in younger patients ≤60 years old with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy [abstract]
.
Blood
.
2017
;
130
(
suppl 1
). Abstract
566
.
31.
Altman
JK
,
Foran
JM
,
Pratz
KW
,
Trone
D
,
Cortes
JE
,
Tallman
MS
.
Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia
.
Am J Hematol
.
2018
;
93
(
2
):
213
-
221
.
32.
Pratz
KW
,
Cherry
M
,
Altman
JK
, et al
.
Updated results from a phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed acute myeloid leukemia (AML) [abstract]
.
Blood
.
2018
;
132
(
suppl 1
). Abstract
564
.
33.
Levis
M
,
Ravandi
F
,
Wang
ES
, et al
.
Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse
.
Blood
.
2011
;
117
(
12
):
3294
-
3301
.
34.
Esteve
J
,
Schots
R
,
Del Castillo
TB
, et al
.
Multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in newly diagnosed FLT3 mutated (FLT3mut+) acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy: findings from the safety cohort [abstract]
.
Blood
.
2018
;
132
(
suppl 1
). Abstract
2736
.
35.
McMahon
CM
,
Ferng
T
,
Canaani
J
, et al
.
Clonal selection with Ras pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia
.
Cancer Discov
.
2019
;
9
(
8
):
1050
-
1063
.
36.
Mathew
NR
,
Baumgartner
F
,
Braun
L
, et al
.
Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells [published correction appears in Nat Med. 2018;24(4):526]
.
Nat Med
.
2018
;
24
(
3
):
282
-
291
.
37.
Burchert
A
,
Bug
G
,
Finke
J
, et al
.
Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: results from the randomized, double-blind, placebo-controlled multicentre Sormain trial [abstract]
.
Blood
.
2018
;
132
(
suppl 1
). Abstract
661
.
38.
Prébet
T
,
Gore
SD
,
Thépot
S
, et al
.
Outcome of acute myeloid leukaemia following myelodysplastic syndrome after azacitidine treatment failure
.
Br J Haematol
.
2012
;
157
(
6
):
764
-
766
.
39.
Boddu
P
,
Kantarjian
HM
,
Garcia-Manero
G
, et al
.
Treated secondary acute myeloid leukemia: a distinct high-risk subset of AML with adverse prognosis
.
Blood Adv
.
2017
;
1
(
17
):
1312
-
1323
.
40.
Ball
B
,
Komrokji
RS
,
Adès
L
, et al
.
Evaluation of induction chemotherapies after hypomethylating agent failure in myelodysplastic syndromes and acute myeloid leukemia
.
Blood Adv
.
2018
;
2
(
16
):
2063
-
2071
.
41.
Nanah
R
,
McCullough
K
,
Hogan
W
, et al
.
Outcome of elderly patients after failure to hypomethylating agents given as frontline therapy for acute myeloid leukemia: single institution experience
.
Am J Hematol
.
2017
;
92
(
9
):
866
-
871
.
42.
Wang
J
,
Ma
Z
,
Wang
Q
, et al
.
Prognostic significance of IDH1 and IDH2 mutations in older patients with primary cytogenetically normal acute myeloid leukemia [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract
5058
.
43.
DiNardo
CD
,
Ravandi
F
,
Agresta
S
, et al
.
Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML
.
Am J Hematol
.
2015
;
90
(
8
):
732
-
736
.
44.
DiNardo
CD
,
Stein
EM
,
de Botton
S
, et al
.
Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML
.
N Engl J Med
.
2018
;
378
(
25
):
2386
-
2398
.
45.
Dinardo
CD
,
Stein
AS
,
Stein
EM
, et al
.
Mutant IDH1 inhibitor ivosidenib (IVO; AG-120) in combination with azacitidine (AZA) for newly diagnosed acute myeloid leukemia (ND AML) [abstract]
.
J Clin Oncol
.
2019
;
37
(
suppl 15
). Abstract
7011
.
46.
Dinardo
C
,
Takahashi
K
,
Kadia
T
, et al
.
A phase 1b/2 clinical study of targeted IDH1 inhibition with ivosidenib, in combination with the BCL-2 inhibitor venetoclax, for patients with IDH1-mutated (mIDH1) myeloid malignancies: PF291 [abstract]
.
HemaSphere
.
2019
;
3
(
suppl 1
). Abstract
97
.
47.
Fathi
AT
,
DiNardo
CD
,
Kline
I
, et al;
AG221-C-001 Study Investigators
.
Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study
.
JAMA Oncol
.
2018
;
4
(
8
):
1106
-
1110
.
48.
Tallman
MS
,
Altman
JK
.
How I treat acute promyelocytic leukemia
.
Blood
.
2009
;
114
(
25
):
5126
-
5135
.
49.
Rowe
JM
,
Tallman
MS
.
How I treat acute myeloid leukemia
.
Blood
.
2010
;
116
(
17
):
3147
-
3156
.
50.
Zuckerman
T
,
Ganzel
C
,
Tallman
MS
,
Rowe
JM
.
How I treat hematologic emergencies in adults with acute leukemia
.
Blood
.
2012
;
120
(
10
):
1993
-
2002
.
51.
Thol
F
,
Schlenk
RF
,
Heuser
M
,
Ganser
A
.
How I treat refractory and early relapsed acute myeloid leukemia
.
Blood
.
2015
;
126
(
3
):
319
-
327
.
52.
Ossenkoppele
G
,
Löwenberg
B
.
How I treat the older patient with acute myeloid leukemia
.
Blood
.
2015
;
125
(
5
):
767
-
774
.
53.
Röllig
C
,
Ehninger
G
.
How I treat hyperleukocytosis in acute myeloid leukemia
.
Blood
.
2015
;
125
(
21
):
3246
-
3252
.
54.
Ofran
Y
,
Tallman
MS
,
Rowe
JM
.
How I treat acute myeloid leukemia presenting with preexisting comorbidities
.
Blood
.
2016
;
128
(
4
):
488
-
496
.
55.
Pratz
KW
,
Levis
M
.
How I treat FLT3-mutated AML
.
Blood
.
2017
;
129
(
5
):
565
-
571
.
56.
Goodyear
OC
,
Dennis
M
,
Jilani
NY
, et al
.
Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML)
.
Blood
.
2012
;
119
(
14
):
3361
-
3369
.
57.
Stone
R
.
The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18-60 with FLT3 mutations (muts): an international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]) [abstract]
.
Blood
.
2015
;
126
(
23
). Abstract
6
.
58.
Lancet
JE
,
Uy
GL
,
Cortes
JE
, et al
.
CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia
.
J Clin Oncol
.
2018
;
36
(
26
):
2684
-
2692
.
59.
Adès
L
,
Thomas
X
,
Bresler
AG
, et al
.
Arsenic trioxide is required in the treatment of newly diagnosed acute promyelocytic leukemia. Analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL group
.
Haematologica
.
2018
;
103
(
12
):
2033
-
2039
.
60.
DiNardo
CD
,
Pratz
K
,
Pullarkat
V
, et al
.
Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia
.
Blood
.
2019
;
133
(
1
):
7
-
17
.
61.
Roboz
GJ
,
Dinardo
CD
,
Stein
EM
, et al
.
Ivosidenib (IVO; AG-120) in IDH1-mutant newly-diagnosed acute myeloid leukemia (ND AML): updated results from a phase 1 study [abstract]
.
J Clin Oncol
.
2019
;
37
(
suppl 15
). Abstract
7028
.
62.
Stein
EM
,
DiNardo
CD
,
Fathi
AT
, et al
.
Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib
.
Blood
.
2019
;
133
(
7
):
676
-
687
.
63.
Siegel
DH
,
Ashton
GH
,
Penagos
HG
, et al
.
Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome
.
Am J Hum Genet
.
2003
;
73
(
1
):
174
-
187
.
64.
Quek
L
,
David
MD
,
Kennedy
A
, et al
.
Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib
.
Nat Med
.
2018
;
24
(
8
):
1167
-
1177
.
65.
Amatangelo
MD
,
Quek
L
,
Shih
A
, et al
.
Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response
.
Blood
.
2017
;
130
(
6
):
732
-
741
.
66.
Intlekofer
AM
,
Shih
AH
,
Wang
B
, et al
.
Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations
.
Nature
.
2018
;
559
(
7712
):
125
-
129
.
You do not currently have access to this content.