Abstract

Tyrosine kinase inhibitors (TKIs) are the mainstay of treatment for patients with chronic myeloid leukemia. The standard dose has been established for each drug according to the indication for the various stages of the disease and whether as initial therapy or after failure of previous therapies. The recommended doses are fixed for all patients and dose adjustments are mostly recommended for management of adverse events. The standard doses have been derived largely from phase 1 studies, but as we discuss in this review, the current model may not be optimal for this purpose for drugs such as TKIs that are meant to be used for extended periods of time. Subsequent studies have led to changes in the initial recommendations for some drugs. In others, experience and real-world data have led to the use of TKIs using doses and adjustments that may be different than what clinical trials have recommended. In other scenarios, available data suggest that the current standard dose may need to be revisited. It may also be time to reconsider the standard approach of starting therapy with the standard dose and adjusting merely based on adverse events. We propose a flexible model that perhaps reflects more accurately what is being done frequently in the clinic.

1.
Druker
BJ
,
Talpaz
M
,
Resta
DJ
, et al
.
Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia
.
N Engl J Med
.
2001
;
344
(
14
):
1031
-
1037
.
2.
Druker
BJ
,
Sawyers
CL
,
Kantarjian
H
, et al
.
Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome
.
N Engl J Med
.
2001
;
344
(
14
):
1038
-
1042
.
3.
Kantarjian
H
,
Giles
F
,
Wunderle
L
, et al
.
Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL
.
N Engl J Med
.
2006
;
354
(
24
):
2542
-
2551
.
4.
Talpaz
M
,
Shah
NP
,
Kantarjian
H
, et al
.
Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias
.
N Engl J Med
.
2006
;
354
(
24
):
2531
-
2541
.
5.
Cortes
JE
,
Kantarjian
HM
,
Brümmendorf
TH
, et al
.
Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib
.
Blood
.
2011
;
118
(
17
):
4567
-
4576
.
6.
Cortes
JE
,
Kantarjian
H
,
Shah
NP
, et al
.
Ponatinib in refractory Philadelphia chromosome-positive leukemias
.
N Engl J Med
.
2012
;
367
(
22
):
2075
-
2088
.
7.
Hughes
TP
,
Mauro
MJ
,
Cortes
JE
, et al
.
Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure
.
N Engl J Med
.
2019
;
381
(
24
):
2315
-
2326
.
8.
Hughes
TP
,
Laneuville
P
,
Rousselot
P
, et al
.
Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia
.
Haematologica
.
2019
;
104
(
1
):
93
-
101
.
9.
Kantarjian
HM
,
Hughes
TP
,
Larson
RA
, et al
.
Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis
.
Leukemia
.
2021
;
35
(
2
):
440
-
453
.
10.
Cortes
JE
,
Kim
DW
,
Pinilla-Ibarz
J
, et al
.
Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial
.
Blood
.
2018
;
132
(
4
):
393
-
404
.
11.
Cortes
JE
,
Saglio
G
,
Kantarjian
HM
, et al
.
Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial
.
J Clin Oncol
.
2016
;
34
(
20
):
2333
-
2340
.
12.
Brümmendorf
TH
,
Cortes
JE
,
Milojkovic
D
, et al
.
Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial
.
Leukemia
.
2022
;
36
(
7
):
1825
-
1833
.
13.
Hochhaus
A
,
Saglio
G
,
Hughes
TP
, et al
.
Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial
.
Leukemia
.
2016
;
30
(
5
):
1044
-
1054
.
14.
Christopher
LJ
,
Cui
D
,
Wu
C
, et al
.
Metabolism and disposition of dasatinib after oral administration to humans
.
Drug Metab Dispos
.
2008
;
36
(
7
):
1357
-
1364
.
15.
Shah
NP
,
Kasap
C
,
Weier
C
, et al
.
Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis
.
Cancer Cell
.
2008
;
14
(
6
):
485
-
493
.
16.
Hochhaus
A
,
Kantarjian
HM
,
Baccarani
M
, et al
.
Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy
.
Blood
.
2007
;
109
(
6
):
2303
-
2309
.
17.
Shah
NP
,
Kantarjian
HM
,
Kim
DW
, et al
.
Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia
.
J Clin Oncol
.
2008
;
26
(
19
):
3204
-
3212
.
18.
Garrett
M
,
Knight
B
,
Cortes
JE
,
Deininger
MW
.
Population modeling of bosutinib exposure-response in patients with newly diagnosed chronic phase chronic myeloid leukemia
.
Cancer Med
.
2023
;
12
(
17
):
17981
-
17992
.
19.
Cortes
JE
,
Gambacorti-Passerini
C
,
Deininger
MW
, et al
.
Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial
.
J Clin Oncol
.
2018
;
36
(
3
):
231
-
237
.
20.
Cortes
JE
,
Kim
DW
,
Kantarjian
HM
, et al
.
Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial
.
J Clin Oncol
.
2012
;
30
(
28
):
3486
-
3492
.
21.
Naqvi
K
,
Jabbour
E
,
Skinner
J
, et al
.
Long-term follow-up of lower dose dasatinib (50 mg daily) as frontline therapy in newly diagnosed chronic-phase chronic myeloid leukemia
.
Cancer
.
2020
;
126
(
1
):
67
-
75
.
22.
Murai
K
,
Ureshino
H
,
Kumagai
T
, et al
.
Low-dose dasatinib in older patients with chronic myeloid leukaemia in chronic phase (DAVLEC): a single-arm, multicentre, phase 2 trial
.
Lancet Haematol
.
2021
;
8
(
12
):
e902
-
e911
.
23.
Hughes
TP
,
Branford
S
,
White
DL
, et al
.
Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy
.
Blood
.
2008
;
112
(
10
):
3965
-
3973
.
24.
Kantarjian
H
,
Talpaz
M
,
O'Brien
S
, et al
.
High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia
.
Blood
.
2004
;
103
(
8
):
2873
-
2878
.
25.
Cortes
JE
,
Baccarani
M
,
Guilhot
F
, et al
.
Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study
.
J Clin Oncol
.
2010
;
28
(
3
):
424
-
430
.
26.
Jain
P
,
Kantarjian
H
,
Alattar
ML
, et al
.
Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials
.
Lancet Haematol
.
2015
;
2
(
3
):
e118
-
e128
.
27.
Yeung
DT
,
Osborn
MP
,
White
DL
, et al
.
TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets
.
Blood
.
2015
;
125
(
6
):
915
-
923
.
28.
O'Brien
SG
,
Guilhot
F
,
Larson
RA
, et al
.
Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia
.
N Engl J Med Overseas Ed
.
2003
;
348
(
11
):
994
-
1004
.
29.
Saglio
G
,
Kim
D-W
,
Issaragrisil
S
, et al
.
Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia
.
N Engl J Med
.
2010
;
362
(
24
):
2251
-
2259
.
30.
Kantarjian
H
,
Shah
NP
,
Hochhaus
A
, et al
.
Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia
.
N Engl J Med
.
2010
;
362
(
24
):
2260
-
2270
.
31.
Cortes
J
,
Apperley
J
,
Lomaia
E
, et al
.
Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial
.
Blood
.
2021
;
138
(
21
):
2042
-
2050
.
32.
Réa
D
,
Mauro
MJ
,
Boquimpani
C
, et al
.
A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs
.
Blood
.
2021
;
138
(
21
):
2031
-
2041
.
33.
Asciminib. Prescribing information
.
Food and Drug Administration
;
2021
.
34.
Cortes
JE
,
Sasaki
K
,
Kim
DW
, et al
.
Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results
.
Leukemia
.
2024
;
38
(
7
):
1522
-
1533
.
35.
Kota
V
,
Brümmendorf
TH
,
Gambacorti-Passerini
C
, et al
.
Efficacy and safety following bosutinib dose reduction in patients with Philadelphia chromosome‒positive leukemias
.
Leuk Res
.
2021
;
111
:
106690
.
36.
Santos
FP
,
Kantarjian
H
,
Fava
C
, et al
.
Clinical impact of dose reductions and interruptions of second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukaemia
.
Br J Haematol
.
2010
;
150
(
3
):
303
-
312
.
37.
Claudiani
S
,
Apperley
JF
,
Szydlo
R
, et al
.
TKI dose reduction can effectively maintain major molecular remission in patients with chronic myeloid leukaemia
.
Br J Haematol
.
2021
;
193
(
2
):
346
-
355
.
38.
Castagnetti
F
,
Bocchia
M
,
Abruzzese
E
, et al
.
Bosutinib dose optimization in the second-line treatment of elderly CML patients: extended 3-year follow-up and final results of the best study
.
HemaSphere
.
2022
;
6
:
593
-
594
.
39.
Guilhot
F
,
Hughes
T
,
Cortes
J
, et al
.
Plasma exposure of imatinib and its correlation with clinical response in the tyrosine kinase inhibitor optimization and selectivity trial
.
Haematologica
.
2012
;
97
(
5
):
731
-
738
.
40.
Picard
S
,
Titier
K
,
Etienne
G
, et al
.
Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia
.
Blood
.
2007
;
109
(
8
):
3496
-
3499
.
41.
Yoshida
C
,
Komeno
T
,
Hori
M
, et al
.
Adherence to the standard dose of imatinib, rather than dose adjustment based on its plasma concentration, is critical to achieve a deep molecular response in patients with chronic myeloid leukemia
.
Int J Hematol
.
2011
;
93
(
5
):
618
-
623
.
42.
Rousselot
P
,
Mollica
L
,
Guilhot
J
, et al
.
Dasatinib dose optimisation based on therapeutic drug monitoring reduces pleural effusion rates in chronic myeloid leukaemia patients
.
Br J Haematol
.
2021
;
194
(
2
):
393
-
402
.
43.
Allegra
S
,
Dondi
E
,
Chiara
F
,
De Francia
S
.
Pharmacokinetics of four tyrosine kinase inhibitors in adult and paediatric chronic myeloid leukaemia patients
.
Biomedicines
.
2023
;
11
(
9
):
2478
.
44.
Wylie
AA
,
Schoepfer
J
,
Jahnke
W
, et al
.
The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1
.
Nature
.
2017
;
543
(
7647
):
733
-
737
.
45.
Manley
PW
,
Barys
L
,
Cowan-Jacob
SW
.
The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase
.
Leuk Res
.
2020
;
98
:
106458
.
46.
Hochhaus
A
,
Réa
D
,
Boquimpani
C
, et al
.
Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL
.
Leukemia
.
2023
;
37
(
3
):
617
-
626
.
47.
Naqvi
K
,
Cortes
JE
,
Luthra
R
, et al
.
Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR-ABL kinase domain mutations
.
Int J Hematol
.
2018
;
107
(
6
):
689
-
695
.
48.
US Food and Drug Administration
.
Project Optimus. Reforming the dose optimization and dose selection paradigm in oncology
. Accessed 21 January 2025. https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus.
You do not currently have access to this content.
Sign in via your Institution