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Expert Opinion on Drug Safety
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ieds20
Bosutinib – related pleural effusion in patients
with chronic myeloid leukemia
Mebrure Burçak Yüzbaşıoğlu & Ahmet Emre Eşkazan
To cite this article:
Mebrure Burçak Yüzbaşıoğlu & Ahmet Emre Eşkazan (2021): Bosutinib –
related pleural effusion in patients with chronic myeloid leukemia, Expert Opinion on Drug Safety,
DOI: 10.1080/14740338.2021.1867103
To link to this article: https://doi.org/10.1080/14740338.2021.1867103
Published online: 08 Jan 2021.
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EDITORIAL
Bosutinib – related pleural effusion in patients with chronic myeloid leukemia
Mebrure Burçak Yüzbaşıoğlu
aand Ahmet Emre Eşkazan
ba
Department of Internal Medicine, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey;
bDivision of Hematology,
Department of Internal Medicine, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey
ARTICLE HISTORY Received 14 October 2020; Accepted 17 December 2020
KEYWORDS Adverse event; bosutinib; chronic myeloid leukemia; pleural effusion; tyrosine kinase inhibitor
1. Introduction
Tyrosine kinase inhibitors (TKIs) are the mainstay of the current
management of chronic myeloid leukemia (CML) [
1
]. With the
introduction of imatinib, many CML patients in chronic phase
(CML-CP) were able to achieve and maintain durable responses,
however, approximately 40% of these patients switch to
alterna-tive TKIs due to intolerance and/or failure [
2
]. Knowing the fact
that second-generation TKIs (2GTKIs) are more potent than
imati-nib, inducing more rapid and profound responses with lower rates
of transformation to advanced disease, these drugs are often
considered as a better treatment option over imatinib in the
upfront setting. Besides the potency and efficacy of these drugs,
2GTKIs can be associated with both hematologic and
nonhema-tologic toxicities [
3
,
4
], which might interfere with patient health-
related quality of life [
5
]. In addition to targeting BCR-ABL1, 2GTKIs
also inhibit other kinases and most of the nonhematologic adverse
events (AEs) of these drugs are thought to be due to these off-
target effects.
2. Dasatinib – related pleural effusions
Dasatinib is a 2GTKI, which is utilized in CML treatment both in
the upfront and salvage settings [
2
]. Lymphocytosis [
6
], pleural
effusion (PE) [
7
], and rarely pulmonary hypertension [
8
] are
among the nonhematologic AEs, which can be observed during
dasatinib therapy. Clonal NK/T lymphocytosis under dasatinib is
generally associated with favorable clinical outcomes [
6
], and it is
known that lymphocytosis may accompany PE [
9
,
10
]. It was also
shown that the generation of PE generally does not affect short-
or long-term efficacy, especially if managed properly [
11
,
12
], and
what is more, it can be associated with better responses and
long-term outcomes in CML patients receiving second-line
dasa-tinib [
13
]. Dasatinib inhibits not only BCR-ABL1, but also it
inhi-bits SRC family kinases (SFKs), c-KIT, and PDGFR-β [
14
]. The off-
target effects of dasatinib, including lymphocytosis and PE, are
most probably due to the inhibition of these kinases other than
BCR-ABL1, especially the SFKs. Dasatinib-related PE may occur
through inhibition of SFKs and PDGFR-β, which leads to vascular
endothelial permeability changes and reduction in interstitial
fluid pressure [
15–17
]. Age, advanced disease, higher daily
dose, male sex, history of cardiac disease, hypertension,
hypercholesterolemia are among the previously reported risk
factors for PE generation under dasatinib therapy [
13
,
14
,
18
,
19
].
3. Bosutinib – related pleural effusions
Bosutinib is another potent 2GTKI, which can also be used in
the first- and subsequent-lines in patients with CML [
20
]. It is
a dual Src/Abl TKI, and it exhibits minimal inhibitory activity
against c-KIT or PDGFR [
21
]. Diarrhea is the most common AE
of bosutinib therapy, and PE can also be observed in patients
receiving bosutinib [
22
], but rarely when bosutinib is used in
newly diagnosed cases and as second-line treatment following
imatinib failure.
The BELA trial [
23
] compared bosutinib 500 mg/day with
imatinib 400 mg/day in newly diagnosed, Ph-positive CML-CP
patients. None of the patients receiving bosutinib experienced
PE after a median follow-up of 13.8 months in the BELA trial.
On the other hand, the phase III BFORE trial [
24
] also
com-pared bosutinib and imatinib in the upfront setting; and with
a median exposure of 14.1 months, PE was observed in 1.9%
of the patients receiving bosutinib, none of which were grade
III or higher (
Table 1
).
In a phase I/II study, where safety and efficacy of bosutinib
was evaluated in CML patients with resistance or intolerance
to imatinib, PE of any grade was reported in 4% of patients,
with only one event of grade III/IV [
25
] (
table 1
).
On the other hand, the percentage of PE during bosutinib
therapy increases, when it is used after dasatinib therapy and
especially in those who had experienced PE under dasatinib.
When used following imatinib plus dasatinib and/or nilotinib,
20 patients (17%) receiving bosutinib had PE in the long-term
(≥48 months) evaluation [
26
] (
table 1
). Among these 20
patients who experienced PE, fourteen had a history of PE
and 19 had prior dasatinib therapy. Four patients had to quit
bosutinib due to PE [
26
].
When bosutinib was used as a fourth-line treatment, the
most common grade II–IV toxicity on prior TKIs was PE, which
was detected in 25 patients (40%) [
27
]. All of these 25 cases
had experienced PE while on dasatinib, 7 patients (28%) also
had PE during bosutinib therapy, and two had to discontinue
bosutinib due to PE (
table 1
).
CONTACT : Ahmet Emre Eşkazan, [email protected] Division of Hematology, Department of Internal Medicine, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey.
EXPERT OPINION ON DRUG SAFETY https://doi.org/10.1080/14740338.2021.1867103
In the study by Tiribelli et al. [
28
], the authors evaluated the
efficacy and safety of bosutinib in 20 patients who experienced
PE under dasatinib. After a median of 18 months of bosutinib, 15
were still on therapy and 6 (30%) developed PE (grade I in two
patients and grades II–III in four cases). Three of 4 patients with
grades II–III PE permanently stopped bosutinib [
28
] (
table 1
).
In the phase IV BYOND trial [
29
] 163 CML patients resistant or
intolerant to prior TKIs received bosutinib 500 mg/day as
the second or later treatment. With a median duration of
23.7 months of bosutinib therapy, 27 (16.6%) of the patients
had PE and 10 (6.1%) of them experienced grade ≥ III PE (
table 1
).
4. Conclusion
Putting all these together, it is not wrong to speculate that the
incidences of PE during first-line bosutinib and in patients
receiving second-line bosutinib following imatinib failure are
low. On the other hand, the percentage of PE increases, when
it is used after dasatinib therapy and especially in those who had
experienced PE under dasatinib. Both dasatinib and bosutinib
inhibit SFKs and PDGFR-β, which might play a role in the
patho-genesis of TKI-related PE. But this is not enough in most of the
cases, since dasatinib-naïve patients rarely develop PE under
bosutinib. Similar to dasatinib-associated PE, which is exudative
in more than 80% of the cases [
6
], it was shown that bosutinib-
related PE can be consistent with a lymphocytic predominant
exudate [
27
]. Lymphocytosis may accompany PE under
dasati-nib, but lymphocytosis is not observed during bosutinib therapy.
Risk factors for the generation of bosutinib-related PE should be
determined, and no relationship between PE generation and
efficacy was recognized yet for bosutinib, as was shown with
dasatinib [
13
], which could be evaluated in future studies.
5. Expert opinion
Bosutinib is a potent 2GTKI and it can be utilized in patients
with CML both in the upfront and salvage settings. Bosutinib
can be associated with hematologic and nonhematologic
toxi-cities including PE. Although there are limited cases displayed
in the literature so far, bosutinib-related PE has not been
studied thoroughly.
The incidence of PE during first-line bosutinib therapy is
low (1.9% in BFORE trial). Following imatinib, the rate of PE
under second-line bosutinib is still low; however, the
percen-tage of PE increases, especially in those who experienced PE
under prior dasatinib use.
As previously shown for dasatinib-associated PE, the
possi-ble molecular mechanisms and the risk factors for bosutinib-
related PE should be identified in the future. If the mechanism
and the risk factors of PE development under bosutinib are
clearly understood, maybe it would be easier to predict,
pre-vent, and/or manage this toxicity especially in those receiving
bosutinib in the salvage setting.
In addition, we think that planning studies evaluating the
possible relationship between the generation of bosutinib-
related PE and bosutinib treatment response and exploring
the impact of bosutinib-associated PE on quality of life are of
great interest.
Table 1. Bosutinib studies and data on pleural effusion generation (DAS, dasatinib; IM, imatinib; NIL, nilotinib; NR, not reported; PE, pleural effusion). aFirst author, year, reference number Line of bosutinib therapy TKI(s) prior to bosutinib Number of patients, n Number of patients receiving dasatinib prior to bosutinib, n (%) Daily dose of bosutinib Median duration of bosutinib use, months Median time to PE generation under bosutinib therapy, months Patients with PE (all grades), n (%) Patients with grades III–IV PE, n (%) Patients with PE + prior dasatinib use, n (%) Patients who discontinued bosutinib due to PE, n (%) BELA, 2012, [ 23 ] 1 st None 248 None 500 mg 13.8 NR NR NR None NR BFORE, 2017, [ 24 ] 1 st None 268 None 400 mg 14.1 NR 6 (1.9) None None None Cortes, 2011, [ 25 ] 2 nd IM (n = 288) 288 None 500 mg 24.2 NR 12 (4) 1 (0.3) None None Cortes, 2017, [ 26 ] 3 rd , 4 th IM+DAS (n = 88) IM+NIL (n = 26) IM+NIL±DAS (n = 5) 119 93(78) 500 mg 8.6 NR 20 (17) NR 19 (16) 4 (3) García-Gutiérrez, 2018, [ 27 ] 4 th IM+DAS+NIL (n = 62) 62 62 (100) 500 mg 9.1 NR 7 (11) NR 7 (11) 2 (3.2) Tiribelli, 2019, [ 28 ] 2 nd , 3 rd , 4 th DAS (n = 4) IM+DAS (n = 13) IM+NIL+DAS (n = 3) 20 20 (100) 500 mg (n = 4) 300 mg (n = 6) 200 mg (n = 10) 13 3 6 (30) 4 (20) 6 (30) 3 (15) BYOND, 2020, [ 29 ] 2 nd , 3 rd , 4 th IM (n = 35) DAS (n = 5) NIL (n = 6) IM+NIL+DAS (n = 49) 156 95 (60.9) 500 mg 23.7 NR 27 (16.6) 10 (6.1) NR NR 2 EDITORIALFunding
This paper was not funded.
Declaration of interests
MB Yüzbaşıoğlu has no conflict of interest to declare. AE Eşkazan has received advisory board honoraria from Novartis, and Pfizer and he also received speaker bureau honoraria from Novartis, Bristol-Myers Squibb, and Pfizer outside the present study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consul-tancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
A reviewer on this manuscript has disclosed that they have received honoraria and speaker fees from Bristol-Myers Squibb and Pfizer Inc. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
ORCID
Ahmet Emre Eşkazan http://orcid.org/0000-0001-9568-0894
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