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Blood Res 2021; 56(4):
Published online December 31, 2021
https://doi.org/10.5045/br.2021.2021117
© The Korean Society of Hematology
A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities
Correspondence to : Ebrahim Salehifar, Ph.D.
Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute, Department of Clinical Pharmacy, Mazandaran University of Medial Scienses, Sari Mazandaran 48175-861, Iran
E-mail: Esalehifar@mazums.ac.ir
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Chronic myeloid leukemia (CML), a myeloproliferative disorder caused by the over activity of BCR-ABL1 (breakpoint cluster region-Abelson), has been successfully treated by Tyrosine kinase inhibitors (TKIs). While imatinib is known as the first-line treatment of CML, in some cases other TKIs including dasatinib, nilotinib, bosutinib, and ponatinib may be preferred. Dasatinib, a second-generation TKI, inhibits multiple family kinases including BCR-ABL, SRC family kinases, receptor kinases, and TEC family kinases. It is effective against most imatinib-resistant cases except T315I mutation. Despite the superiority of dasatinib in its hematologic and cytogenetic responses in CML compared to imatinib, its potentially harmful pulmonary complications including pleural effusion (PE) and pulmonary arterial hypertension (PAH) may limit its use. Appropriate management of these serious adverse reactions is critical in both improving the quality of life and the outcome of the patient. In this narrative review, we will scrutinize the pulmonary complications of dasatinib and focus on the management of these toxicities.
Keywords Dasatinib, Pleural effusion, Pulmonary arterial hypertension, Chronic myeloid leukemia, Pharmacotherapy
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Review Article
Blood Res 2021; 56(4): 229-242
Published online December 31, 2021 https://doi.org/10.5045/br.2021.2021117
Copyright © The Korean Society of Hematology.
A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities
Zahra Nekoukar1, Minoo Moghimi1, Ebrahim Salehifar2
1Department of Clinical Pharmacy, Mazandaran University of Medical Sciences, 2Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute, Department of Clinical Pharmacy, Mazandaran University of Medial Scienses, Sari, Iran
Correspondence to:Ebrahim Salehifar, Ph.D.
Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute, Department of Clinical Pharmacy, Mazandaran University of Medial Scienses, Sari Mazandaran 48175-861, Iran
E-mail: Esalehifar@mazums.ac.ir
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Chronic myeloid leukemia (CML), a myeloproliferative disorder caused by the over activity of BCR-ABL1 (breakpoint cluster region-Abelson), has been successfully treated by Tyrosine kinase inhibitors (TKIs). While imatinib is known as the first-line treatment of CML, in some cases other TKIs including dasatinib, nilotinib, bosutinib, and ponatinib may be preferred. Dasatinib, a second-generation TKI, inhibits multiple family kinases including BCR-ABL, SRC family kinases, receptor kinases, and TEC family kinases. It is effective against most imatinib-resistant cases except T315I mutation. Despite the superiority of dasatinib in its hematologic and cytogenetic responses in CML compared to imatinib, its potentially harmful pulmonary complications including pleural effusion (PE) and pulmonary arterial hypertension (PAH) may limit its use. Appropriate management of these serious adverse reactions is critical in both improving the quality of life and the outcome of the patient. In this narrative review, we will scrutinize the pulmonary complications of dasatinib and focus on the management of these toxicities.
Keywords: Dasatinib, Pleural effusion, Pulmonary arterial hypertension, Chronic myeloid leukemia, Pharmacotherapy
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Table 1 . FDA approved pharmacological classes for treatment of PAH..
Class Drug Rout of administration Dose Prostacyclin derivatives Epoprostenol IV Initial dose of 2 ng kg-1min-1 Iv infusion, titrated by 1–2 ng kg-1min-1q 15 min if tolerated Iloprost Inhaled 2.5 μg inhaled, if tolerated then 5 μg, 6–9 times a day PRN; Maintenance: 2.5–5 μg dose-1 (max: 45 μg daily) Treprostinil PO PO: 0.125 mg TID or 0.25 mg BID, titrated by 0.125 mg TID every 3–4 days Continuous IV or SC infusion IV or SC infusion: 1.25 ng kg-1min-1 titrated by no more than 1.25 ng kg-1min-1per wk based on clinical response; after 4 wk, titrated by no more than 2.5 ng kg-1min-1 per wk based on clinical response Endothelin receptor antagonists Bosentan Oral 125 mg twice daily Ambrisentan Oral 5 or 10 mg once daily Macitentan Oral 10 mg once daily Phosphodiesterase type-5 inhibitors Sildenafil Oral 20 mg TID IV Injection Tadalafil Oral 40 mg once daily Soluble cGMP stimulators Riociguat Oral 0.5–1.0 mg TID (titrated by 0.5 mg every 2 wk as tolerated to maximum dose 2.5 mg) Prostacyclin receptor agonists Selexipag Oral 200 mg twice daily, titrated as tolerated to maximum dose of 16,000 mg twice daily Abbreviations: cGMP, Cyclic guanosine monophosphate; FDA, Food and Drug Administration; h, hour; IV, Intravenous; PAH, pulmonary arterial hypertension; SC, subcutaneous..
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Table 2 . Cases of dasatinib-induced PAH and their pharmacotherapy..
Study N of participants/diagnosis Age, yr/
gender, M or FTime from dasatinib initiation to PAH diagnosis (mo) DASA dose, mg/day Treatment
line of DASAConcomitant PE Intervention Improved items Jose et al . (2017) [64]1, CML 61, M 26 140 Second Yes DASA D/C
Tad 20 mg QD and Amb 5 mg daily. The Tad was up-titrated over a period of 4 wk to 40 mg QD, followed by an up titration of Amb to 10 mg QD over the following 4 wkAfter 4 mo,
mPAP
PCWP
PVR
6-MWD
WHO FCIbrahim et al . (2019) [62]1, CML 46, F 120 70 Second Yes DASA D/C
Amb 5 mg daily+Tad 20 mg
QDAfter 1 wk,
PAPOrlandi et al . (2012) [80]1, CML 53, F 31 100 Second No DASA D/C
Sil 20 mg
TIDAfter 2 mo,
WHO FC
PAP
6-MWDSano et al . (2012) [81]1, CML 61, F 27 140 Second Yes DASA D/C
Sil 60 mg QDAfter 1 mo,
WHO FC
RVSP
NT-pro BNP
PAPWang et al . (2015) [82]1, CML 33, M 63 100 Second No DASA D/C
SilAfter 3 mo,
PASPTaçoy et al .(2015) [94]1, ALL 50, M 24 140 Second Yes DASA D/C
Bos 62.5 mg BID and in 2 wk increased to 125 mg BIDAfter 1 mo,
NYHA FC
After 9 mo,
Pro BNP
6-MWDGroeneveldt et al . (2013) [85]1, CML 57, M 37 70 Second No Sil
DASA D/CThe patient did not improve in NYHA FC class by sildenafil and diuretics.
3 mo after substitution DASA with NIL,
NYHA FC after start NILNishimori et al . (2018) [86]1, CML 24, M 48 100 Second Yes DASA D/C
Sil 20 mg
TID+Bos 62.5 mg BIDAfter 1 mo,
WHO FC
PAP
BNPHelgeson et al . (2016) [115]1, CML 30, F 36 NR Second Yes DASA D/C
EPO 20 ng kg-1 min-1 for 5 mo, then EPO 4 ng kg-1 min-1 for 5 mo and discontinuation with mild rebound of MPAP, therefore, Sil was initiatedAfter 1 wk EPO,
DyspneaToya et al . (2019) [104]1, CML and scleroderma 63, M 36 100 Second Yes DASA D/C
Tad 40 mg QD+Mac 10 mg QD+Sel 1.2 mg
BIDAfter 1 mo,
mPAP
PVR
6-MWDBuchelli et al . (2014) [71]1, CML 50, M 48 100 Second Yes DASA D/C
Sil 20 mg TIDAfter 21 mo,
WHO FC
RVSP
NT-pro BNP
mPAP
PVR
6-MWD
CO
CISeegobin et al . (2017) [98]1, CML 52, M 48 NR Second Yes DASA D/C
AmbNR,
Symptoms as well as effusions improvedDaccord et al . (2018) [99]1, CML 32, M 36 NR Third Yes DASA D/C
PDE-5 inhibitor+ERANR,
NYHA FC
mPAP
6-MWD
PVR
CIDumitrescu et al . (2011) [83]1, CML 47, M 72 100 Second Yes DASA D/C
SilAfter 2 mo,
WHO FC
PAP
COSkride et al . (2017) [70]1, CML 67, M 42 100 Second Yes DASA D/C
Sil 20 mg TIDNR,
mPAP
6-MWD
PVR
COOrlikow et al . (2019) [147]1, CML 73, F 9 NR Second Yes DASA D/C
Nif 30 mg QDAfter 12 mo,
CO
CI
PVRHennigs et al . (2011) [84]1, CML 70, M 32 140 Second Yes DASA D/C
Sil 20 mg TIDAfter 10 mo,
CO
RVSP
NT-proBNP
6-MWD
Mpap
WHO FC
PVRHong et al . (2015) [61]2, CML 43, M 69 140 Second Yes DASAD/C
Sil+CCB+DiureticsNR,
NYHA FC
PAP
RVSP52, M 38 140 Second Yes DASA D/C
Sil 25 mg QDNR,
RVSP
BNP
6-MWDMontani et al . (2012) [15]3, CML 74, F 33 100 Second Yes DASA D/C
CCB for 6 mo, then stoppedAfter 3 mo,
NYHA FC,
mPAP
6-MWT
PVR
BNP29, F 36 100 Second Yes DASA D/C
BosAfter 2 mo,
NYHA FC
After 6 mo,
mPAP
6-MWT
PVR39, F 34 100 Second Yes DASA D/C
BosAfter 1 mo,
NYHA FCAbbreviations: 6-MWD, 6-minute walk distance; ALL, acute lymphoblastic leukemia; Amb, ambrisentan; BID, two times a day; BNP, b-type natriuretic peptide; Bos, bosentan; CCB, calcium channel blocker; CI, cardiac index; CML, chronic myeloid leukemia; CO, cardiac output; DASA, dasatinib; D/C, discontinuation; EPO, epoprostenol; ERA, endothelin receptor-1 antagonist; F, female; FC, functional classification; M, male; Mac, macitentan; mPAP, mean pulmonary artery pressure; Nif, nifedipine; NIL, nilotinib; NT-pro BNP, N-terminal pro b-type natriuretic peptide; NYHA, New York heart association; PAH, pulmonary arterial hypertension; PAP, pulmonary artery pressure; PASP, pulmonary artery systolic pressure; PCWP, pulmonary capillary wedge pressure; PDE-5, phosphodiesterase-5; PE, pulmonary embolism; Pro BNP, pro hormone b-type natriuretic peptide; PVR, pulmonary vascular resistance; QD, once a day; RVSP, right ventricular systolic pressure; Sel, selexipag; Sil, sildenafil; Tad, tadalafil; TID, three times a day; WHO, world health organization; WU, wood unit..
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