A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities

Zahra Nekoukar; Minoo Moghimi; Ebrahim Salehifar

doi:10.5045/br.2021.2021117

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Blood Res 2021; 56(4):

Published online December 31, 2021

https://doi.org/10.5045/br.2021.2021117

A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities

Zahra Nekoukar¹, Minoo Moghimi¹, Ebrahim Salehifar²

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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

Received: June 17, 2021; Revised: August 15, 2021; Accepted: August 25, 2021

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.

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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

Article

Review Article

Blood Res 2021; 56(4): 229-242

Published online December 31, 2021 https://doi.org/10.5045/br.2021.2021117

A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities

Zahra Nekoukar¹, Minoo Moghimi¹, Ebrahim Salehifar²

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

Received: June 17, 2021; Revised: August 15, 2021; Accepted: August 25, 2021

Abstract

Keywords: Dasatinib, Pleural effusion, Pulmonary arterial hypertension, Chronic myeloid leukemia, Pharmacotherapy

Abstract

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Figure 1.Management of dasatinib-induced pleural effusion.

Blood Research 2021; 56: 229-242https://doi.org/10.5045/br.2021.2021117

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..

Table 2 . Cases of dasatinib-induced PAH and their pharmacotherapy..

Study	N of participants/diagnosis	Age, yr/ gender, M or F	Time from dasatinib initiation to PAH diagnosis (mo)	DASA dose, mg/day	Treatment line of DASA	Concomitant 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 wk	After 4 mo, mPAP PCWP PVR 6-MWD WHO FC
Ibrahim et al. (2019) [62]	1, CML	46, F	120	70	Second	Yes	DASA D/C Amb 5 mg daily+Tad 20 mg QD	After 1 wk, PAP
Orlandi et al. (2012) [80]	1, CML	53, F	31	100	Second	No	DASA D/C Sil 20 mg TID	After 2 mo, WHO FC PAP 6-MWD
Sano et al. (2012) [81]	1, CML	61, F	27	140	Second	Yes	DASA D/C Sil 60 mg QD	After 1 mo, WHO FC RVSP NT-pro BNP PAP
Wang et al. (2015) [82]	1, CML	33, M	63	100	Second	No	DASA D/C Sil	After 3 mo, PASP
Taçoy 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 BID	After 1 mo, NYHA FC After 9 mo, Pro BNP 6-MWD
Groeneveldt et al. (2013) [85]	1, CML	57, M	37	70	Second	No	Sil DASA D/C	The patient did not improve in NYHA FC class by sildenafil and diuretics. 3 mo after substitution DASA with NIL, NYHA FC after start NIL
Nishimori et al. (2018) [86]	1, CML	24, M	48	100	Second	Yes	DASA D/C Sil 20 mg TID+Bos 62.5 mg BID	After 1 mo, WHO FC PAP BNP
Helgeson 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 initiated	After 1 wk EPO, Dyspnea
Toya 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 BID	After 1 mo, mPAP PVR 6-MWD
Buchelli et al. (2014) [71]	1, CML	50, M	48	100	Second	Yes	DASA D/C Sil 20 mg TID	After 21 mo, WHO FC RVSP NT-pro BNP mPAP PVR 6-MWD CO CI
Seegobin et al. (2017) [98]	1, CML	52, M	48	NR	Second	Yes	DASA D/C Amb	NR, Symptoms as well as effusions improved
Daccord et al. (2018) [99]	1, CML	32, M	36	NR	Third	Yes	DASA D/C PDE-5 inhibitor+ERA	NR, NYHA FC mPAP 6-MWD PVR CI
Dumitrescu et al. (2011) [83]	1, CML	47, M	72	100	Second	Yes	DASA D/C Sil	After 2 mo, WHO FC PAP CO
Skride et al. (2017) [70]	1, CML	67, M	42	100	Second	Yes	DASA D/C Sil 20 mg TID	NR, mPAP 6-MWD PVR CO
Orlikow et al. (2019) [147]	1, CML	73, F	9	NR	Second	Yes	DASA D/C Nif 30 mg QD	After 12 mo, CO CI PVR
Hennigs et al. (2011) [84]	1, CML	70, M	32	140	Second	Yes	DASA D/C Sil 20 mg TID	After 10 mo, CO RVSP NT-proBNP 6-MWD Mpap WHO FC PVR
Hong et al. (2015) [61]	2, CML	43, M	69	140	Second	Yes	DASAD/C Sil+CCB+Diuretics	NR, NYHA FC PAP RVSP
Hong et al. (2015) [61]	2, CML	52, M	38	140	Second	Yes	DASA D/C Sil 25 mg QD	NR, RVSP BNP 6-MWD
Montani et al. (2012) [15]	3, CML	74, F	33	100	Second	Yes	DASA D/C CCB for 6 mo, then stopped	After 3 mo, NYHA FC, mPAP 6-MWT PVR BNP
		29, F	36	100	Second	Yes	DASA D/C Bos	After 2 mo, NYHA FC After 6 mo, mPAP 6-MWT PVR
		39, F	34	100	Second	Yes	DASA D/C Bos	After 1 mo, NYHA FC

Abbreviations: 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..