Bosutinib – related pleural effusion in patients with chronic myeloid leukemia

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 alternative TKIs due to intolerance and/or failure [2]. Knowing the fact that second-generation TKIs (2GTKIs) are more potent than imatinib, 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 nonhematologic 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 dasatinib [13]. Dasatinib inhibits not only BCR-ABL1, but also it inhibits 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 compared 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).

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

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).

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 pathogenesis 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 dasatinib, 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 toxicities 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 percentage of PE increases, especially in those who experienced PE under prior dasatinib use.

As previously shown for dasatinib-associated PE, the possible 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, prevent, 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.

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, consultancies, 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.

Additional information

Funding

This paper was not funded.