Dasatinib-related pleural effusion and lymphocytosis rates are different between adult and pediatric patients with Philadelphia chromosome-positive leukemias: are age and comorbidities only to blame?

KEYWORDS:

• Chronic myeloid leukemia
• CML
• dasatinib
• lymphocytosis
• pleural effusion
• tyrosine kinase inhibitor

1. Introduction

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder, which is responsible for the 15% of newly diagnosed leukemia cases in adults [1]. The median age of diagnosis is 60–65 years for the adult population and 11–12 years for the pediatric population [2]. However, CML is quite rare in children, and accounts for only 2% of all leukemias in children <15 years and 9% of all leukemias in adolescents between 15 and 19 years [3].

Dasatinib is a second-generation tyrosine kinase inhibitor (2GTKI), which is approved for chronic phase CML (CML-CP) both in the salvage and upfront settings (100 mg QD) following CA180 – 034 [4] and DASISION [5] trials, respectively. It is also approved for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) [6].

Being an efficacious 2GTKI, dasatinib has been shown to be associated with both hematologic and non-hematologic toxicities [7]. The most common non-hematologic adverse events (AEs) include bleeding diathesis, QTc prolongation, and fluid retention – particularly pleural effusion (PE) [7]. Besides the inhibition of BCR::ABL1, dasatinib also inhibits other signaling pathways such as c-KIT, PDGFR-β, and SRC family kinases (SFKs) and some of the ‘off-target’ effects of the drug can be attributed to the inhibition of these kinases [8,9].

PE is a well-recognized AE of dasatinib among adult CML population, the incidence of PE in dasatinib-treated adult patients differs between 30% and 40% [8,10]. On the other hand, PE is extremely rare among children with Ph⁺ leukemias receiving dasatinib [2].

In this paper, we try to elucidate the possible factors that can be responsible for the different rates of PE and lymphocytosis observed among adults and children with Ph⁺ leukemias together with the possible mechanisms that might play a role in the development of these AEs.

2. Dasatinib-related PE and lymphocytosis in adult patients with CML and Ph⁺ ALL

CA180 – 034 is a phase III study of dasatinib, which was conducted in patients with CML-CP who are resistant or intolerant to imatinib [4], and DASISION is the phase III study comparing dasatinib 100 mg/day with imatinib 400 mg/day in newly diagnosed patients with CML-CP [5]. In the CA180 – 034 trial, after a median treatment duration of 8 months, the rate of dasatinib-related PE was 7% in the 100 mg QD arm [4]. Similarly, during the first year of DASISION trial, the rate of dasatinib-related PE was 10% [5]. As the duration of dasatinib exposure extends, PE rates increase, and supporting this, the 5- and 7-year updates of the DASISION and CA180 – 034 studies showed that, the rates of dasatinib-related PE were 28% and 33%, respectively [11,12]. Moreover, in these trials, 6% and 7% of CML patients discontinued dasatinib due to PE.

Various risk factors were reported to be associated with dasatinib-related PE, including, age, advanced-phase disease, history of cardiac disease, hypertension, higher daily dose, anemia, longer disease duration, prior interferon therapy, autoimmune disease, hypercholesterolemia, and skin rash during imatinib treatment [13,14]. Lymphocytosis can be observed under dasatinib with different prevalences in different studies varying between 22% and 45% [8], which can be due to a clonal T-cell expansion with typical large granular lymphocyte (LGL) morphology [15]. Also, it was reported that lymphocytosis can accompany PE [8,15]. However, in a recent multivariate analysis, although some of the risk factors including heart failure and anemia were not included, lymphocytosis was not found to be significantly associated with the development of PE, and advanced age was defined as the only significant risk factor for PE generation under dasatinib among the previously described factors [16].

Although there are conflicting results in the literature regarding the association of PE and treatment responses and outcomes under dasatinib [8,17,18], the recently published multivariate analysis showed that, achievement of MMR and MR^4.5 was found to be correlated with a higher risk of developing PE [16]. This might be because patients without optimal responses may have discontinued dasatinib earlier than those with a response, and since patients doing well on dasatinib remain on treatment longer, they might be more likely to develop PE [16]. However, development of PE was not associated with a long-term survival benefit.

3. Dasatinib-related PE in pediatric patients with CML and Ph⁺ ALL

CML is rare, and usually more aggressive in children [3]. There are several unique characteristics of CML in children, adolescents, and young adults, compared to adults. The difference between pediatric and adult CML can be attributed to host factors as well as CML cell biology [3], for example, ASXL1 mutation is detected in around 60% of pediatric patients compared to only 15% of adults [19].

In a phase I trial of dasatinib enrolling 53 children, three (5.7%) developed PE, two were grade 1 and one was grade 2 [20]. Following this trial, dasatinib 60 mg/m² and 80 mg/m² once-daily dosing were selected for phase II studies.

CA180-226/NCT00777036 was a phase II, open-label, and non-randomized prospective trial for children receiving dasatinib [21]. Children with CML-CP received dasatinib 60 mg/m² once daily, while dasatinib was administered at a dose of 80 mg/m² once daily in advanced-phase disease. In this trial, PE was not detected.

In another study, patients with newly diagnosed Ph⁺ ALL received dasatinib 60 mg/m² per day continuously starting at induction day 15 [22]. None of the patients experienced PE during the follow-up.

4. Possible pathogenetic mechanisms of dasatinib-related PE and lymphocytosis

PE might be associated with an immune-mediated mechanism by the inhibition of SFKs and PDGFR-β. Inhibition of PDGFR-β may lead to a reduction in interstitial fluid pressure, while inhibition of SFKs may lead to vascular endothelial permeability changes [10].

Dasatinib was shown to increase the production of mitochondrial reactive oxygen species (ROS) in rats [23]. Consequently, increased oxidative stress disorganizes cell–cell connections and causes endothelial dysfunction in the lung by disrupting the structure and function of junctional proteins in both endothelial and epithelial cells of rats. This mechanism might also cause PE in humans receiving dasatinib. Additionally, the fact that very low dasatinib concentrations (<10 nM) protect the endothelial barrier is in line with this hypothesis [24].

BCR::ABL1 negative LGL lymphocytosis could result from an expansion of a preexisting memory cell clone due to dasatinib inhibition of immune regulatory kinases, as the marked lymphocytes were absent in the patient samples taken before dasatinib treatment [24]. Furthermore, CD8⁺ T-cells isolated from patients with LGL expansion had increased cytotoxicity against pulmonary non-transformed endothelial cells [24,25]. Interestingly, the percentage of regulatory T-cells in peripheral blood was shown to be significantly lower in the patients with LGL lymphocytosis compared to healthy controls or patients without LGL lymphocytosis [15]. These phenomena may contribute to a dysregulation in the immune system and may result in a disruption among the endothelial cells of the lung caused by CD8⁺ T-cells with enhanced cytotoxicity.

Expansion of LGLs can be observed during a primary immune response against viral antigens, such as cytomegalovirus (CMV) [25]. On the other hand, in a large proportion of CMV⁺ patients, regardless of CMV reactivation, CMV-associated adaptive NK cells are demonstrated to enhance during dasatinib therapy. Furthermore, these cells can also be observed at the moment of the leukemia diagnosis [26]. Therefore, expansion of LGLs under dasatinib therapy may occur due to exacerbation of these differentiated NK cells through subclinical CMV reactivation.

5. The hypothetical contributing factors to the discrepancy of PE and lymphocytosis rates between adults and children

TKIs have a high therapeutic index, and thus, these drugs are administered at fixed doses [27]. However, it has been shown that there can be a high inter-individual variability [28]. Supporting the findings in the animal model [23], lower daily doses of dasatinib is associated with lower PE risk [29]. The OPTIM-dasatinib study also showed that therapeutic drug monitoring (TDM) reduced the cumulative incidence dasatinib-related PE without sacrificing efficacy [30]. Dasatinib dose was reduced in some patients having a dasatinib concentration (C)min ≥3 nmol/l resulting in the reduction of dasatinib-induced toxicities. Interestingly, median age of patients with a high (C)min was significantly higher than that of cases with a low (C)min (59 vs. 49.4 years, p < 0.001) [30]. These results and the previous findings [31] suggest that therapeutic window for older patients may be narrower relative to younger (i.e. pediatric) cases, resulting in the increased risk of PE in elderly patients.

Lymphocytosis under dasatinib treatment was reported far less in children compared to the adults [2]. The kinase(s) targeted by dasatinib, resulting in lymphocyte mobilization, are unknown. Eventually, the off-target inhibitions by dasatinib may not affect children as in adults based upon different functions of immune mediators, and cytotoxic T- and NK-cells of the pediatric immune system.

The inhibition of PDGF signaling and exacerbation of the production of mitochondrial ROS by dasatinib could lead to altered functions on fibroblasts, vascular smooth muscle cells and capillary endothelial cells. Moreover, due to divergences in PDGF, or aging-related differences in fibroblasts in the lung together with an increase in oxidative stress may cause alterations in the functions of the pulmonary pleura resulting in the fluid retention [32,33]. However, minor levels of aging-related fibrotic differences and lower oxidative stress may provide lower rates of PE under dasatinib in children, together with the possible different acting mechanisms of PDGF. In addition, during childhood, SFKs, c-KIT, and PDGFR-β may exist in different structures with identical functions and dasatinib may not inhibit these forms of tyrosine kinase families. Moreover, expression of these TKs might be lower in children compared to adults, consequently the minor expressions might cause lower rates of PE.

Lymphocytosis was shown to be correlated with some of the dasatinib-related side effects particularly PE and colitis. PE may have an immune-mediated etiology in patients receiving dasatinib [34]. There are clear differences in autoimmune diseases in adults and children [35]. Some of these may contribute to the different rates of AEs in dasatinib-treated individuals.

In addition to these mechanisms, some preventive substances on the pediatric pleura may exist against PE as in the regulation of thermogenesis and homeostasis through thermogenin protein in the brown adipose tissue [36]. Structures like thermogenin may be found in pediatric pleura to prevent the formation of PE and these structures may vanish overtime, causing pleura vulnerable to PE generation under dasatinib.

Last but not the least, although initial observations showed that rates of dasatinib-related PE were very low among children receiving dasatinib, most of the studies in children with dasatinib have a shorter follow-up than that of the adult trials. As PE incidence increases over time, a longer follow-up period may be needed to understand the exact incidence of dasatinib-related in children.

6. Conclusion

The rate of PE under dasatinib is higher in adult CML patients than observed in pediatric cases. LGL lymphocytosis may accompany PE in adults under dasatinib, however, similarly to PE, LGL lymphocytosis has not been described in children under dasatinib. Although advanced age and comorbidities are thought to be the reasons for this disparity, we think there is still much to be done in understanding the mechanism of PE under dasatinib. At least one of the hypothetical explanations discussed in this paper might be the underlying mechanism causing the discrepancy between the rates of dasatinib-related PE and lymphocytosis observed in adult and pediatric CML cases, where further research is warranted.

Declaration of Interest

A E Eşkazan has received advisory board and speaker bureau honoraria from Novartis, Bristol-Myers Squibb, and Pfizer. G N Özdemir has received advisory board and speaker bureau honorarium from Pfizer. 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 apart from those disclosed.

Reviewer Disclosures

A reviewer on this manuscript has disclosed that they have received honoraria and speaker fees from Bristol, Novartis, Otsuka Pharmaceutical, Ono Pharmaceutical, and Pfizer. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.