Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with Philadelphia chromosome t (9;22)(q34;q11) and/or the
The disease is defined as 3 phases: chronic phase (CP), accelerated phase (AP), and blast phase (BP). Uncontrolled chronic phase will lead to accelerated and blast phases of CML within 3 to 5 years . The diagnosis of CML is based on the detection of the Philadelphia chromosome, the
Previously, recombinant interferon-alfa, low dose of cytarabine and allogeneic hematopoietic cell transplantation (HCT) were used as standard of care for CML . HCT may be associated with a definite cure but complications and related mortality limits the utility . Over the past 2 decades, patients with
Imatinib, nilotinib, dasatinib, bosutinib, and ponatinib are TKIs approved by the US Food and Drug Administration (FDA) for treatment of patients with CML. These agents are different in efficacy and toxicity. Selection of a TKI depends on particular clinical feature and toxicity profile of each agent and also patient’s age, underlying diseases, and the goal of treatment [4, 9]. Imatinib 400 mg daily is the gold standard for treatment of CML. In patients who did not achieve clinical response or those did not tolerate treatment, higher doses (600 or 800 mg daily) is not recommended due to more adverse effects without improvement of clinical outcomes. Some second generation TKIs including nilotinib (300 mg twice daily) and dasatinib (100 mg once daily) may be used as the first line treatment [10, 11]. Efficace
The incidence of pulmonary toxicities of TKIs is less than 1% . The most reported toxicities were pulmonary artery hypertension (PAH), pleural effusion (PE), interstitial lung disease (ILD), pulmonary edema, chylothorax, cough, pneumonitis, bronchospasm and upper respiratory tract infection [15-21]. Most of these adverse reactions need discontinuing treatment and initiating a medical intervention . Although PAH was not reported by using imatinib or nilotinib and rarely reported with lapatinib, ponatinib, and bosutinib, it is a known complication of dasatinib [23-27]. PE mostly occurres following treatment with dasatinib and bosutinib which could alter the patient’s compliance to the therapy. TKIs associated ILD is less likely to happen in which different histological markings lead to various clinical presentations . In the following sections, we will focus on dasatinib-induced PE and PAH as two major pulmonary toxicities and their management will be discussed.
We searched scientific databases for indexed studies on PubMed and Google-scholar based on the terms: “dasatinib”, “chronic myeloid leukemia”, “tyrosine kinase inhibitors”, “pulmonary arterial hypertension”, “pleural effusion”, and “pulmonary toxicity”. The Boolean operators (AND/OR) were also used to combine search terms. All case reports, case series, clinical trials, and relevant review articles were selected without limitation of the year of publication. Studies in languages other than English and those with only abstracts available were excluded.
Dasatinib, an oral potent second generation TKI, was approved in 2010 by FDA for management of newly diagnosed CML patients who are in chronic phase (100 mg once daily), and any phases of disease that is resistant or intolerant to previous treatment (70 mg twice daily) . It is also used with 70 mg twice daily regimen in
Despite a dramatic improvement of survival of CML patients following approval of TKIs, various early and late adverse effects including gastrointestinal, cardiovascular, endocrine, hematologic and pulmonary toxicities were reported [36-39]. Gastrointestinal adverse effects include nausea and vomiting, diarrhea, abdominal pain, hemorrhagic colonic ulcers, acute hepatitis, anorexia, dyspepsia, and gastrointestinal bleeding as a result of platelet dysfunction. The mucosal inflammation including mucositis/stomatitis, constipation, acute pancreatitis, abdominal distension and colitis were seen in less than 10% of the cases. Endocrine disorders were gynecomastia, irregular menses, hypoglycemia, hyperglycemia and increased triglyceride and cholesterol levels [30, 32, 38, 40-42]. The most common cardiovascular effects were fluid retention, pericardial effusion, and to a lesser extent, cardiac dysfunction including cardiomegaly, angina, congestive heart failure and cardiac dysrhythmia including tachycardia and QTc prolongation [43-46]. Anemia, thrombocytopenia and neutropenia were reported with dasatinib which are most observed in Ph+ ALL patients and advanced phase CML patients compared to chronic phase. Thrombo-cytopenia is more clinically substantial and may result in central nervous system hemorrhage and gastrointestinal bleeding so that it is recommended to administrate dasatinib with caution in those receiving anticoagulation or antiplatelet agents [38, 46].
Dasatinib-induced pleural effusion: Pleural Effusion (PE) is a lymphocyte-predominant exudate, which has been observed with all
Dasatinib-induced chylothorax is a rare pulmonary adverse effect that is a subgroup of PE and defined as triglycerides and cholesterol concentrations of pleural ﬂuid more than 110 mg dL-1 (1.24 mmol L-1) and less than 200 mg dL-1 (5.18 mmol L-1), respectively . Chylothorax results from obstruction or disruption of thoracic duct which leads to leakage of chyle into pleural space . Despite aforementioned explanations, the exact molecular mechanism of PE and chylothorax has not been elucidated and needs further investigation [54, 57].
Dasatinib-induced pulmonary arterial hypertension: Pulmonary Arterial Hypertension (PAH) is one of the most severe pulmonary toxicities of TKIs and was mostly reported with dasatinib [14, 58]. PAH is a rare complication (0.45%) which is defined as increased mean pulmonary arterial pressure (mPAP) >25 mmHg at rest or >30 mmHg by exercising in the absence of elevated pulmonary capillary wedge pressure (PCWP) and pulmonary vascular resistance (PVR) >3 woods units that leads to right ventricular and progressively left ventricular failure . In the presence of dyspnea, atypical chest pain, fatigue or unexplained syncope, Chest X-Ray (CXR) or trans-thoracic echocardiography (TTE) should be used and if PAH was proposed, right heart catheterization (RHC) should be performed to confirm the diagnosis . On the basis of RHC results, PAH is determined as elevated right ventricular systolic pressure (RVSP) and/or pulmonary arterial systolic pressure above 40 mmHg. In addition, Toya
Since the widespread use of TKIs has made a tremendous change in the treatment of CML, the complications associated with these medications need to be identified and managed appropriately.
As noted above, treatment of CML with dasatinib was associated with a high prevalence and recurrence rate of PE. In a multivariate analysis, the most significant risk factor for incidence of PE was the patient’s age . Dasatinib-induced PE has a clinically ameliorative nature in most cases. Dose interruption, dose reduction and drug therapy have been suggested for PE management [50, 54]. Based on radiographic features, patients with class 1 PE do not need any intervention. In patients who are categorized in class 2 or more and are asymptomatic, treatment should be interrupted and diuretics may be started in the presence of fluid retention. Therapy of CML should be resumed after resolution of effusion. Dose should be reduced in the case of further episodes. In symptomatic patients with PE≥class 2 or asymptomatic patients with PE≥class 3, dasatinib should be discontinued and corticosteroids (prednisone 40 mg daily for four days) should be initiated. Therapeutic thoracentesis should also be performed and the pleural fluid should be investigated to rule out other effusion causes. Dasatinib could be reintroduced in the case of effusion resolution. In symptomatic patients with PE≥class 2 or asymptomatic patients with PE≥class 3, dasatinib should be discontinued with recurrent PE .
Another approach for treatment is based on a different classification of PE severity. Cortes
Based on radical scavenging property, N-acetylcysteine (NAC) was effective in preventing increased pulmonary endothelial permeability which is one of the underlying causes of PE .
Pulmonary arterial hypertension (PAH) is a life threatening complication of long-term therapy with dasatinib, especially in the presence of PE. PAH may lead to right ventricular failure if left untreated [70, 71]. Reports represent low mortality rate due to dasatinib-induced PAH. Early diagnosis of PAH and cessation treatment with dasatinib are strongly recommended . Discontinuation of dasatinib leads to notable symptomatic improvement, however this may not be associated with a complete hemodynamic recovery [64, 72]. Phosphodiesterase type-5 inhibitors, prostacyclin derivatives, and endothelin receptor antagonists (ERAs) are FDA approved pharmacological classes used for treatment of PAH. Riociguat, an oral soluble guanylate cyclase stimulator, is also another choice for management of PAH. A prostacyclin receptor agonist, selexipag has been approved by the FDA for PAH in 2015 . Different FDA approved pharmacologic drugs, routes of administration and doses have been presented in Table 1. Several reports have been published according to the management of dasatinib-induced PAH. Clinical characteristics of patients, the intervention and outcome of therapy have been presented in Table 2.
Phosphodiesterase-5 inhibitors: Phosphodiesterase-5 (PDE-5) is the dominant isotype of PDE in the pulmonary vascular smooth cell muscles which is upregulated in PAH. It metabolizes cyclic guanosine monophosphate; hence PDE-5 inhibitors could induce nitric oxide-mediated vasodilation and possibly have some anti-proliferative effects [74, 75]. Sildenafil, tadalafil, and vardenafil have been studied in PAH and only sildenafil and tadalafil which are different in chemical structure have been approved by FDA for treatment of PAH [76, 77]. Due to the longer half-life of tadalafil (17.5 hr) as compared to that of sildenafil (∼4 hr), it is prescribed once daily whereas the other is taken 3 times per day . They are similar in adverse effects profile and both tadalafil and sildenafil were associated with beneficial effects in exercise tolerability, hemodynamic parameters and clinical status of dasatinib-induced PAH .
WHO functional class, 6-MWD, mPAP, and clinical worsening were assessed in 278 PAH patients who received either placebo or sildenafil (20 mg, 40 mg, or 80 mg) orally 3 times daily for 12 weeks. A notable improvement in all mentioned values was achieved after all doses. Since complete inhibition of PDE-5 at the dose of 20 mg 3 times was achieved, dose escalation to get much more response is not reasonable . The efficacy of sildenafil in dasatinib-induced PAH has been evaluated in numerous case reports [80-84]. Groeneveldt and coworkers reported a case with mPAP of 55 mmHg and NYHA functional class 4 who had no improvement in NYHA functional class after being treated with sildenafil. Actually, dasatinib was not discontinued in spite of emphasis on stopping treatment immediately after the appearance of PAH [59, 85]. Sildenafil was also evaluated in combination with bosentan (20 mg TDS and 62.5 mg BD, respectively) in a patient with mPAP of 37 mmHg, WHO functional class 2 and BNP 685 pg mL-1. All variables improved after 6 months of treatment . In another case, right ventricle systolic pressure (RVSP) was reduced from 71 mmHg to 55 mmHg after treatment with 25 mg once daily sildenafil. Re-challenging of dasatinib after reduction of RVSP was associated with a faster incidence of PAH appearance .
In a large trial, tadalafil, another PDE-5 inhibitor, was investigated in doses of 2.5 mg, 10 mg, 20 mg and 40 mg once daily for management of PAH in 405 patients. Borg dyspnea score (BDS), 6-MWD, clinical worsening, health-related quality of life and WHO functional class were assessed. Only the 40 mg/day dose showed statistically significant improvement in all of measurements except WHO functional class and BDS . Until today there is no study to evaluate tadalafil monotherapy in dasatinib-induced PAH, as it was used in combination with other drugs. An abstract published in January 2020 in European Heart Journal Cardiovascular Imaging showed that combination of tadalafil and ambrisentan is effective in improvement of systolic PAP and secondary myocardium changes caused by dasatinib . Two other different dosage regimens of tadalafil and ambrisentan combination were used: “tadalafil (40 mg daily)+ambrisentan (10 mg daily)” and “tadalafil (20 mg daily)+ambrisentan (5 mg daily)”. Both revealed improvement in pulmonary symptoms, mPAP, 6-MWD, BNP level and WHO functional class [62, 64].
Endothelin receptor-1 antagonists (ERAs): Bosentan, ambrisentan and macitentan are ERAs approved by FDA for management of PAH. Bosentan, the oldest member of ERAs is a non-selective competitive antagonist of endothelin receptor-1 (ET-1) that irreversibly blocks both ET-1A and ET-1B [89, 90]. The efficacy of bosentan in PAH was evaluated in BREATHE-1 study. Patients were treated with 62.5 mg BD bosentan for 4 weeks and then randomly assigned to receive 125 mg or 250 mg twice daily for a minimum of additional 12 weeks. Amelioration of exercise capacity as primary outcome of the trial was seen in both bosentan-treated groups (
Among above mentioned three agents, ambrisentan is a selective blocker of ET-1A which is responsible for smooth muscle cells vasoconstriction. The incidence of liver impairment and drug interactions of ambrisentan was lower but it was associated with a more frequency of peripheral edema [95-97]. Data demonstrated that selectivity on ETR blockage was not an important factor in choosing an agent for PAH management. The role of ambrisentan in combination with tadalafil in dasatinib-induced PAH was evaluated just in case reports as mentioned previously . Along with discontinuation of dasatinib, ambrisentan in combination with sildenafil and treprostinil was associated with improvement in mPAP, 6-MWD and NYHA functional class. However, an unexpected progression of PAH occurred after 3 years which was not controlled by intensive anti PAH therapy and resulted in need for lung transplantation. It is notable that the CML therapy may be resumed with nilotinib in patients with PAH following dasatinib use .
Macitentan is a novel non-selective ET-1 antagonist with an active metabolite with a longer half-life compared to the parent drug. Macitentan and its active metabolite have a higher tendency to tissue and bind more potently to ET receptors compared to the other ET-1As . It has a good safety profile with well-tolerated adverse events include nausea, vomiting and headache and less liver toxicity compared to bosentan and ambrisentan . This highly potent ERAs was studied in SERAPHIN trial with the dosage regimens of 3 mg and 10 mg once daily versus placebo in 742 PAH cases (not dasatinib-induced PAH). Both 3 mg (
Epoprostenol and prostaglandin I2 (PGI2) derivatives: Epoprostenol as a synthetic derivative of PGI2 received FDA approval in 1995. PGI2 acts as a direct vasodilator and also a cytoprotective agent which inhibits platelet aggregation [108-110]. Epoprostenol has beneficial effects on PAH symptoms, disease progression, 6-MWD and survival [111-115]. A case of dasatinib-induced PAH was treated successfully with epoprostenol along with discontinuation of dasatinib . According to epoprostenol instability in plasma, continuous intravenous infusion (IV) is the preferred route of administration, though it is linked to catheter-related thrombosis and infection [114, 117, 118]. Other adverse effects were ascites, thrombocytopenia, flushing, headache, nausea, loose stool, jaw discomfort and musculoskeletal pain [110, 119].
Treprostinil is another prostanoid with longer half-life used in treatment of PAH. It was associated with improvement in quality of life, exercise capacity, functional class, pulmonary hemodynamics, and survival of patients [120-123]. Treprostinil can be used in oral, inhaled, subcutaneous or IV routes which the 2 latter are assumed bioequivalent at steady state in the dose of 10 ng kg-1min-1. It is also used as SC infusion. Local pain following infusion may occur and could be decreased by titrating of dose during 6 months [124, 125]. Transition from IV epoprostenol to IV or SC treprostinil is rational when patient is intolerant to epoprostenol or in the case of worsening of clinical status [126-128]. Inhaled treprostinil in patients with severe pulmonary hypertension revealed a significant sustained impact on pulmonary vascular resistance compared to the same doses of inhaled iloprost with a better tolerability profile . According to a double-blind, randomized, placebo-controlled trial, continuous SC infusion of treprostinil enhances exercise capacity regardless of the PAH etiology. Considering this dose-related effect, treprostinil could be an appropriate agent for management of dasatinib-induced PAH .
Iloprost, an analog of PGI2 has a short half-life of 20–25 minutes and was used as inhalation or IV forms with frequent doses (e.g., 6–9 times daily) . It can improve 6-MWD, Mahler dyspnea index, quality of life and NYHA functional class in PAH by inhaled formulation . Despite its inhalation form, IV iloprost did not receive FDA approval for PAH. Both iloprost and treprostinil inhalation formulations lead to cough .
Beraprost is an oral rapid onset analog of PGI2 that improves 6-MWD, disease progression and WHO functional class. Considering WHO functional class, the beneficial effects is limited to 6 months . Beraprost and Iloprost have not yet studied for management of dasatinib-induced PAH, but they could be acceptable drugs since both have proven efficacy in ameliorating the PAH with other etiologies.
Selexipag is another oral prostacyclin IP2-receptor (IP2r) agonist with a non-prostanoid structure. It has a vasodilator effect on large and small pulmonary arterial branches [135-137]. Selexipag has the highest affinity for IP2r with similar side effect profile of other IP2r agonists. Headache is the most common adverse effect along with jaw pain, nausea and diarrhea which are often observed with rapid dose-titration and are reduced over time . Selexipag showed a significant improvement in the primary composite endpoint of death, complications related to PAH, pulmonary vascular resistance and 6-MWD in GRIPHON trial . As mentioned previously, selexipag has been studied in dasatinib-induced PAH in combination with macitentan and tadalafil resulted in rapid improvement of mPAP, 6-MWD and NYHA functional class .
Calcium channel blockers (CCBs): CCBs reduces the influx of calcium in smooth muscle cells leading to systemic peripheral arterial dilation. Therapeutic effects of CCBs will be obtained when used at high doses for a long time [139-143]. Among long acting nifedipine, diltiazem and amlodipine, diltiazem is preferred when the heart rate is above 80 beats min-1 [144, 145]. Verapamil is not recommended due to its notable negative inotropic effect . Although CCBs have been noted nearly in all PAH treatment guidelines, in fact a very few numbers of patients with PAH including idiopathic-PAH patients, genetically associated PAH, or anorexigen-induced PAH will benefit from using high doses and long term CCB therapy . It doesn’t seem that CCBs are effective in dasatinib-induced PAH .
Pulmonary complications of TKIs need to be diagnosed and managed promptly. Dasatinib was associated with a higher prevalence and recurrence rate of PE and PAH among TKIs. In symptomatic patients with mild PE, dasatinib should be interrupted and in the case of fluid retention, diuretics should be initiated. Therapy of CML should be resumed after resolution of effusion. In symptomatic patients with PE ≥class 2 or asymptomatic patients with PE ≥class 3, dasatinib should be discontinued and corticosteroids (prednisone 40 mg daily for four days) should be initiated along with therapeutic thoracentesis. PAH is a life threatening complication of long-term therapy with dasatinib. Phosphodiesterase type-5 inhibitors (e.g., sildenafil and tadalafil) alone or in combination with endothelin receptor-1 antagonists (e.g., bosentan and macitentan) and also synthetic derivatives of PGI2 or non-prostanoid prostacyclin-receptor agonist (e.g., selexipag) were successfully used in the management of dasatinib-induced PAH. Current recommendations regarding the management of pulmonary toxicities of TKIs including dasatinib are based on published case reports and evaluating the safety and efficacy of different available pharmacotherapies require conducting multi-center randomized controlled trials.
No potential conflicts of interest relevant to this article were reported.