Six-Year Follow-Up Of Dasatinib-Related Pulmonary Arterial Hypertension (PAH) For Chronic Myeloid Leukemia In Single Center

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4017-4017 ◽  
Author(s):  
Young-Woo Jeon ◽  
Sung-Eun Lee ◽  
Soo-Hyun Kim ◽  
Soo-Young Choi ◽  
Jin-Eok Park ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Pulmonary Arterial Hypertension ◽  
Chronic Myeloid Leukemia ◽  
Arterial Hypertension ◽  
Myeloid Leukemia ◽  
Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
Dasatinib Treatment

Abstract Introduction Recent randomized trial (DASISION trial), compared clinical outcomes between dasatinib and imatinib in newly diagnosed (chronic myeloid leukemia) CML patients. Results showed that dasatinib had faster and deeper responses compared with imatinib, and thus dasatinib became to be considered as a first-line therapy in CML patients. However, the long-term administration of dasatinib has been reported to have a risk of pleural effusion and dasatinib-related (pulmonary arterial hypertension) PAH. So, we have prospectively evaluated for emergence of PAH in all CML patients treated with dasatinib in our institute. Materials and methods Between May 2005 and July 2013, a total of 89 CP CML patients on dasatinib treatment were tested with laboratory studies, Brain natriuretic peptide (BNP), echocardiography (echo) in the Catholic University of Korea, Seoul, and baseline functional capacity (NYHA or WHO functional class) was assessed. PAH was defined as mean pulmonary artery pressure (mPAP) of >25mmHg at rest, with wedge pressure < 15mmHg, or Rt. Ventricular systolic pressure (RVSP) of 40 mmHg on echocardiography. And patients who had abnormal RVSP and/or symptoms (New York heart association-NYHA class 3, 4) were performed with additional studies such as pulmonary angiographic catheterization or pulmonary arterial computed tomography. Results So far, 62 patients (70%) of total 89 were evaluated with echocardiography (46 male, 16 female). The median age was 48 year old (range, 22∼72). The median duration of disease was 8.5 years (range, 0.8∼16.1). The median mean daily dosage of dasatinib was 102mg (range, 73∼140mg). The duration of dasatinib treatment was 34.6 months (range, 0.5∼99.6). 8 of 66 patients (12.1%) showed abnormal echocardiographic findings as increased right ventricular systolic pressure or symptom. All of 8 patients had treated with dasatinib as second line, and had exertional dyspnea (2 patients on class 2, and 5 patients on class 3 of NYHA). 5 patients of these showed abnormal BNP levels. The mean RVSP in screened patients was 65.2 mmHg (range, 40∼108mmHg), 2 of 8 patients were confirmed diagnosis with overt PAH on as pulmonary angiographic catheterization, and right ventricular hypertrophy on pulmonary angiographic computed tomography. Clinical, functional, or hemodynamic improvements were observed within 5 months of dasatinib discontinuation and then, in 5 patients the treatment was switched to radotinib, and another 3 patients received reduced dosage of dasatinib. Conclusion Although the lowest estimate of incident PAH occurring in patients exposed to dasatinib was 0.45% in France group. our preliminary data show more higher incidence rates (8 of 66 patients, 12.1%) in Korea. So, we suggest that the long-term dasatinib treatment for CML requires careful attention to cardiopulmonary adverse effects. and routine cardiovascular and pulmonary evaluation on regular basis is strongly recommended before and during treatment with dasatinib. Disclosures: No relevant conflicts of interest to declare.

Lupus-like symptoms with anti-RNP/Sm and anti-nuclear antibodies positivity: An extremely rare adverse event of dasatinib

2019 ◽  
Vol 26 (3) ◽  
pp. 738-741 ◽  
Author(s):  
Senem Maral ◽  
Sule Mine Bakanay ◽  
Orhan Kucuksahin ◽  
Imdat Dilek
Keyword(s):  
Adverse Event ◽  
Pulmonary Arterial Hypertension ◽  
Pleural Effusion ◽  
Chronic Myeloid Leukemia ◽  
Pericardial Effusion ◽  
Arterial Hypertension ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Pulmonary Arterial ◽  
Dasatinib Treatment

Introduction Dasatinib is a potent tyrosine-kinase inhibitor which is used for chronic myeloid leukemia treatment. Pleural effusion is a frequent side effect in patients during dasatinib treatment. Pulmonary arterial hypertension is a rare and life-threatening adverse event of dasatinib. The relationship between dasatinib and autoimmune disorders is unclear, but there are reports of possible mechanisms that have triggered autoimmunity by dasatinib. Case report A 53-year-old male was diagnosed with chronic myeloid leukemia and initiated imatinib mesylate as a treatment. Imatinib was changed to dasatinib as the patient was unresponsive in the first year of treatment. In the fourth year of dasatinib when chronic myeloid leukemia was in both hematological and cytogenetical remission, the patient presented with bilateral massive exudative pleural effusion. Echocardiography was consistent with pericardial effusion with right ventricle enlargement and normal left-side cardiac function. Pulmonary arterial hypertension was diagnosed with high systolic pulmonary arterial pressure. When he had fever and arthralgia, further investigation showed positivity of anti-nuclear antibodies (1/160 titer) and anti-RNP/Sm, which have high specificity for the diagnosis of Systemic Lupus Erythematosus (SLE). Management and outcome Dasatinib was discontinued and nilotinib was initiated. As the pleural effusion persisted despite diuretics and methylprednisolone, mycophenolate mofetil was initiated as a steroid-sparing immune-suppressive agent. The lupus-like symptoms disappeared, and antibodies became undetectable after dasatinib discontinuation. Pericardial effusion improved and pleural effusion did not relapse. Discussion Screening for auto-antibodies may be recommended for patients with a history or symptoms of autoimmune disease before starting dasatinib. All patients who develop pleural effusion while on dasatinib treatment should be investigated for antibodies for lupus.

Long-Term Assessment of Dasatinib-Induced Pulmonary Arterial Hypertension in Chronic Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5535-5535 ◽  
Author(s):  
Jee Hyun Kong ◽  
Young-Woo Jeon ◽  
Sung-Eun Lee ◽  
Soo Young Choi ◽  
Soo-Hyun Kim ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pleural Effusion ◽  
Chronic Myeloid Leukemia ◽  
Arterial Hypertension ◽  
Doppler Echocardiography ◽  
Myeloid Leukemia ◽  
Treatment Duration ◽  
Pulmonary Arterial ◽  
Dasatinib Treatment

Abstract Background: To explore a real incidence of dasatinib-induced pulmonary arterial hypertension (D-PAH) in clinical practice, we investigated 82 imatinib or other 2G tyrosine kinase inhibitor (TKI)-failed chronic myeloid leukemia (CML) patients who received dasatinib as a second-line therapy. Methods: Routine chest X-ray and Doppler echocardiography were regularly evaluated in all patients and additional tests were performed if dyspnea developed on treatment. Results: Median age at the time of starting dasatinib was 48 (16-82) years. Of 82 patients, 8 patients (9.8%) showed an elevation of right ventricular systolic pressure (RVSP>35mmHg) by Doppler echocardiography. Among them, 7 patients (8.5%) were considered D-PAH with a median dasatinib treatment duration of 32.6 (10.3-108.7) months. They underwent follow-up Doppler echocardiography median 5 (2-9) times. Five patients showed severe D-PAH (RVSP >70mmHg), 1 was moderate (RVSP 46mmHg), and 1 was mild (RVSP 41mmHg). Advanced studies such as pulmonary angiographic catheterization (patient 1 and 2) or pulmonary arterial computed tomography (patient 3 and 4) were performed for confirming D-PAH or ruling out PAH due to pulmonary vascular abnormality. Six patients had bilateral pleural effusion and 1 had unilateral pleural effusion. With sildenafil (n=5) + dose reduction (n=1) + switch to other TKI (n=6), all of patients improved dyspnea, and RVSP level was completely resolved in 3 patients. In addition, previous nilotinib therapy and concomitant pleural effusion were significant contributing factors for D-PAH. Conclusion: Regardless of complete resolution of pleural effusion, a patient with sustained dyspnea on dasatinib treatment should be carefully evaluated by Doppler echocardiography and a regular monitoring will be needed for early intervention. Abstract 5535. Table 1. Characteristics of patients with dasatinib-induced PAH Cohort Age at PAH diagnosis (year) Sex Treatment duration before dasatinib (month) Previous therapy for CML Duration between initiation of dasatinib and diagnosis of PAH (month) Daily mean dose of dasatinib (mg/d) Duration between diagnosis of D-PAH and last follow up (month) Treatment of D-PAH Switch to other TKI Outcome 1 53 M 54.4 Interferon, Hydroxyurea, Imatinib, nilotinib 26.4 123 73.5 Sildenafil nilotinib and ponatinib partial 2 50 M 36.6 Interferon, Hydroxyurea, Imatinib, dasatinib, nilotinib 50.3 112 55.2 Sildenafil nilotinib and radotinib partial 3 37 F 31.7 Imatinib, nilotinib 21.7 88 39.7 SildenafilDose de-escalation radotinib partial 4 45 M 70.9 Hydroxyurea, Imatinib 69.8 101 35.2 SildenafilDose de-escalation ponatinib complete 5 59 F 107.4 Interferon, Hydroxyurea, Imatinib 83.6 92 14.3 none radotinib partial 6 46 F 12.6 Imatinib 29.1 76 13.0 Steroid, Sildenafil radotinib complete 7 38 F 30.2 Imatinib 33.1 98 10.2 Dose reduction NA complete Disclosures No relevant conflicts of interest to declare.

Effects of Crocin on CCL2/CCR2 Inflammatory Pathway in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

2021 ◽  
pp. 1-19
Author(s):  
Yanling Sheng ◽  
Xiaowei Gong ◽  
Jing Zhao ◽  
Yan Liu ◽  
Yadong Yuan
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Stress Responses ◽  
Systolic Pressure ◽  
Pathological Feature ◽  
Arterial Remodeling ◽  
Inflammatory Pathway ◽  
Ventricular Systolic Pressure ◽  
Rat Models ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a malignant cardiopulmonary disease, in which pulmonary arterial remodeling is regarded as the prominent pathological feature. So far, the mechanism of PAH is still unclear, so its treatment remains a challenge. However, inflammation plays an important part in the occurrence and progression of PAH. It is well known that crocin has anti-inflammatory properties, so we investigated whether crocin could be a potential drug for the treatment of PAH rat models. Rats injected subcutaneously with monocrotaline (MCT) were treated with crocin via a gastric tube daily for four weeks. The results showed that crocin treatment significantly reduced the right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) in the PAH rat models. Moreover, crocin treatment reduced the proliferation of pulmonary arteriole smooth muscle cells (PASMCs). In addition, crocin treatment not only relieved inflammatory cell infiltration and collagen fiber hyperplasia in the lung and right ventricle, but also decreased the expression of the CCL2/CCR2 inflammatory pathway in the lung of PAH rat models. Furthermore, crocin treatment reduced the inflammatory cytokines and oxidative stress responses. In summary, crocin may play a protective role in MCT-induced PAH rats by alleviating inflammatory response, improving pulmonary arterial remodeling, and preventing PAH. Therefore, crocin as a new treatment for PAH may be quite worthy of consideration.

scholarly journals Baicalin prevents pulmonary arterial remodeling in vivo via the AKT/ERK/NF-κB signaling pathways

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401987859 ◽  
Author(s):  
Guosen Yan ◽  
Jinxia Wang ◽  
Tao Yi ◽  
Junfen Cheng ◽  
Haixu Guo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Signaling Pathways ◽  
Vascular Remodeling ◽  
Systolic Pressure ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Pulmonary arterial hypertension is a rapidly progressive and often fatal disease. As the pathogenesis of pulmonary arterial hypertension remains unclear, there is currently no good drug for pulmonary arterial hypertension and new therapy is desperately needed. This study investigated the effects and mechanism of baicalin on vascular remodeling in rats with pulmonary arterial hypertension. A rat pulmonary arterial hypertension model was constructed using intraperitoneal injection of monocrotaline, and different doses of baicalin were used to treat these rats. The mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured with a right heart catheter. Moreover, the hearts were dissected to determine the right ventricular hypertrophy index (RVHI). The lung tissues were stained with H&E and Masson's staining to estimate the pulmonary vascular remodeling and collagen fibrosis, and the expression of proteins in the AKT, ERK, and NF-κB p65 phosphorylation (p-AKT, p-ERK, p-p65) was examined by Western blot analysis. We found that compared with untreated pulmonary arterial hypertension rats, baicalin ameliorated pulmonary vascular remodeling and cardiorespiratory injury, inhibited p-p65 and p-ERK expression, and promoted p-AKT and p-eNOS expression. In conclusion, baicalin interfered with pulmonary vascular remodeling and pulmonary arterial hypertension development in rats through the AKT/eNOS, ERK and NF-κB signaling pathways.

scholarly journals Leptin signalling system as a target for pulmonary arterial hypertension therapy

2015 ◽  
Vol 45 (4) ◽  
pp. 1066-1080 ◽  
Author(s):  
Alice Huertas ◽  
Ly Tu ◽  
Raphaël Thuillet ◽  
Morane Le Hiress ◽  
Carole Phan ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Perivascular Inflammation ◽  
Current Therapies ◽  
Pulmonary Arterial ◽  
Anti Inflammatory ◽  
Pulmonary Arterial Hypertension Therapy

Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH.In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ≤5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH (pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH.We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH.

scholarly journals Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension

2021 ◽  
Author(s):  
Takanori Watanabe ◽  
Mariko Ishikawa ◽  
Kohtaro Abe ◽  
Tomohito Ishikawa ◽  
Satomi Imakiire ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Uric Acid ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Pressure Increase ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

scholarly journals EXPRESS: Carfilzomib-associated Pulmonary Arterial Hypertension in Multiple Myeloma

2021 ◽  
pp. 204589402110493
Author(s):  
Jenny Yang ◽  
Taylor Buckstaff ◽  
Anna Narezkina ◽  
Timothy Fernandes
Keyword(s):  
Multiple Myeloma ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
New Drugs ◽  
Heart Catheterization ◽  
Drug Induced ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Drug-induced pulmonary arterial hypertension (PAH) is constantly evolving as new drugs are developed. Carfilzomib is a recently approved therapy for relapsed and refractory multiple myeloma. While it has been associated with cardiovascular adverse events, such as ischemic heart disease and heart failure, PAH has not been a well-described side effect. We present two patients who developed PAH associated with initiation of carfilzomib. They both initially presented with severe dyspnea, had elevated right ventricular systolic pressure on transthoracic echocardiography and ultimately underwent right heart catheterization. With discontinuation of carfilzomib, both patients had improvement in hemodynamics. However, one patient required initiation of PAH-targeted therapies and has had worsening right ventricular function again despite permanent discontinuation of carfilzomib. It is important to recognize the association between carfilzomib and PAH. Echocardiography can be an important initial screening tool. PAH from carfilzomib therapy may be reversible, especially if diagnosed early, however extended follow up is essential.

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