Αριστοτέλειο Πανεπιστήμιο Θεσσαλονίκης Α Καρδιολογική Κλινική ΑΧΕΠΑ Ιατρείο Πνευμονικής Υπέρτασης ΟΜΑΔΑ ΕΡΓΑΣΙΑΣ ΒΑΛΒΙΔΟΠΑΘΕΙΩΝ, ΣΥΓΓΕΝΩΝ ΚΑΡΔΙΟΠΑΘΕΙΩΝ ΕΝΗΛΙΚΩΝ ΚΑΙ ΠΝΕΥΜΟΝΙΚΗΣ ΥΠΕΡΤΑΣΗΣ Σοφία Αναστασία Μουράτογλου Ειδ/νη Καρδιολογίας Α Καρδιολογική Κλινική ΓΠΝΘ ΑΧΕΠΑ 10/2/2018 1 1
Conflicts of interest None 10/2/2018 2
Πρωινός καφές
Ή πρωινός καφές???
ΠΕΡΙΣΤΑΤΙΚΑ ΠΝΕΥΜΟΝΙΚΗΣ ΥΠΕΡΤΑΣΗΣ ΜΕ ΤΟΝ ΠΡΩΪΝΟ ΚΑΦΕ Πνευμονική αρτηριακή υπέρταση οφειλόμενη σε φάρμακα
ΜΔ Male DoB: 07/12/1946, 71yo
Background I 1999 Buerger's disease (thromboangiitis obliterans) 2000 Stenting of both femoral arteries 2013 Prostate Ca (prostatectomy and actinotherapy) considered cured 2013 Dyslipidaimia Smoker (40pack/years) 10/2/2018 7
Background II 2014 CML put on Dasatinib 10/2/2018 8
Current condition WHO III BSA: 1.85m2 BP: 138/74mmHg S1, S2: rhythmic, no murmurs, enhanced P2 Mild hepatomegaly / peripheral edema / pulsatile jugular veins ECG: SR, RVH pre post SpO 2 99 96 HR 60 88 Borg 0 3 Total distance walked in 6min: 230m 10/2/2018 9
Background (01/2016) Normal renal and liver function Normal thyroid function Normal immunologic blood tests NT-proBNP 254 pg/ml (<125pg/ml) Normal LFT CBC WBC (Κ/μL) 7.66 Neut (%) 62.5 Lymph (%) 28.1 Mono (%) 7.4 Eos (%) 1.6 Baso (%) 0.4 RBC (M/μL) 4.33 Hb (g/dl) 10.5 Hct (%) 32.2 PLT (Κ/μL) 259
Treatment Dasatinib 100mg BiD Clopidogrel 75mg OD Pentoxifilline 400mg OD Pravastatin/fenofibrate 40/160 OD Iron supplementation
TAPSE=2cm
RHC BSA: 1.85 Hb: 10.8mg.dl BP: 138/74 HR: 71bpm Baseline Pressure (mmhg) SAT (%) RA 12 RV 83/11 PAP 81/26/m46 68 PAWP 13 PVR (Wood) 4.6 PVRi (Woodxm 2 ) 8.6 CO (L/min) 7.1 CI (L/min/m2) 3.8 10/2/2018 15
V/Q scan
HRCT
HRCT
DIAGNOSIS?
Diagnosis Dasatinib induced PAH CML induced PH 10/2/2018 20
PAH PATHOGENESIS IN TREATMENT WITH DASATINIB
Src family of TK Independent of Src inhibition TWIK related K-1 channel inhibition Mitochondrial reactive oxygen species vasoconstriction Endothelial dysfunction Injury Apoptosis Fox L et al, Blood 2016 Shah NP et al, Blood 2014 Montani D et al, Circulation 2012 Baumgart B et al, Cancer Chemother Pharmacol 2017 PAH Daccord C et al, Eur Respir J 2018 Weatherald J et al, Eur Respir J 2017 Shah NP eta al, Am. J. Hematol 2015 Montani D et al, Eur Respir J 2013 Guignabert C, Eur Respir J 2013 de Jesus Perez V et al, Int J Clin Pract 2011 Groeneveldt JA et al, Eur Respir J 2013
PH PATHOGENESIS IN CML
Οbstruction of pulmonary capillaries by megakaryocyte Thrombotic material in the lung capillaries Stasis Secondary microthrombosis Increased thrombopoietin Endothelial dysfunction PH Dingli D et al, Chest 2001 Guilpain R et al, Respiration 2008 Adir Y et al, Eur Respir Rev 2015 Gupta R et al, J Natl Med Assoc 2006 Roach E et al, J HeartLungTransplant2015 Rostango C et al, Circulaiton 1999 Garcia-Manero G et al, Am J Hemat 1999
Diagnosis?? CML stable Dasatinib induced PAH 10/2/2018 25
Dasatinib induced PAH Incidence: 0.45%-1.2% in treated patients Αrises 8 to 48 months after therapy initiation May be complicated by pleural effusion Initial starting dose is usually > 70 mg BID Hemodynamic improvement after Dasatinib discontinuation Shah et al, Am J hematol 2015 Fox L et al, Blood 2017 Weatherald J et al, Eur Respir J 2017 10/2/2018 26
Are there any predisposing factors? Histopathological lesions similar to IPAH Genetic predisposition? Daccord C et al, Eur Respir J 2018 10/2/2018 27
Therapeutic options in dasatinib induced PAH 10/2/2018 28
Risk assessment 10/2/2018 Guidelines for the diagnosis and treatment of pulmonary hypertension, Eur Heart J 2015 29
Stop dasatinib Weatherald J et al, Eur Respir J 2017
Step #1 Discontinue dasatinib! 10/2/2018 31
Weatherald J et al, Eur Respir J 2017
Is Dasatinib discontinuation enough? Shah NP et al, Am J Hematol 2015
Course of Dasatinib induced PAH +146 m N=21 37%:persistent PAH N=19 45 (30 70) 26 (17 50) 10/2/2018 6.1 (3.2 27.3) 2.6 (1.2 5.9) 6.9 (4.9 9.9) 6.0 (2.3 9.2) 34 Weatherald J et al, Eur Respir J 2017
The role of advanced PAH treatment N=21 Stop Dasatinib: 21 PAH treatment: 11 10/2/2018 35 Weatherald J et al, Eur Respir J 2017
Survival aspects FU years 1 3 5 Survival (%) 90.5 90.5 85.7 10/2/2018 36 Weatherald J et al, Eur Respir J 2017
Step #2 10/2/2018 38
Take home messages PH may be a rare complication of chronic myeloid leukemia Tyrocine kinase inhibitors such as Dasatinib used to treat CML may potentially cause PAH Although rare, increased awareness is advised in patients with CML, especially when treated with TKI Recession of Dasatinib may be followed by hemodynamic improvement or normalization Advanced treatment may be helpful in the management of Dasatinib induced PAH 10/2/2018 39
Acknowledgements AHEPA University Hospital Pulmonary Hypertension Unit Thank you 10/2/2018 40
Pathophysiology of PAH
Treatment Start Macitentan 10mg OD 10/2/2018 42