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.
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 | Sildenafil Dose de-escalation | radotinib | partial |
| 4 | 45 | M | 70.9 | Hydroxyurea, Imatinib | 69.8 | 101 | 35.2 | Sildenafil Dose 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 |
| 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 | Sildenafil Dose de-escalation | radotinib | partial |
| 4 | 45 | M | 70.9 | Hydroxyurea, Imatinib | 69.8 | 101 | 35.2 | Sildenafil Dose 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 |
No relevant conflicts of interest to declare.
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