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Alemtuzumab and de novo pulmonary arterial hypertension: A potential association?
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CASE ANECDOTES, COMMENTS AND OPINIONS Alemtuzumab and de novo pulmonary arterial hypertension: A potential association? Laura Beaumier, MSc,a Sébastien Chanoine, PharmD,a,b Boubou Camara, MD,c Christophe Pison, MD, PhD,b,c and Pierrick Bedouch, PharmD, PhDa,b From the aPôle Pharmacie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France; bFacultés de Médecine et de Pharmacie, Université Grenoble Alpes, Grenoble, France; and the cClinique Universitaire de Pneumologie, Pôle Thorax et Vaisseaux, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
Pulmonary arterial hypertension (PAH) may involve medications as triggers, such as anorectic drugs and, more recently, tyrosine kinase inhibitors.1,2 Here, we report a case involving alemtuzumab in PAH onset. The patient was a 67-year-old man treated by alemtuzumab for B-cell chronic lymphocytic leukemia (B-CLL) from May to July 2009.3 After exposure to alemtuzumab, the patient developed progressive worsening in New York Heart Association functional capacity. In July 2012, transthoracic echocardiography showed an increased systolic pulmonary arterial pressure and a left ventricular hypertrophy, without dilatation or inversion of the right-to-left ventricular diameter ratio. The left ventricular ejection fraction was 55%, left atrial diameter was 3.4 cm, and the ratio of peak early diastolic mitral inflow velocity to early diastolic mitral annular velocity was 4. Right-sided heart catheterization confirmed precapillary pulmonary hypertension, with a mean pulmonary arterial pressure of 30 mm Hg, a pulmonary artery wedge pressure of 9 mm Hg, a pulmonary vascular resistance of 3 Wood units, and a cardiac index of 2.6 liters min–1 m–2 (Table 1). Vasoreactivity testing was negative. PAH etiologies were investigated. Coronarography revealed normal coronary arteries. Imaging excluded pulmonary fibrosis and pulmonary veno-occlusive disease. The diffusing capacity of lung for carbon monoxide was 16.3 ml min–1 mm Hg–1 (58%), alveolar ventilation was 6.5 liters/min (91%), and the partial pressure of arterial oxygen was 61.9 mm Hg. Laboratory results for anti-nuclear antibodies, anti-tissues antibodies, thyroid markers, and
anti-phospholipid antibodies were negative. Status for human immunodeficiency virus and human herpes virus 8 was negative. Perfusion and ventilation lung scanning ruled out recent pulmonary thromboembolism or postembolic sequelae. Ultrasonography of the abdomen and pelvis excluded portal hypertension. The accountability of drug-induced PAH is difficult due to (1) the rare reversibility of PAH after drug offset, (2) the absence of therapeutic class effect excepted for anorectic agents, (3) the variable period of drug exposure, and (4) the unclear pathogenesis. However, drug-induced PAH is increasingly being reported in the literature, leading to health care professionals to be aware. Descriptions in the literature of chemotherapeutic agents, and mainly tyrosine kinase inhibitors, as being responsible for PAH have recently increased.1,2 A case of PAH in a patient with CLL receiving rituximab has been reported, as well as in a patient treated by fludarabine, cyclophosphamide, and rituximab in Waldenström macroglobulinemia.4,5 Except alemtuzumab, for which data are unknown, our patient had taken no other suspicious drugs, such as benfluorex, and had not been exposed to toxins known to cause PAH. We acknowledge that a protopathic bias might have occurred and that the patient received chemotherapy with cyclophosphamide for B-CLL relapse from October 2011 to February 2012. No strong evidence was highlighted to consider the alkylating agent in the occurrence of PAH, because respiratory symptoms occurred before cyclophosphamide initiation, and no pulmonary veno-occlusive disease was found. Finally, this case brings out the probable accountability of alemtuzumab in PAH onset.6 In conclusion, alemtuzumab therapy requires enhanced medical follow-up to detect as soon as possible this complication, especially because the European Medicines Agency and the United States Food and Drug Administration have recently approved alemtuzumab for relapsing forms of multiple sclerosis and the drug is increasingly being used off-label for induction after lung transplantation.
Disclosure statement S.C. reports non-financial support from Chiesi France, MSD France, GSK France, Actelion France, and LFB Biomedicaments outside the submitted work. C.P. reports these last 3 years, in the context of treatments for PAH, fees for lectures from Pfizer France, Bayer France, GSK France, MSD France, Actelion France, personal financial support to attend medical meetings from Actelion France, outside the submitted work, and his institution,
1053-2498/$ - see front matter r 2016 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2016.10.013
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
2 Table 1
Evolution of Invasive Hemodynamic, Clinical, and Imaging Parameters and Treatment
Variables
July 2012
February 2013
August 2013
February 2014
April 2014
August 2014
March 2016
42 21 30 9
42 26 32 14
39 15 25 6
52 27 35 9
54 24 39 13
56 37 45 14
50 20 31 14
40 5 6 3 2.6 6.1 45 II
40 10 11 3 2.18 5.1 55 0.54 422 III
39 8 5 3 2.6 6.0 65 0.53 372 III
51 9 8 4 2.5 5.9 265 III–IV
54 7 6 4 2.46 5.6 45 0.81 200 III–IV
61 16 9 5 2.71 6.17 45 0.64 290 III–IV
50 12 16 2 3.12 6.8 55 1.26 220 III
-
40 20 to 40 -
40 -
80 -
160 60 -
125 120 125 to 250 -
125 120 Until 20
Clinical, imaging, and hemodynamic parameters PAP, mm Hg Systolic Diastolic Mean PAWP, mm Hg RVP, mm Hg Systolic Diastolic RAP, mm Hg PVR, Wood units Cardiac index, liters min–1 m–2 Cardiac output, liters/min LVEF, % RV-to-LV diameter ratio 6MWT, m NYHA Functional Class Non-specific and specific PAH medications Furosemide, mg/day Tadalafil, mg/day Sildenafil, mg/day Bosentan, mg/day Epoprostenol, ng kg–1 min–1
6MWT, 6-minute walk test; LV, left ventricular; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PAP, pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RV, right ventricular; RVP, right ventricular pressure.
Centre Hospitalier Universitaire Grenoble Alpes via its Research Department, received honoraria linked to phase 2 and 3 randomized controlled trials from Gilead, Bayer and Actelion France, outside the submitted work. P.B. reports grants and non-financial support from Actelion France, grants from Pfizer, GSK, and the French Association for Clinical Pharmacy, and personal fees for participation in a scientific advisory board from Actelion France, outside the submitted work. The other authors do not have a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. The authors gratefully acknowledge Dr Marion Lepelley, from Centre Régional de Pharmacovigilance de Grenoble, France, and Prof Gilbert Ferretti (radiologist), Dr Adrien Jankowski (radiologist), Dorothée Duron (pharmacist resident), Hélène Pluchart (pharmacist resident), Prof Benoît Allenet (clinical pharmacist), and Dr Hélène Bouvaist (cardiologist), all from Centre Hospitalier Universitaire Grenoble Alpes, France, for their accurate analysis of this case anecdote and their significant contribution for the elaboration of this manuscript.
References 1. Montani D, Seferian A, Savale L, Simonneau G, Humbert M. Druginduced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev 2013;22:244-50. 2. Quilot FM, Georges M, Favrolt N, et al. Pulmonary hypertension associated with ponatinib therapy. Eur Respir J 2016;47:676-9. 3. Turgut B, Vural O, Pala FS, et al. 17p Deletion is associated with resistance of B-cell chronic lymphocytic leukemia cells to in vitro fludarabine-induced apoptosis. Leuk Lymphoma 2007;48:311-20. 4. Montrone D, Correale M, Franzese MG, Ieva R, Di Biase M, Capalbo SF. Pulmonary arterial hypertension in a chronic lymphocytic leukemia patient in treatment with rituximab. J Cardiovasc Med 2015;16 (Suppl 1):S65. 5. Lazarevic VL, Liljeholm M, Forsberg K, Söderberg S, Wahlin A. Fludarabine, cyclophosphamide and rituximab (FCR) induced pulmonary hypertension in Waldenström macroglobulinemia. Leuk Lymphoma 2008;49:1209-11. 6. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30: 239-45.
CASE ANECDOTES, COMMENTS AND OPINIONS Alemtuzumab and de novo pulmonary arterial hypertension: A potential association? Laura Beaumier, MSc,a Sébastien Chanoine, PharmD,a,b Boubou Camara, MD,c Christophe Pison, MD, PhD,b,c and Pierrick Bedouch, PharmD, PhDa,b From the aPôle Pharmacie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France; bFacultés de Médecine et de Pharmacie, Université Grenoble Alpes, Grenoble, France; and the cClinique Universitaire de Pneumologie, Pôle Thorax et Vaisseaux, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
Pulmonary arterial hypertension (PAH) may involve medications as triggers, such as anorectic drugs and, more recently, tyrosine kinase inhibitors.1,2 Here, we report a case involving alemtuzumab in PAH onset. The patient was a 67-year-old man treated by alemtuzumab for B-cell chronic lymphocytic leukemia (B-CLL) from May to July 2009.3 After exposure to alemtuzumab, the patient developed progressive worsening in New York Heart Association functional capacity. In July 2012, transthoracic echocardiography showed an increased systolic pulmonary arterial pressure and a left ventricular hypertrophy, without dilatation or inversion of the right-to-left ventricular diameter ratio. The left ventricular ejection fraction was 55%, left atrial diameter was 3.4 cm, and the ratio of peak early diastolic mitral inflow velocity to early diastolic mitral annular velocity was 4. Right-sided heart catheterization confirmed precapillary pulmonary hypertension, with a mean pulmonary arterial pressure of 30 mm Hg, a pulmonary artery wedge pressure of 9 mm Hg, a pulmonary vascular resistance of 3 Wood units, and a cardiac index of 2.6 liters min–1 m–2 (Table 1). Vasoreactivity testing was negative. PAH etiologies were investigated. Coronarography revealed normal coronary arteries. Imaging excluded pulmonary fibrosis and pulmonary veno-occlusive disease. The diffusing capacity of lung for carbon monoxide was 16.3 ml min–1 mm Hg–1 (58%), alveolar ventilation was 6.5 liters/min (91%), and the partial pressure of arterial oxygen was 61.9 mm Hg. Laboratory results for anti-nuclear antibodies, anti-tissues antibodies, thyroid markers, and
anti-phospholipid antibodies were negative. Status for human immunodeficiency virus and human herpes virus 8 was negative. Perfusion and ventilation lung scanning ruled out recent pulmonary thromboembolism or postembolic sequelae. Ultrasonography of the abdomen and pelvis excluded portal hypertension. The accountability of drug-induced PAH is difficult due to (1) the rare reversibility of PAH after drug offset, (2) the absence of therapeutic class effect excepted for anorectic agents, (3) the variable period of drug exposure, and (4) the unclear pathogenesis. However, drug-induced PAH is increasingly being reported in the literature, leading to health care professionals to be aware. Descriptions in the literature of chemotherapeutic agents, and mainly tyrosine kinase inhibitors, as being responsible for PAH have recently increased.1,2 A case of PAH in a patient with CLL receiving rituximab has been reported, as well as in a patient treated by fludarabine, cyclophosphamide, and rituximab in Waldenström macroglobulinemia.4,5 Except alemtuzumab, for which data are unknown, our patient had taken no other suspicious drugs, such as benfluorex, and had not been exposed to toxins known to cause PAH. We acknowledge that a protopathic bias might have occurred and that the patient received chemotherapy with cyclophosphamide for B-CLL relapse from October 2011 to February 2012. No strong evidence was highlighted to consider the alkylating agent in the occurrence of PAH, because respiratory symptoms occurred before cyclophosphamide initiation, and no pulmonary veno-occlusive disease was found. Finally, this case brings out the probable accountability of alemtuzumab in PAH onset.6 In conclusion, alemtuzumab therapy requires enhanced medical follow-up to detect as soon as possible this complication, especially because the European Medicines Agency and the United States Food and Drug Administration have recently approved alemtuzumab for relapsing forms of multiple sclerosis and the drug is increasingly being used off-label for induction after lung transplantation.
Disclosure statement S.C. reports non-financial support from Chiesi France, MSD France, GSK France, Actelion France, and LFB Biomedicaments outside the submitted work. C.P. reports these last 3 years, in the context of treatments for PAH, fees for lectures from Pfizer France, Bayer France, GSK France, MSD France, Actelion France, personal financial support to attend medical meetings from Actelion France, outside the submitted work, and his institution,
1053-2498/$ - see front matter r 2016 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2016.10.013
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
2 Table 1
Evolution of Invasive Hemodynamic, Clinical, and Imaging Parameters and Treatment
Variables
July 2012
February 2013
August 2013
February 2014
April 2014
August 2014
March 2016
42 21 30 9
42 26 32 14
39 15 25 6
52 27 35 9
54 24 39 13
56 37 45 14
50 20 31 14
40 5 6 3 2.6 6.1 45 II
40 10 11 3 2.18 5.1 55 0.54 422 III
39 8 5 3 2.6 6.0 65 0.53 372 III
51 9 8 4 2.5 5.9 265 III–IV
54 7 6 4 2.46 5.6 45 0.81 200 III–IV
61 16 9 5 2.71 6.17 45 0.64 290 III–IV
50 12 16 2 3.12 6.8 55 1.26 220 III
-
40 20 to 40 -
40 -
80 -
160 60 -
125 120 125 to 250 -
125 120 Until 20
Clinical, imaging, and hemodynamic parameters PAP, mm Hg Systolic Diastolic Mean PAWP, mm Hg RVP, mm Hg Systolic Diastolic RAP, mm Hg PVR, Wood units Cardiac index, liters min–1 m–2 Cardiac output, liters/min LVEF, % RV-to-LV diameter ratio 6MWT, m NYHA Functional Class Non-specific and specific PAH medications Furosemide, mg/day Tadalafil, mg/day Sildenafil, mg/day Bosentan, mg/day Epoprostenol, ng kg–1 min–1
6MWT, 6-minute walk test; LV, left ventricular; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PAP, pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RV, right ventricular; RVP, right ventricular pressure.
Centre Hospitalier Universitaire Grenoble Alpes via its Research Department, received honoraria linked to phase 2 and 3 randomized controlled trials from Gilead, Bayer and Actelion France, outside the submitted work. P.B. reports grants and non-financial support from Actelion France, grants from Pfizer, GSK, and the French Association for Clinical Pharmacy, and personal fees for participation in a scientific advisory board from Actelion France, outside the submitted work. The other authors do not have a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. The authors gratefully acknowledge Dr Marion Lepelley, from Centre Régional de Pharmacovigilance de Grenoble, France, and Prof Gilbert Ferretti (radiologist), Dr Adrien Jankowski (radiologist), Dorothée Duron (pharmacist resident), Hélène Pluchart (pharmacist resident), Prof Benoît Allenet (clinical pharmacist), and Dr Hélène Bouvaist (cardiologist), all from Centre Hospitalier Universitaire Grenoble Alpes, France, for their accurate analysis of this case anecdote and their significant contribution for the elaboration of this manuscript.
References 1. Montani D, Seferian A, Savale L, Simonneau G, Humbert M. Druginduced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev 2013;22:244-50. 2. Quilot FM, Georges M, Favrolt N, et al. Pulmonary hypertension associated with ponatinib therapy. Eur Respir J 2016;47:676-9. 3. Turgut B, Vural O, Pala FS, et al. 17p Deletion is associated with resistance of B-cell chronic lymphocytic leukemia cells to in vitro fludarabine-induced apoptosis. Leuk Lymphoma 2007;48:311-20. 4. Montrone D, Correale M, Franzese MG, Ieva R, Di Biase M, Capalbo SF. Pulmonary arterial hypertension in a chronic lymphocytic leukemia patient in treatment with rituximab. J Cardiovasc Med 2015;16 (Suppl 1):S65. 5. Lazarevic VL, Liljeholm M, Forsberg K, Söderberg S, Wahlin A. Fludarabine, cyclophosphamide and rituximab (FCR) induced pulmonary hypertension in Waldenström macroglobulinemia. Leuk Lymphoma 2008;49:1209-11. 6. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30: 239-45.