Leukemia & Lymphoma, October 2014; 55(10): 2408–2409 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.887714
LETTER TO THE EDITOR
Acute respiratory failure from nilotinib-associated diffuse alveolar hemorrhage Christopher Donatelli1, Daych Chongnarungsin2 & Rendell Ashton2 1Department of Internal Medicine, Medicine Institute and 2Department of Pulmonary, Allergy and Critical Care Medicine,
Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA
The treatment of chronic myeloid leukemia (CML) has been revolutionized with the introduction of tyrosine kinase inhibitors. Nilotinib, the second generation of this class of medications, was first introduced as the secondline treatment for patients who develop resistance to or intolerance of treatment with imatinib. Studies have also demonstrated its superior efficacy over imatinib as an initial treatment agent [1,2], which has led to increasing use of this agent. Compared with imatinib and dasatinib, another second-generation agent, pulmonary toxicity from nilotinib is rare, which makes it the preferred option for patients with underlying lung disease. We report a case of acute respiratory failure associated with nilotinib therapy, which may represent drug-induced pneumonitis as has been seen with the other agent in this class. A 79-year-old Caucasian male was diagnosed with CML (chronic phase, Phildelphia chromosome positive [Ph⫹] [BCR/ABL1]) in August 2013. His past medical history included diabetes mellitus type 2, coronary artery disease, obstructive sleep apnea and hyperlipidemia. Treatment with nilotinib 300 mg twice daily was started as first-line therapy. Two weeks after initiation of treatment, he presented to our hospital with the complaint of abdominal pain. He was found to have acute kidney injury (creatinine at 2.78 mg/dL from 0.9–1.0 mg/dL at baseline) and hyperuricemia (uric acid of 7.2 from 4.9 at baseline). The diagnosis of tumor lysis syndrome was made, and treatment with intravenous fluid and allopurinol was started. The treatment with nilotinib was continued at that time. The patient had a good response to the treatment with improvement of kidney function and good urine output. On the fourth day of hospitalization, the patient started to complain of shortness of breath. He was found to have an increase in oxygen requirement to 30 liters per minute (LPM) by high-flow nasal cannula to maintain oxygen saturation at 98%, which was increased from 2 LPM by nasal cannula the day before. He was afebrile with diffuse
crackles on examination. Chest X-ray revealed progressive bilateral diffuse interstitial opacities, and chest computed tomography (CT) (Figure 1) revealed patchy peribronchial consolidation and ground glass opacities. The patient was started on meropenem, vancomycin and ciprofloxacin for the treatment of possible hospital-acquired pneumonia. Methylprednisolone 80 mg intravenous (IV) every 12 h was started for the concern of possible acute interstitial pneumonitis from a drug reaction, and nilotinib was discontinued. The patient still continued to have difficulty breathing despite all the above treatments, and was intubated on the sixth day of his hospital stay. Bronchoscopy with bronchoalveolar lavage (BAL) was performed in the right middle lobe (RML) revealing blood-tinged fluid, which became increasingly hemorrhagic with sequential aliquots, compatible with the diagnosis of alveolar hemorrhage. BAL fluid analysis revealed a white blood cell (WBC) count of 290/μL with 90% neutrophils, negative gram stain, acid-fast bacilli (AFB) stain, fungal culture, viral culture, bacterial culture and pneumocystis polymerase chain reaction (PCR). Two days after intubation, the patient’s respiratory status improved dramatically. He was extubated and was maintained on 6 LPM of oxygen by nasal cannula and discharged on the 10th day of hospital admission. At the time of discharge, the patient did not require supplemented oxygen, and his chest X-ray revealed partial resolution of the interstitial opacities. Methylprednisolone was later switched to prednisone, which was slowly tapered. The treatment for his underlying CML was changed from nilotinib to imatinib. On follow-up 2 months later, the patient reported having no difficulty in breathing and required no oxygen supplement. Only one report of nilotinib-induced interstitial lung disease was found on literature review [3]. Go et al. described a patient who developed chronic interstitial lung disease after being treated with nilotinib for 3 years. Compared to that reported case, our patient had a completely
Correspondence: Daych Chongnarungsin, Cleveland Clinic Foundation, Respiratory Institute, 9500, Euclid Avenue, Cleveland, OH 44195, USA. E-mail: [email protected] Received 19 December 2013; revised xx xxx xxxx ; accepted 18 January 2014
2408
Letter to the Editor 2409 due to the severe reaction in this case, the decision was made to not use nilotinib again and switch therapy to imatinib. In summary, we report a case of severe acute interstitial lung disease and diffuse alveolar hemorrhage related to treatment with nilotinib. Clinicians caring for patients treated with nilotinib who develop acute respiratory failure should have a high index of suspicion of this condition, since initiation of steroids and cessation of nilotinib may lead to rapid clinical improvement.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal. Figure 1. Computed tomography scan of the chest revealed diffuse ground glass opacities.
References different presentation, with acute respiratory failure and diffuse alveolar hemorrhage requiring mechanical ventilatory support. Similar manifestations were reported in a patient taking imatinib by Lin et al. in this journal in 2006 [4]. The pathogenesis of tyrosine kinase-induced interstitial lung disease is not completely understood. In our patient, the rapid onset of severe respiratory failure and prompt response to treatment with corticosteroids suggest that the immunologic reaction was the likely cause of the diffuse alveolar damage leading to diffuse alveolar hemorrhage. There is a report of successful reintroduction of the same agent [5] after such an episode; however,
[1] Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010;362:2251–2259. [2] Hochhaus A , Saglio G, Larson RA , et al. Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2013;121:3703–3708. [3] Go SI, Lee WS, Lee GW, et al. Nilotinib-induced interstitial lung disease. Int J Hematol 2013;98:361–365. [4] Lin JT, Yeh KT, Fang HY, et al. Fulminant, but reversible interstitial pneumonitis associated with imatinib mesylate. Leuk Lymphoma 2006;47:1693–1695. [5] Izumiyama N, Noguchi K, Takahashi H, et al. Successful reintroduction of mesylate imatinib after pneumonitis in two patients with gastrointestinal stromal tumor (GIST). Nihon Kokyuki Gakkai Zasshi 2009;47:918–923.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
LETTER TO THE EDITOR
Acute respiratory failure from nilotinib-associated diffuse alveolar hemorrhage Christopher Donatelli1, Daych Chongnarungsin2 & Rendell Ashton2 1Department of Internal Medicine, Medicine Institute and 2Department of Pulmonary, Allergy and Critical Care Medicine,
Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA
The treatment of chronic myeloid leukemia (CML) has been revolutionized with the introduction of tyrosine kinase inhibitors. Nilotinib, the second generation of this class of medications, was first introduced as the secondline treatment for patients who develop resistance to or intolerance of treatment with imatinib. Studies have also demonstrated its superior efficacy over imatinib as an initial treatment agent [1,2], which has led to increasing use of this agent. Compared with imatinib and dasatinib, another second-generation agent, pulmonary toxicity from nilotinib is rare, which makes it the preferred option for patients with underlying lung disease. We report a case of acute respiratory failure associated with nilotinib therapy, which may represent drug-induced pneumonitis as has been seen with the other agent in this class. A 79-year-old Caucasian male was diagnosed with CML (chronic phase, Phildelphia chromosome positive [Ph⫹] [BCR/ABL1]) in August 2013. His past medical history included diabetes mellitus type 2, coronary artery disease, obstructive sleep apnea and hyperlipidemia. Treatment with nilotinib 300 mg twice daily was started as first-line therapy. Two weeks after initiation of treatment, he presented to our hospital with the complaint of abdominal pain. He was found to have acute kidney injury (creatinine at 2.78 mg/dL from 0.9–1.0 mg/dL at baseline) and hyperuricemia (uric acid of 7.2 from 4.9 at baseline). The diagnosis of tumor lysis syndrome was made, and treatment with intravenous fluid and allopurinol was started. The treatment with nilotinib was continued at that time. The patient had a good response to the treatment with improvement of kidney function and good urine output. On the fourth day of hospitalization, the patient started to complain of shortness of breath. He was found to have an increase in oxygen requirement to 30 liters per minute (LPM) by high-flow nasal cannula to maintain oxygen saturation at 98%, which was increased from 2 LPM by nasal cannula the day before. He was afebrile with diffuse
crackles on examination. Chest X-ray revealed progressive bilateral diffuse interstitial opacities, and chest computed tomography (CT) (Figure 1) revealed patchy peribronchial consolidation and ground glass opacities. The patient was started on meropenem, vancomycin and ciprofloxacin for the treatment of possible hospital-acquired pneumonia. Methylprednisolone 80 mg intravenous (IV) every 12 h was started for the concern of possible acute interstitial pneumonitis from a drug reaction, and nilotinib was discontinued. The patient still continued to have difficulty breathing despite all the above treatments, and was intubated on the sixth day of his hospital stay. Bronchoscopy with bronchoalveolar lavage (BAL) was performed in the right middle lobe (RML) revealing blood-tinged fluid, which became increasingly hemorrhagic with sequential aliquots, compatible with the diagnosis of alveolar hemorrhage. BAL fluid analysis revealed a white blood cell (WBC) count of 290/μL with 90% neutrophils, negative gram stain, acid-fast bacilli (AFB) stain, fungal culture, viral culture, bacterial culture and pneumocystis polymerase chain reaction (PCR). Two days after intubation, the patient’s respiratory status improved dramatically. He was extubated and was maintained on 6 LPM of oxygen by nasal cannula and discharged on the 10th day of hospital admission. At the time of discharge, the patient did not require supplemented oxygen, and his chest X-ray revealed partial resolution of the interstitial opacities. Methylprednisolone was later switched to prednisone, which was slowly tapered. The treatment for his underlying CML was changed from nilotinib to imatinib. On follow-up 2 months later, the patient reported having no difficulty in breathing and required no oxygen supplement. Only one report of nilotinib-induced interstitial lung disease was found on literature review [3]. Go et al. described a patient who developed chronic interstitial lung disease after being treated with nilotinib for 3 years. Compared to that reported case, our patient had a completely
Correspondence: Daych Chongnarungsin, Cleveland Clinic Foundation, Respiratory Institute, 9500, Euclid Avenue, Cleveland, OH 44195, USA. E-mail: [email protected] Received 19 December 2013; revised xx xxx xxxx ; accepted 18 January 2014
2408
Letter to the Editor 2409 due to the severe reaction in this case, the decision was made to not use nilotinib again and switch therapy to imatinib. In summary, we report a case of severe acute interstitial lung disease and diffuse alveolar hemorrhage related to treatment with nilotinib. Clinicians caring for patients treated with nilotinib who develop acute respiratory failure should have a high index of suspicion of this condition, since initiation of steroids and cessation of nilotinib may lead to rapid clinical improvement.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal. Figure 1. Computed tomography scan of the chest revealed diffuse ground glass opacities.
References different presentation, with acute respiratory failure and diffuse alveolar hemorrhage requiring mechanical ventilatory support. Similar manifestations were reported in a patient taking imatinib by Lin et al. in this journal in 2006 [4]. The pathogenesis of tyrosine kinase-induced interstitial lung disease is not completely understood. In our patient, the rapid onset of severe respiratory failure and prompt response to treatment with corticosteroids suggest that the immunologic reaction was the likely cause of the diffuse alveolar damage leading to diffuse alveolar hemorrhage. There is a report of successful reintroduction of the same agent [5] after such an episode; however,
[1] Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010;362:2251–2259. [2] Hochhaus A , Saglio G, Larson RA , et al. Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2013;121:3703–3708. [3] Go SI, Lee WS, Lee GW, et al. Nilotinib-induced interstitial lung disease. Int J Hematol 2013;98:361–365. [4] Lin JT, Yeh KT, Fang HY, et al. Fulminant, but reversible interstitial pneumonitis associated with imatinib mesylate. Leuk Lymphoma 2006;47:1693–1695. [5] Izumiyama N, Noguchi K, Takahashi H, et al. Successful reintroduction of mesylate imatinib after pneumonitis in two patients with gastrointestinal stromal tumor (GIST). Nihon Kokyuki Gakkai Zasshi 2009;47:918–923.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
