Lenalidomide‐associated pneumonitis in patients with plasma cell dyscrasias

Lenalidomide is an immunomodulatory drug (IMiD) that has been approved for the treatment of relapsed or refractory multiple myeloma (MM) [1, 2]. Common side effects of lenalidomide treatment include myelosupression, diarrhea, fever, muscle cramps, neuropathy, constipation, rash, fatigue, and deep vein thrombosis [1-4]. Pulmonary complications are believed to be uncommon. So far, three cases of lenalidomide-induced pulmonary toxicity have been reported, commonly presented with dyspnea, fever, and hypoxia [5-7]. To assess the incidence, characteristics and outcome of pneumonitis associated with lenalidomide, we assessed the incidence and outcome of lenalidomide-induced pneumonitis in 237 consecutive unselected patients with MM or AL amyloidosis. We identified eight (3.37%) patients with clinical radiographic and laboratory criteria of lenalidomide-induced pneumonitis. In all patients lenalidomide was discontinued and most received systemic corticosteroids. In four of eight patients lenalidomide was reinstituted after symptom resolution. These data suggest that clinicians should be alert for the early recognition and prompt management of this complication. In an expanded access program of lenalidomide with dexamethasone in 1,438 patients, respiratory symptoms such as dyspnea of unspecified nature, cough or pneumonia were recorded in about 10–15% of patients each [4]. So far, three cases of lenalidomide-induced pulmonary toxicity have been reported [5-7]. In these cases, presentation may have been confused with lower respiratory tract infection, given that these patients presented with dyspnea, fever, and hypoxia [5-7]. Pulmonary toxicity has also been recorded in patients receiving thalidomide [8] or bortezomib [8, 9] or pomalidomide [10]. Drug-associated pulmonary diseases vary in their pathophysiology, clinical and radiographic presentation, and prognosis and a high index of suspicion are required for the diagnosis [11, 12]. Among 237 consecutive patients, who received lenalidomide, (myeloma: 190 patients, AL amyloidosis: 47 patients) we identified eight patients (3.37%) who fulfilled all the criteria for the diagnosis of lenalidomide-related pneumonitis. The patients' characteristics are summarized in Table I. Five patients received lenalidomide combined with cyclophosphamide and dexamethasone, two patients received lenalidomide with melphalan and prednisone and one lenalidomide with dexamethasone. Only one patient (12.5%) had a history of a prior respiratory disorder (asthma). Symptoms of lenalidomide-related pneumonitis developed within 0.5 to 24 (median 5) months from the initiation of lenalidomide-based treatment and the most common were dyspnea (7/8 patients), dry cough (5/8), and fever (3/8), followed by fatigue (2/8) and skin rash (2/8 patients). Auscultation revealed bilateral lung field fine crackles in all patients. Leukocyte counts varied (mean 8,210/ml, range 1,120–12,400/ml), C-reactive protein levels were elevated (mean 10.1 mg/dl, range 1.4–20.3 mg/dl, ULN 0.5 mg/dl), and were reduced within normal range after the resolution of the symptoms. Peripheral blood eosinophilia was not found in any patient. Arterial blood gas analysis revealed hypoxemia in all patients with normal/low pCO2. Pulmonary function tests revealed a restrictive pattern with low TLCO (corrected for the degree of anemia). Chest radiography showed no gross abnormalities. Chest CT high resolution computed tomography (HRCT) scanning displayed symmetrical, bilateral interstitial abnormalities with areas of ground glass opacity, predominantly involving middle lung fields and lung bases compatible with nonspecific interstitial pneumonitis (Figure 1). In all patients cardiac echocardiography was performed to exclude a cardiac cause of interstitial lung disease. Chest CT scanning showing symmetrical, bilateral interstitial abnormality with areas of ground glass opacity predominantly involving middle lung fields and lung bases. Three out of the eight patients (37.5%) received antibiotics, whereas seven of the eight (87.5%) patients were hospitalized but none required mechanical ventilation. Lenalidomide was held in all patients during the acute event and corticosteroid therapy (prednisolone at a starting dose of 25–75 mg per day) was administered in 7/8 (87.5%) of patients. Standard supportive care (oxygen, bronchodilators, hydration) was given, while in one out of eight patients prolonged (>2 weeks) oxygen therapy was needed. An infectious cause of respiratory dysfunction was excluded in all patients as indicated by negative blood and sputum cultures and negative serology and PCR for certain fungi and viruses. Clinical symptoms of pneumonitis resolved in all patients within 9–50 days after discontinuation of lenalidomide: fever and dyspnea resolved within 2–4 days, whereas dry cough and hypoxia lasted longer. Repeated HRCTs, 2–3 months after the resolution of symptoms, showed significant improvement without residual interstitial fibrosis. Lenalidomide was discontinued permanently in four cases: its dose reduced in two cases, while in two patients lenalidomide was reintroduced without dose modification, but with concomitant low-dose corticosteroids. Drug-induced pneumonitis is a side effect of several drugs, including cytotoxic, immune-modifying, antiarrhythmic drugs, etc. [12]. Our report is the first systematic effort to record this complication of lenalidomide-based therapy in an unselected population of consecutive patients with plasma cell dyscrasias. In our series of 237 patients, we found that 3.4% of patients developed clinical and radiographic evidence of pneumonitis. However, given the nonspecific presentation of drug-induced pneumonitis, we cannot exclude the possibility that the diagnosis of lenalidomide-induced pneumonitis may have been missed in some patients. The development of pneumonitis in combination with concomitant use of cyclophosphamide needs further evaluation. Cyclophosphamide, in high doses, has been reported to be related with the development of interstitial pneumonitis [13, 14]. However, single agent low dose oral cyclophosphamide, only rarely, has been reported to cause interstitial pneumonitis [15]. Whether, its combination with lenalidomide may increase the risk of interstitial pneumonitis requires further evaluation. The development of lenalidomide-induced pneumonitis is a relatively early complication [5-7], with a median time to the development of symptoms of about 3–5 months in our series, indicating a hypersensitivity-related mechanism, similar to that seen in patients with hypersensitivity pneumonitis. The development of rash in two of our patients supports an underlying hypersensitivity-induced mechanism. However, in three patients symptoms developed after 10–24 months of lenalidomide treatment—thus, a different mechanism perhaps associated with total dose or time of exposure may also coexist. Management of drug-induced interstitial pneumonitis is based on the discontinuation of the presumed causal agent and in some cases systemic corticosteroids, depending on the severity of hypoxemia and extent of pulmonary infiltrates, after the exclusion of an active infection [12]. This strategy was also followed in our patients. In our experience, therapy with systemic corticosteroids resulted in rapid symptom resolution and improvement of oxygenation. There are no data to support routine use of antibiotics. However, in immunocompromised patients such as those with MM receiving antimyeloma therapy, broad spectrum antibiotics may be used until the diagnosis has been established, since pulmonary infections with several infectious agents may present with a radiographic pattern of interstitial pneumonitis. The decision to restart therapy with lenalidomide is based on the severity of pneumonitis and the availability of other treatment options. Our data indicate that with appropriate dose reduction and with the concomitant administration of corticosteroids, treatment with lenalidomide may be reinstituted in some patients. It is difficult to make firm recommendations based on the limited available data. However, it would be prudent to stop permanently lenalidomide treatment for patients with severe pneumonitis (such as those with life-threatening respiratory compromise). A strategy involving dose reduction in patients with less severe pneumonitis may be indicated, based on careful assessment of the individual patient. For patients with only mild symptoms initial addition of corticosteroids with close surveillance with or without dose reduction may be considered. However, if symptoms recur then lenalidomide should be held and dose reduced or even discontinued. Data from ongoing clinical studies and the increasing experience with the use of lenalidomide will help to refine these recommendations. In conclusion, within the limitations of this retrospective study, our data indicate that although an unusual complication, clinicians should be alert for the early recognition of pneumonitis associated with lenalidomide. Moreover, these results suggest a need for the monitoring of pulmonary adverse events and the necessity for guidelines regarding the management of pneumonitis in future studies involving lenalidomide. We reviewed the medical records of 237 patients with MM or AL amyloidosis, who were treated with lenalidomide-based therapy in our centre to identify patients with the diagnosis of lenalidomide-induced interstitial pneumonitis. All patients received lenalidomide in combination with dexamethasone, or with melphalan and prednisone, or with dexamethasone and low dose oral cyclophosphamide. The causal relationship of pulmonary symptoms to lenalidomide was based on World Health Organization's classification of causal criteria for the adverse effects of medications [16]. The diagnosis of pneumonitis was based on clinical, radiographic, and laboratory criteria that required the presence of all of the following: (1) dyspnea, dry cough, fever, and fatigue; (2)patchy shadows on chest radiograph and ground glass shadows and/or reticular opacities on HRCT; (3) a restrictive pulmonary functional impairment pattern (as assessed by pulmonary function tests) with hypoxemia; (4) absence of pulmonary infection with bacteria, fungi, acid fast bacilli, and viruses and congestive heart failure; (5) symptomatic improvement of pneumonitis after the discontinuation of lenalidomide. Flora Zagouri*, Maria Roussou*, Efstathios Kastritis*, Andreas Koureas , Eleni Tsokou , Magdalini Migkou*, Maria Gavriatopoulou*, Nikitas Nikitas*, Maria Gkotzamanidou*, Evangelos Terpos*, Meletios-Athanasios Dimopoulos*, * Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, University of Athens, Greece, Department of Radiology, University of Athens, Areteion Hospital, Athens, Greece, Department of Radiology, Alexandra Hospital, Athens, Greece.