|Year : 2018 | Volume
| Issue : 1 | Page : 26-37
Pneumonitis after precision oncology therapies: A concise review
Akash Jain, Vickie R Shannon, Ajay Sheshadri
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
|Date of Web Publication||31-Jul-2018|
Dr. Ajay Sheshadri
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Units 1462, Houston, Texas
Source of Support: None, Conflict of Interest: None
With greater understanding of the molecular biology of cancer, precision oncology therapies are becoming increasingly prevalent. Adverse events associated with these therapies may cause significant harm to patients if not promptly recognized and treated. In this review, we focus on pneumonitis that occurs as a side effect of treatment with precision oncology agents. We discuss the incidence and time to onset of pneumonitis associated with a broad array of precision oncology agents. We highlight the common patterns of pneumonitis and offer a comprehensive approach to evaluation and treatment with therapy-specific guidelines where available.
Keywords: Pneumonitis, precision oncology agent, pulmonary adverse events
|How to cite this article:|
Jain A, Shannon VR, Sheshadri A. Pneumonitis after precision oncology therapies: A concise review. J Immunother Precis Oncol 2018;1:26-37
|How to cite this URL:|
Jain A, Shannon VR, Sheshadri A. Pneumonitis after precision oncology therapies: A concise review. J Immunother Precis Oncol [serial online] 2018 [cited 2019 Mar 26];1:26-37. Available from: http://www.jipoonline.org/text.asp?2018/1/1/26/237832
| Introduction|| |
Almost 40% of individuals will be diagnosed with cancer at some point in their lives. In the United States of America, the incidence of new cases of cancer is estimated at 455 cases per 100,000 individuals per year, and an estimated 171.2 deaths per 100,000 individuals are attributed to cancer. Surgery, chemotherapy, and radiation are the mainstays of therapy for most cancers. However, despite improvements in outcomes for many early-stage cancers, survival rates for late-stage cancers have plateaued. For example, 5-year survival rates have remained stable for late-stage non-small cell lung cancers over the last decade despite numerous clinical trials of conventional therapies. New strategies are needed to mitigate the morbidity and mortality associated with late-stage cancers.
Late-stage cancers are often resistant to conventional chemotherapy and radiation. Molecular profiling of late-stage cancer may identify specific mutations which can be targeted for treatment. The strategy of identifying mutations in pathways associated with cancer progression and then directly targeting them is broadly termed “precision oncology." Prominent examples of improvements in early survival with precision oncology approaches include BRAF inhibitors in melanoma and epidermal growth factor receptor (EGFR) inhibitors in EGFR-mutant lung adenocarcinoma., However, improvements in long-term survival remain elusive.
With the advent of precision oncology therapies, oncologists now face a new array of adverse effects that may require prompt recognition and treatment. The purpose of this review is to highlight pulmonary adverse events with common precision oncology agents. We propose a standardized clinical algorithm to evaluate and treat cancer patients receiving precision oncology therapies who are suspected of having pneumonitis. Furthermore, we highlight common manifestations of pneumonitis after treatment with EGFR inhibitors, HER2/neu receptor inhibitors, mammalian target of rapamycin (mTOR) inhibitors, anti-CD20 and anti-CD30 monoclonal antibodies, breakpoint cluster (BCR)-Abelson tyrosine kinase inhibitors (TKIs), anaplastic lymphoma kinase (ALK) inhibitors, and Bruton's tyrosine kinase (BTK) inhibitors.
| Patterns of Pneumonitis After Precision Oncology Therapies|| |
Interstitial lung diseases (ILDs) are a collection of various diseases of the lung parenchyma with varying incidences, manifestations, and prognoses. Pulmonary complications of precision oncology therapies often mimic certain ILDs seen in the general population. In this section, we choose three specific patterns of pneumonitis – nonspecific interstitial pneumonitis (NSIP), organizing pneumonia (OP), and diffuse alveolar damage (DAD) – that are commonly seen in patients receiving precision oncology therapies and discuss the pathophysiology, clinical features, and prognosis [summarized in [Table 1]. [Figure 1] shows representative images from patients who developed NSIP, OP, and DAD after precision oncology therapies. A more complete discussion of the clinical features and pathophysiology of various ILDs is available elsewhere.,
|Table 1: Clinical, radiological, and histopathological features of common patterns of pneumonitis in patients receiving precision oncology therapies|
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|Figure 1: Representative images of (a) nonspecific interstitial pneumonitis, (b) organizing pneumonia, and (c) diffuse alveolar damage in patients receiving precision oncology therapies.|
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Nonspecific interstitial pneumonitis
NSIP may be idiopathic or arise in association with various conditions such as autoimmune disease, human immunodeficiency virus infection, or after exposure to certain drugs. NSIP is one of the most common manifestations of drug-induced ILD. NSIP typically presents with nonspecific symptoms of cough and dyspnea. Histologically, NSIP is characterized by dense fibrosis with diffuse inflammatory cell infiltration and uniform and diffuse thickening of alveolar walls, but without loss of alveolar structural integrity. High-resolution computed tomography (HRCT) imaging of NSIP most commonly shows increased reticular markings, traction bronchiectasis, and ground-glass opacities.,, Subpleural sparing of pulmonary opacities helps distinguish NSIP from idiopathic pulmonary fibrosis, but is neither sensitive nor specific for the diagnosis. These radiologic and histopathologic patterns may be seen in other ILDs such as hypersensitivity pneumonitis (HP). However, the presence of poorly formed granulomas or multinucleated giant cells on surgical biopsies and the presence of air trapping on inspiratory and expiratory imaging may help distinguish HP from NSIP. HP is a less common manifestation of pneumonitis after precision oncology therapies than NSIP, but HP and NSIP are similar in terms of clinical presentation and course. Therefore, for the purposes of this review, we considered radiologic HP to be a subtype of NSIP.
Treatment of NSIP depends on the severity of disease, the underlying cause, and the rate of progression. For drug-related NSIP, drug interruption is generally recommended for symptomatic patients and in certain cases may be curative. Optimal dosing and duration of corticosteroid treatment for NSIP have not been established, and the following are our recommendations. Patients with NSIP who have minimal symptoms and no change in pulmonary function may be observed, but most patients require corticosteroid therapy (0.5–1 mg/kg/day of prednisone or its equivalent) for 8–12 weeks. Steroid-refractory disease is more commonly seen in NSIP than in OP and may require further therapy with intravenous corticosteroids and/or cytotoxic therapies, though the efficacy of noncorticosteroid agents has not been well established.
OP is an ILD that mainly affects distal respiratory bronchioles and alveoli. Clinical features of OP include nonproductive cough, dyspnea, and weight loss.,,, In some patients, symptoms of malaise and fatigue may be present for weeks prior to diagnosis, but are nonspecific for the diagnosis of OP. Respiratory infections are often implicated as a cause of OP, though the mechanism remains unclear. On histopathology, OP is characterized by excessive proliferation of granulation tissues in the distal bronchus and alveoli along with mild-to-moderate infiltration of plasma cells and lymphocytes., HRCT imaging of the chest in patients with OP may reveal patchy areas of consolidation or ground-glass opacities which are often seen in the periphery.,,,,,,,,,,,, The reverse halo sign can be seen in OP but is not pathognomonic.
Treatment of OP is dependent on the severity of disease. In mild OP, resolution can occur spontaneously, but requires close monitoring of respiratory symptoms, imaging, and/or pulmonary function. For patients who have progressive and/or persistent symptoms with evidence of pulmonary function impairment, corticosteroid therapy is typically highly efficacious, with doses usually starting at 0.5–1 mg/kg/day of prednisone or its equivalent for 3–6 months. Interruptions in corticosteroid treatment may result in recurrence of OP, and rarely OP can be resistant to corticosteroid therapy. Optimal treatment regimens for OP have not been studied in randomized trials. Treatment recommendations are generally based on clinical experience and observations from small case series and are based on symptom severity, pulmonary function impairment at presentation, disease progression, and radiographic extent of disease. Withholding the offending agent is generally recommended, for patients with asymptomatic or mild disease. Drug withdrawal and initiation of systemic corticosteroids is recommended among patients with progressive symptoms and/or moderate-to-severe disease. The addition of other therapies, such as cyclophosphamide, cyclosporine, rituximab, and macrolides, has been associated with anecdotal success in small case series of steroid-refractory patients.,,,
Diffuse alveolar damage
DAD is a rare and fulminant form of ILD caused by alveolar injury leading to noncardiogenic pulmonary edema., DAD usually occurs more rapidly than NSIP or OP and is characterized by progressive dyspnea and cough over days to weeks. The diagnosis of DAD is suggested by clinical evidence of acute respiratory distress syndrome and its histopathologic correlate, DAD. The histopathology of DAD is characterized by an inflammatory interstitial infiltrate associated with thickened alveolar membranes, edema of the alveolar septa, and hyaline membrane deposition.,
HRCT images of DAD show widespread bilateral airspace opacities which may be more prominent in the dependent areas of the lung., Clinical, pathologic, and microbiologic evaluations are important to exclude competing diagnoses such as infection, heart failure, DAH, and other rare ILDs such as acute eosinophilic pneumonia. Supportive therapies, including noninvasive or invasive mechanical ventilation, are often the mainstay of treatment for DAD, as respiratory failure is common. Early initiation of high-dose systemic corticosteroids is generally recommended, although data supporting this practice are very limited. Despite aggressive therapy, DAD often has a fulminant course with high rates of mortality.
| Clinical Algorithm for Diagnosis of Pneumonitis After Precision Oncology Therapies|| |
Symptoms of pneumonitis may be subtle and masked by other comorbid symptoms of the underlying malignancy. Chest radiography is not sufficiently sensitive to detect subtle findings of pneumonitis. Thus, new or worsening cough, shortness of breath, chest tightness, or pleurisy should prompt HRCT imaging of the chest. Pulmonary consultation for bronchoscopic examination with bronchoalveolar lavage should be sought early among patients with compatible clinical histories and/or suspicious findings on chest CT imaging to rule out alternative diagnoses, such as pneumonia. If there is no evidence of infection and there are no other contraindications, surgical biopsies of the involved lung parenchyma should be considered in select patients to determine the pattern of ILD. Transbronchial biopsies are not recommended due to low sensitivity for detection of ILD and poor diagnostic yield.
A general approach to the management of pneumonitis with drug-related adverse effects is provided by the Common Terminology Criteria for Adverse Events (CTCAEs) criteria [Table 2]. Indications for drug interruption and resumption vary according to the specific agent in question. In general, when specific guidelines are not available, we recommend corticosteroid treatment in Grade 2 or higher pneumonitis, guided by the radiologic or histopathologic pattern of ILD. In the following section, we provide the incidences and patterns of pneumonitis seen with common precision oncology agents and, when available, provide unique strategies associated with each class of drugs. We highlight specific nuances, such as the timing of drug interruption and whether resumption of therapy is advisable.
|Table 2: Grading of pneumonitis as outlined by the Common Terminology Criteria for Adverse Events v5.0 and general recommendations for treatment|
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| Pneumonitis After Precision Oncology Therapies|| |
Epidermal growth factor receptor inhibitors
The EGFR belongs to the tyrosine kinase family and is expressed in several tissues such as the lung, breast, gastrointestinal tract, and the oropharynx.,, Activation of the EGFR pathway by any of its ligands induces increased cellular proliferation and survival and angiogenesis through the activation of several downstream mediators such as KRAS, phosphoinositide 3-kinase, phospholipase C, and AKT.,,,, Not surprisingly, cancers can increase activity of the EGFR pathway to promote tumor cell proliferation and survival through increased tumor expression of EGFR or mutations in EGFR leading to increased activity.,
Anticancer agents target the EGFR pathway in two distinct ways. Monoclonal antibodies bind to the extracellular part of EGFR receptor and block ligand binding, while small molecule TKIs target the intracellular component of the EGFR receptor and prevent downstream signaling. Commonly used drugs include the TKIs gefitinib, erlotinib, osimertinib, and afatinib, and the monoclonal antibodies, namely, cetuximab and panitumumab.
EGFR TKIs are more commonly associated with pneumonitis than anti-EGFR monoclonal antibodies. Pneumonitis occurs in about 1% of cases of erlotinib and gefitinib therapy, with fatality being reported in up to one-third of cases.,,,,,, Pneumonitis after afatinib therapy has been reported, but is rare. Cases of pneumonitis after gefitinib and osimertinib therapy more commonly present as NSIP,,, while pneumonitis after erlotinib more commonly presents as OP. The incidence of pneumonitis due to osimertinib is 2%–4%, and 0.4%–0.5% of patients develop fatal pneumonitis.
EGFR TKIs are also associated with radiation recall pneumonitis. Radiation recall pneumonitis is a poorly understood phenomenon, whereby pneumonitis is triggered by a precipitating drug within lung tissue that has been previously irradiated. The diagnosis is made if the area of pneumonitis corresponds closely to the fields of radiation exposure during treatment. Radiation recall pneumonitis may be more common if the time interval between radiation treatment and systemic chemotherapy is <3 months. Radiation recall pneumonitis may resolve spontaneously, but symptomatic cases require treatment with corticosteroids, potentially withholding the EGFR inhibitor.
Studies have suggested that pneumonitis-related mortality associated with EGFR TKI therapy may be higher in Japanese populations as compared to non-Japanese population (approximately 1.6%–4.3% in Japanese populations and 0.3%–1.0% in non-Japanese populations). This may be related to the higher frequency of EFGR-driven lung cancers, and therefore more frequent use of EGFR-inhibitors in Asian individuals rather than an increased genetic susceptibility to EGFR-related drug toxicity in the Asian population.,,
The incidence of pneumonitis with the anti-EGFR monoclonal antibodies cetuximab and panitumumab has been reported to be around 1.7% and 1.3%, respectively., Cetuximab most commonly presents with NSIP. However, panitumumab-related pneumonitis most commonly presents with DAD, followed by NSIP and OP. Fatalities associated with cetuximab and panitumumab are around 41% and 36%, respectively, suggesting that pneumonitis after these monoclonal antibodies may present with a more fulminant course.
Treatment of pneumonitis after EGFR inhibitor therapy includes corticosteroids and withholding the offending drug. Grading schemes specific to EGFR inhibitors have not been established, but we recommend using the NCI CTCAE [Table 2]. Grade 1 pneumonitis may be managed by close observation with serial imaging. For Grade ≥2 pneumonitis, we would recommend drug interruption, with consideration of changing anti-EGFR therapies when the pneumonitis resolves.
HER2/neu inhibitors are a special class of EGFR inhibitors used in HER2/neu-positive breast cancer. HER2 is a member of the EGFR family gene which activates several signaling pathways which lead to cell proliferation and anti-apoptosis.,, About 20%–30% of breast cancers are HER2/neu positive, and mutations in this gene are associated with poorer prognoses.,
In this review, we will focus on trastuzumab and ado-trastuzumab emtansine., Pertuzumab, which is also approved by the Food and Drug Administration (FDA) for HER2/neu-positive breast cancer, has not been reported to cause pneumonitis. Trastuzumab is a monoclonal antibody which binds to the HER2/neu receptor and causes internalization and downregulation of HER2 and is FDA approved for use in HER2/neu-positive breast cancers., The incidence of pneumonitis is rare, estimated at about 0.5%. However, there have been cases of life-threatening pneumonitis., Ado-trastuzumab emtansine is an antibody drug conjugate which contains trastuzumab and the tubulin inhibitor emtansine., Ado-trastuzumab emtansine is FDA approved for use in metastatic HER2/neu-positive breast cancer that did not respond to trastuzumab or recurred after trastuzumab therapy., The frequency of pneumonitis with ado-trastuzumab is 1.2, higher than with trastuzumab alone.,,, DAD has been reported with HER2/neu inhibitors, but given the rarity of pneumonitis, it is not clear whether this is the most common manifestation. The median time for onset of pneumonitis is 3–4 months after initiation of treatment. Radiation recall pneumonitis has also been reported with trastuzumab.
Treatment of pneumonitis due to HER2/neu inhibitors includes permanent discontinuation of drug and supportive management. There are no specific grading criteria for pneumonitis after HER2/neu inhibitors. Therefore, we recommend use of the NCI CTCAE [Table 2]. The safety of treating those who develop trastuzumab-related pneumonitis subsequently with ado-trastuzumab emtansine is unknown.
Mammalian target of rapamycin inhibitors
mTOR is a serine/threonine kinase which has broad effects on cell survival, cell growth, and cell proliferation., Mutations in several genes can activate the mTOR pathway, which increases the risk of developing several cancers.,,,, Treatment with rapamycin analogs has the potential to inhibit the growth of many cancers that rely on aberrant mTOR signaling for survival. Several mTOR inhibitors have been approved by the FDA or are in clinical trials. In this review, we will focus on the FDA-approved mTOR inhibitors, namely sirolimus, temsirolimus, and everolimus.
Sirolimus is rarely used as a chemotherapeutic agent, but it is more commonly used at lower doses as an immunosuppressive agent. Pulmonary complications after sirolimus are exceedingly rare. Both NSIP and OP have been reported after sirolimus therapy, but imaging and histopathology give discrepant results as to which pattern is more common. The incidence of pneumonitis is higher in the mTOR inhibitors, everolimus and temsirolimus. Larger studies have reported the incidence of pneumonitis after everolimus to be about 10%–23% and in temsirolimus to be about 2%–6%.,,,,, The median time to onset of pneumonitis is about 3 months., The most common patterns of pneumonitis after everolimus and temsirolimus therapy are OP and NSIP.,,, The mechanism by which pneumonitis occurs after mTOR inhibition remains unclear. Of note, mTOR inhibitors are also rarely associated with radiation recall pneumonitis.,
Treatment of pneumonitis after mTOR inhibitor therapy is dependent on the grade of pneumonitis, which varies slightly from the NCI CTCAE [Figure 2]. Asymptomatic pneumonitis (Grade 1) only requires observation. Mild symptoms of cough or shortness of breath (Grade 2a) require close observation and possibly a temporary dose reduction, while more severe symptoms (Grade 2b) require dose reduction and institution of corticosteroid therapy., The need for oxygen or the inability to perform activities of daily living defines Grade 3 and higher pneumonitis from mTOR inhibitor therapy and requires prompt discontinuation of the drug, hospitalization, and corticosteroid therapy. For any patient with life-threatening pneumonitis (e.g., those requiring mechanical ventilation), the mTOR inhibitor should be permanently discontinued.,,
|Figure 2: Suggested algorithm for management of mammalian target of rapamycin inhibitor-associated pneumonitis. Reproduced with permission from Albiges et al., Annals of Oncology 2012.|
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Anti-CD20 and anti-CD30 monoclonal antibodies
The advent of monoclonal antibodies that target cellular markers expressed on B- and T-cells has revolutionized the treatment of lymphomas. The monoclonal antibody, rituximab, binds to the CD20 antigen on B-cells and induces cell death through antibody- and complement-mediated cytotoxicity. Similarly, brentuximab vedotin is comprised of the anti-CD30 antibody, brentuximab, and an anti-mitotic agent, monomethyl auristatin E, which disrupts microtubule function. The FDA has approved rituximab for use in CD20+ lymphoma and chronic lymphocytic leukemia and brentuximab vedotin for use in relapsed Hodgkin's lymphoma and anaplastic large cell lymphoma.
The incidence of rituximab-related pneumonitis is estimated at <0.03% by the manufacturer of the drug. However, in case series of patients receiving rituximab therapy as part of a chemotherapy regimen, incidence rates of rituximab-related pneumonitis have ranged from 4% to 10%.,,,,,, Furthermore, the incidence of pneumonitis in regimens using rituximab with pegylated doxorubicin can exceed 20%. The median time of onset of pneumonitis is 15 days (interquartile range: 7–31 days), and the most common patterns are NSIP, followed by OP and DAD. In a systematic literature review of cases of rituximab-related pneumonitis, there were 18 fatalities out of 99 cases with available outcome data. The mainstays of therapy in rituximab-related pneumonitis are corticosteroids, depending on the pattern of ILD and withholding of the drug. Although data are scant, pneumonitis recurs in about 20% of patients who are re-challenged with rituximab after being treated for rituximab-related pneumonitis.
Brentuximab vedotin is more commonly associated with pneumonitis than rituximab, particularly in the context of bleomycin-containing regimens used in advanced-stage Hodgkin's lymphoma, where the incidence of pneumonitis has been reported to be 44%. As a result, the FDA has placed a black box warning for the use of brentuximab vedotin with bleomycin-containing regimens. In a Phase I study, two out of 11 patients died due to pneumonitis, though the pattern of pneumonitis was not clearly described. Replacing bleomycin with brentuximab vedotin in patients with advanced-stage Hodgkin's lymphoma who are receiving doxorubicin, vinblastine, and dacarbazine reduces the incidence of pneumonitis from 7% to 2% and results in improved progression-free survival. Similarly, in patients with Hodgkin's lymphoma who are undergoing autologous stem cell transplantation after high-dose therapy, brentuximab vedotin is associated with a higher rate of pneumonitis (5% vs. 3% with placebo), but improved progression-free survival. Therefore, the incidence of pneumonitis after brentuximab vedotin therapy is substantially lower in the absence of bleomycin. The most common patterns of pneumonitis after brentuximab vedotin therapy have not been well described, but cases of DAD have been reported. The safety of re-challenging patients with brentuximab vedotin-related pneumonitis is unknown.
Break point cluster-ABL1 tyrosine kinase inhibitors
The Philadelphia chromosome, also known as the BCR-ABL1 fusion gene, is caused by a reciprocal translocation of the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9. This aberrant chromosome 22 results in constitutive activation of ABL1 and abnormal tyrosine kinase signaling, causing the cell to divide uncontrollably. The BCR-ABL1 mutation is seen in nearly all patients with chronic myelogenous leukemia and may be found in some patients with acute lymphoblastic leukemia or acute myelogenous leukemia. In this section, we will discuss toxicities of the BCR-ABL1 TKIs such as imatinib, dasatinib, nilotinib, and bosutinib.,,,,
The overall incidence of imatinib-related pneumonitis is rare, with severe reactions of Grade 3 and Grade 4 occurring in 0.2% and 1.3%, respectively, in one small series. The most common CT presentations of imatinib-related pneumonitis are NSIP, followed by OP. The median interval between drug exposure and the development of pneumonitis is about 2 months. The incidence of dasatinib may as high as 17%. Dastinib-related pneumonitis most often appears radiographically as NSIP. Rare reports of pneumonitis associated with nilotinib and bosutinib therapies have also been documented, but no studies of incidence exist.,
Treatment of pneumonitis after imatinib or dasatinib therapy involves discontinuation of the drug and corticosteroids for persistent pneumonitis.,, Guidelines for the management of pneumonitis after BCR-ABL1 TKI therapy have been proposed by the European Leukemia Net investigators and are summarized in [Table 3]. Grade 1 pneumonitis requires observation but no change in management. Grade 2 and higher pneumonitis require withholding of TKI therapy, and Grades 3 and 4 pneumonitis should prompt a change in TKI therapy if possible.,,, Corticosteroid therapy should be considered in Grade 2 pneumonitis and is indicated in Grades 3 and 4 pneumonitis.
|Table 3: European LeukemiaNet recommendations for the management of pneumonitis after therapy with breakpoint cluster region-Abelson tyrosine kinase inhibitors|
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Anaplastic lymphoma kinase inhibitors
ALK is a tyrosine kinase receptor which activates several pathways that lead to cell proliferation, growth, and survival., Mutations in the ALK gene have been identified in adenocarcinomas of the lung and in large-cell lymphomas. Four ALK receptor inhibitors have been approved by the FDA for treatment of ALK-positive lung cancer – crizotinib, ceritinib, alectinib, and brigatinib.,,,, The incidence of pneumonitis is about 2% following crizotinib therapy, 4% following ceritinib therapy, 0.4% following alectinib therapy, and 6% following brigatinib therapy. The median time to development of pneumonitis after crizotinib therapy is 23 days. Acute pneumonitis following brigatinib therapy has been described and occurs with a median onset of 2 days after brigatinib is initiated. Re-challenge with brigatinib and crizotinib may be feasible in some patients after resolution of pneumonitis. No studies clearly describe the median time to pneumonitis in ceritinib and alectinib. The most common pattern of pneumonitis is NSIP.,,, We recommend following the NCI CTCAE to grade the severity of pneumonitis [Table 2].
Bruton's tyrosine kinase inhibitors
BTK is a protein made by BTK gene which has a critical role in B-cell development and maturation., Mutations in the BTK gene are associated with a variety of disorders related to aberrant B-cell function, including X-linked agammaglobulinemia (loss of function), B-cell lymphomas, chronic lymphocytic leukemia, and Waldenstrom's macroglobulinemia (gain of function).,,,, The FDA has approved ibrutinib and acalabrutinib for use in chronic lymphocytic leukemia. Pneumonitis has not been reported after acalabrutinib therapy, but has been reported after ibrutinib therapy.,, Ibrutinib-related pneumonitis is rare,,,, and both OP and NSIP have been reported after ibrutinib treatment., We recommend the NCI CTCAE to grade pneumonitis severity and to determine the approach to treatment [Table 2].
| Conclusions|| |
Pneumonitis is a rare, but potentially severe complication of precision oncology therapies. Increased awareness of pneumonitis following precision oncology therapies is necessary as these therapies are increasingly employed in the treatment of cancer. Further work is necessary to develop frameworks for detection of early pneumonitis and to help distinguish pneumonia from pneumonitis.
Financial support and sponsorship
The authors disclosed the following: This work was supported by the NIH/NIAID (K23 AI117024; to A.S.).
Conflicts of interest
The authors declared no conflicts of interest.
| References|| |
Sasieni PD, Shelton J, Ormiston-Smith N, Thomson CS, Silcocks PB. What is the lifetime risk of developing cancer? The effect of adjusting for multiple primaries. Br J Cancer
Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al.
Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin
Rizvi NA, Peters S. Immunotherapy for unresectable stage III non-small-cell lung cancer. N Engl J Med
Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell
Birendra KC, Afzal MZ, Sochaki A, Wentland KA, Chang R, Singh S, et al.
Tumor molecular profiling in the treatment of refractory cancers. J Exp Ther Oncol
Senft D, Leiserson MDM, Ruppin E, Ronai ZA. Precision oncology: The road ahead. Trends Mol Med
Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, et al.
Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol
Zhao D, Chen X, Qin N, Su D, Zhou L, Zhang Q, et al.
The prognostic role of EGFR-TKIs for patients with advanced non-small cell lung cancer. Sci Rep
Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med
Antoniou KM, Margaritopoulos GA, Tomassetti S, Bonella F, Costabel U, Poletti V, et al.
Interstitial lung disease. Eur Respir Rev
Lim GI, Lee KH, Jeong SW, Uh ST, Jin SY, Lee DH, et al.
Clinical features of interstitial lung diseases. Korean J Intern Med
Glasser SW, Hardie WD, Hagood JS. Pathogenesis of interstitial lung disease in children and adults. Pediatr Allergy Immunol Pulmonol
Romagnoli M, Nannini C, Piciucchi S, Girelli F, Gurioli C, Casoni G, et al.
Idiopathic nonspecific interstitial pneumonia: An interstitial lung disease associated with autoimmune disorders? Eur Respir
Hashisako M, Fukuoka J. Pathology of idiopathic interstitial pneumonias. Clin Med Insights Circ Respir Pulm Med
Park IN, Jegal Y, Kim DS, Do KH, Yoo B, Shim TS, et al.
Clinical course and lung function change of idiopathic nonspecific interstitial pneumonia. Eur Respir J
Silva CI, Müller NL, Lynch DA, Curran-Everett D, Brown KK, Lee KS, et al.
Chronic hypersensitivity pneumonitis: Differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology
Travis WD, Hunninghake G, King TE Jr., Lynch DA, Colby TV, Galvin JR, et al.
Idiopathic nonspecific interstitial pneumonia: Report of an American Thoracic Society project. Am J Respir Crit Care Med
Akira M, Inoue Y, Kitaichi M, Yamamoto S, Arai T, Toyokawa K, et al.
Usual interstitial pneumonia and nonspecific interstitial pneumonia with and without concurrent emphysema: Thin-section CT findings. Radiology
Raghu G, Brown KK. Interstitial lung disease: Clinical evaluation and keys to an accurate diagnosis. Clin Chest Med
Schwaiblmair M, Behr W, Haeckel T, Märkl B, Foerg W, Berghaus T, et al.
Drug induced interstitial lung disease. Open Respir Med J
Wells AU, Hirani N. Interstitial lung disease guideline. Thorax
2008;63 Suppl 5:v1–58.
Nishino M, Ramaiya NH, Awad MM, Sholl LM, Maattala JA, Taibi M, et al.
PD-1 inhibitor-related pneumonitis in advanced cancer patients: Radiographic patterns and clinical course. Clin Cancer Res
Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med
Cordier JF, Loire R, Brune J. Idiopathic bronchiolitis obliterans organizing pneumonia. Definition of characteristic clinical profiles in a series of 16 patients. Chest
Guerry-Force ML, Müller NL, Wright JL, Wiggs B, Coppin C, Pare PD, et al.
A comparison of bronchiolitis obliterans with organizing pneumonia, usual interstitial pneumonia, and small airways disease. Am Rev Respir Dis
Schwarz MI, King TE Jr. Organizing pneumonia. In: Interstitial Lung Disease. Shelton, CT: People's Medical Publishing House; 2011.
Cordier JF. Organising pneumonia. Thorax
Cordier JF. Cryptogenic organising pneumonia. Eur Respir J
Bouchardy LM, Kuhlman JE, Ball WC Jr., Hruban RH, Askin FB, Siegelman SS, et al.
CT findings in bronchiolitis obliterans organizing pneumonia (BOOP) with radiographic, clinical, and histologic correlation. J Comput Assist Tomogr
Boots RJ, McEvoy JD, Mowat P, Le Fevre I. Bronchiolitis obliterans organising pneumonia: A clinical and radiological review. Aust N Z J Med
Lynch DA, Sverzellati N, Travis WD, Brown KK, Colby TV, Galvin JR, et al.
Diagnostic criteria for idiopathic pulmonary fibrosis: A Fleischner Society White Paper. Lancet Respir Med
Faria IM, Zanetti G, Barreto MM, Rodrigues RS, Araujo-Neto CA, Silva JL, et al.
Organizing pneumonia: Chest HRCT findings. J Bras Pneumol
Lee JW, Lee KS, Lee HY, Chung MP, Yi CA, Kim TS, et al.
Cryptogenic organizing pneumonia: Serial high-resolution CT findings in 22 patients. AJR Am J Roentgenol
Kim SJ, Lee KS, Ryu YH, Yoon YC, Choe KO, Kim TS, et al.
Reversed Halo sign on high-resolution CT of cryptogenic organizing pneumonia: Diagnostic implications. AJR
Costabel U, Teschler H, Guzman J. Bronchiolitis obliterans organizing pneumonia (BOOP): The cytological and immunocytological profile of bronchoalveolar lavage. Eur Respir J
Müller NL, Staples CA, Miller RR. Bronchiolitis obliterans organizing pneumonia: CT features in 14 patients. AJR Am J Roentgenol
Kelkel E, Brambilla E, Pison C, Coulomb M, Massot C, Brambilla C, et al.
Bronchiolitis obliterans with idiopathic organized pneumonia. Anatomoclinical analysis and nosologic discussion apropos of 6 cases. Ann Med Interne (Paris)
Costabel U, Teschler H, Schoenfeld B, Hartung W, Nusch A, Guzman J, et al.
BOOP in Europe. Chest
Miyagawa Y, Nagata N, Shigematsu N. Clinicopathological study of migratory lung infiltrates. Thorax
Lohr RH, Boland BJ, Douglas WW, Dockrell DH, Colby TV, Swensen SJ, et al.
Organizing pneumonia. Features and prognosis of cryptogenic, secondary, and focal variants. Arch Intern Med
Bartter T, Irwin RS, Nash G, Balikian JP, Hollingsworth HH. Idiopathic bronchiolitis obliterans organizing pneumonia with peripheral infiltrates on chest roentgenogram. Arch Intern Med
Godoy MC, Viswanathan C, Marchiori E, Truong MT, Benveniste MF, Rossi S, et al.
The reversed halo sign: Update and differential diagnosis. Br J Radiol
Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, et al.
Interstitial lung disease guideline: The British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax
2008;63 Suppl 5:v1–58.
Pathak V, Kuhn JM, Durham C, Funkhouser WK, Henke DC. Macrolide use leads to clinical and radiological improvement in patients with cryptogenic organizing pneumonia. Ann Am Thorac Soc
Ding QL, Lv D, Wang BJ, Zhang QL, Yu YM, Sun SF, et al.
Macrolide therapy in cryptogenic organizing pneumonia: A case report and literature review. Exp Ther Med
Purcell IF, Bourke SJ, Marshall SM. Cyclophosphamide in severe steroid-resistant bronchiolitis obliterans organizing pneumonia. Respir Med
Koinuma D, Miki M, Ebina M, Tahara M, Hagiwara K, Kondo T, et al.
Successful treatment of a case with rapidly progressive bronchiolitis obliterans organizing pneumonia (BOOP) using cyclosporin A and corticosteroid. Intern Med
Kaarteenaho R, Kinnula VL. Diffuse alveolar damage: A common phenomenon in progressive interstitial lung disorders. Pulm Med
Raanani P, Segal E, Levi I, Bercowicz M, Berkenstat H, Avigdor A, et al.
Diffuse alveolar hemorrhage in acute promyelocytic leukemia patients treated with ATRA – A manifestation of the basic disease or the treatment. Leuk Lymphoma
Spira D, Wirths S, Skowronski F, Pintoffl J, Kaufmann S, Brodoefel H, et al.
Diffuse alveolar hemorrhage in patients with hematological malignancies: HRCT patterns of pulmonary involvement and disease course. Clin Imaging
Gattinoni L, Presenti A, Torresin A, Baglioni S, Rivolta M, Rossi F, et al.
Adult respiratory distress syndrome profiles by computed tomography. J Thorac Imaging
Pelosi P, Crotti S, Brazzi L, Gattinoni L. Computed tomography in adult respiratory distress syndrome: What has it taught us? Eur Respir J
Rogers S. Spencer's pathology of the lung Histopathology 1999;34:470.
Claessens YE, Debray MP, Tubach F, Brun AL, Rammaert B, Hausfater P, et al.
Early chest computed tomography scan to assist diagnosis and guide treatment decision for suspected community-acquired pneumonia. Am J Respir Crit Care Med
Sampsonas F, Kontoyiannis DP, Dickey BF, Evans SE. Performance of a standardized bronchoalveolar lavage protocol in a comprehensive cancer center: A prospective 2-year study. Cancer
Raghu G, Mageto YN, Lockhart D, Schmidt RA, Wood DE, Godwin JD, et al.
The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: A prospective study. Chest
Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: A Review. JAMA Oncol
Bethune G, Bethune D, Ridgway N, Xu Z. Epidermal growth factor receptor (EGFR) in lung cancer: An overview and update. J Thorac Dis
Masuda H, Zhang D, Bartholomeusz C, Doihara H, Hortobagyi GN, Ueno NT, et al.
Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res Treat
Ekman S, Bergqvist M, Heldin CH, Lennartsson J. Activation of growth factor receptors in esophageal cancer – implications for therapy. Oncologist
Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys
Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HS. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol
Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, et al.
Epidermal growth factor receptor (EGFR) signaling in cancer. Gene
Sasaki T, Hiroki K, Yamashita Y. The role of epidermal growth factor receptor in cancer metastasis and microenvironment. Biomed Res Int
Schneider MR, Wolf E. The epidermal growth factor receptor ligands at a glance. J Cell Physiol
Grandis JR, Sok JC. Signaling through the epidermal growth factor receptor during the development of malignancy. Pharmacol Ther
Wells A. EGF receptor. Int J Biochem Cell Biol
Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK, et al.
Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets
Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: Current standards and the promise of the future. Transl Lung Cancer Res
Burotto M, Manasanch EE, Wilkerson J, Fojo T. Gefitinib and erlotinib in metastatic non-small cell lung cancer: A meta-analysis of toxicity and efficacy of randomized clinical trials. Oncologist
Tsuboi M, Le Chevalier T. Interstitial lung disease in patients with non-small-cell lung cancer treated with epidermal growth factor receptor inhibitors. Med Oncol
Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn WD Jr., Morse D, et al.
United states food and drug administration drug approval summary: Gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res
Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R. FDA drug approval summary: Gefitinib (ZD1839) (Iressa) tablets. Oncologist
Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R. FDA drug approval summary: Erlotinib (Tarceva) tablets. Oncologist
Makris D, Scherpereel A, Copin MC, Colin G, Brun L, Lafitte JJ, et al.
Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer. BMC Cancer
Yoneda KY, Shelton DK, Beckett LA, Gandara DR. Independent review of interstitial lung disease associated with death in TRIBUTE (paclitaxel and carboplatin with or without concurrent erlotinib) in advanced non-small cell lung cancer. J Thorac Oncol
Lind JS, Smit EF, Grünberg K, Senan S, Lagerwaard FJ. Fatal interstitial lung disease after erlotinib for non-small cell lung cancer. J Thorac Oncol
Yoo SH, Ryu JA, Kim SR, Oh SY, Jung GS, Lee DJ, et al.
Afatinib-induced acute fatal pneumonitis in metastatic lung adenocarcinoma. Korean J Fam Med
Endo M, Johkoh T, Kimura K, Yamamoto N. Imaging of gefitinib-related interstitial lung disease: Multi-institutional analysis by the West Japan Thoracic Oncology Group. Lung Cancer
Noonan SA, Sachs PB, Camidge DR. Transient asymptomatic pulmonary opacities occurring during osimertinib treatment. J Thorac Oncol
Mamesaya N, Kenmotsu H, Katsumata M, Nakajima T, Endo M, Takahashi T, et al.
Osimertinib-induced interstitial lung disease after treatment with anti-PD1 antibody. Invest New Drugs
Min JH, Lee HY, Lim H, Ahn MJ, Park K, Chung MP, et al.
Drug-induced interstitial lung disease in tyrosine kinase inhibitor therapy for non-small cell lung cancer: A review on current insight. Cancer Chemother Pharmacol
Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, et al.
Osimertinib for pretreated EGFR thr790Met-positive advanced non-small-cell lung cancer (AURA2): A multicentre, open-label, single-arm, phase 2 study. Lancet Oncol
Chiang CL, Chen YW, Wu MH, Huang HC, Tsai CM, Chiu CH, et al.
Radiation recall pneumonitis induced by epidermal growth factor receptor-tyrosine kinase inhibitor in patients with advanced non-small cell lung cancer. J Chin Med Assoc
Ding X, Ji W, Li J, Zhang X, Wang L. Radiation recall pneumonitis induced by chemotherapy after thoracic radiotherapy for lung cancer. Radiat Oncol
Yoshioka H, Komuta K, Imamura F, Kudoh S, Seki A, Fukuoka M, et al.
Efficacy and safety of erlotinib in elderly patients in the phase IV POLARSTAR surveillance study of Japanese patients with non-small-cell lung cancer. Lung Cancer
Oh IJ, Choi S, Kwon YS, Kim KS, Kim YI, Lim SC, et al
. Clinical characteristics of EGFR-TKI-induced interstitial pneumonitis in Korean non-small-cell lung cancer patients.Clinical Lung Cancer
Oshima Y, Tanimoto T, Yuji K, Tojo A. EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. JAMA Oncol
Jan 11, 2018.
Hoag JB, Azizi A, Doherty TJ, Lu J, Willis RE, Lund ME, et al.
Association of cetuximab with adverse pulmonary events in cancer patients: A comprehensive review. J Exp Clin Cancer Res
Osawa M, Kudoh S, Sakai F, Endo M, Hamaguchi T, Ogino Y, et al.
Clinical features and risk factors of panitumumab-induced interstitial lung disease: A postmarketing all-case surveillance study. Int J Clin Oncol
Zhang XC, Chen J, Chen J, Xu N, Zhou J. Interstitial pneumonitis after using cetuximab in cancer patients. Int J Clin Exp Med
Chen YM, Luo YH. Interstitial lung disease induced by targeted therapy for non-small cell lung cancer: A review of diagnosis, workup, and management. J Palliat Care Med
Kim S, Oh IJ, Park SY, Song JH, Seon HJ, Kim YH, et al.
Corticosteroid therapy against treatment-related pulmonary toxicities in patients with lung cancer. J Thorac Dis
Steegmann JL, Baccarani M, Breccia M, Casado LF, García-Gutiérrez V, Hochhaus A, et al.
European leukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia
Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin
Festic E, Ortiz-Diaz E, Lee A, Li G, Kor DJ, Adebola A, et al.
Prehospital use of inhaled steroids and incidence of acute lung injury among patients at risk. J Crit Care
Mitri Z, Constantine T, O'Regan R. The HER2 receptor in breast cancer: Pathophysiology, clinical use, and new advances in therapy. Chemother Res Pract
Roy V, Perez EA. Beyond trastuzumab: Small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer. Oncologist
Olayioye MA. Update on HER-2 as a target for cancer therapy: Intracellular signaling pathways of erbB2/HER-2 and family members. Breast Cancer Res
Le XF, Pruefer F, Bast RC Jr. HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways. Cell Cycle
Bartsch R, Wenzel C, Steger GG. Trastuzumab in the management of early and advanced stage breast cancer. Biologics
Amiri-Kordestani L, Blumenthal GM, Xu QC, Zhang L, Tang SW, Ha L, et al.
FDA approval: Ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res
Bange J, Zwick E, Ullrich A. Molecular targets for breast cancer therapy and prevention. Nat Med
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr., Davidson NE, et al.
Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med
Pepels MJ, Boomars KA, van Kimmenade R, Hupperets PS. Life-threatening interstitial lung disease associated with trastuzumab: Case report. Breast Cancer Res Treat
Bettini AC, Tondini C, Poletti P, Caremoli ER, Guerra U, Labianca R, et al.
A case of interstitial pneumonitis associated with Guillain-Barré syndrome during administration of adjuvant trastuzumab. Tumori
Teicher BA, Doroshow JH. The promise of antibody-drug conjugates. N Engl J Med
Isakoff SJ, Baselga J. Trastuzumab-DM1: Building a chemotherapy-free road in the treatment of human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol
Feng F, Jiang Y, Yuan M, Shen J, Yin H, Geng D, et al.
Association of radiologic findings with mortality in patients with avian influenza H7N9 pneumonia. PLoS One
Vahid B, Mehrotra A. Trastuzumab (Herceptin)-associated lung injury. Respirology
Sugaya A, Ishiguro S, Mitsuhashi S, Abe M, Hashimoto I, Kaburagi T, et al.
Interstitial lung disease associated with trastuzumab monotherapy: A report of 3 cases. Mol Clin Oncol
Lee HE, Jeong NJ, Lee Y, Seo YJ, Kim CD, Lee JH, et al.
Radiation recall dermatitis and pneumonitis induced by trastuzumab (Herceptin®). Int J Dermatol
Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov
Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci
Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer
Armengol G, Rojo F, Castellví J, Iglesias C, Cuatrecasas M, Pons B, et al.
4E-binding protein 1: A key molecular “funnel factor” in human cancer with clinical implications. Cancer Res
Coleman LJ, Peter MB, Teall TJ, Brannan RA, Hanby AM, Honarpisheh H, et al.
Combined analysis of eIF4E and 4E-binding protein expression predicts breast cancer survival and estimates eIF4E activity. Br J Cancer
Ahmad I, Labbé AC, Chagnon M, Busque L, Cohen S, Kiss T, et al.
Incidence and prognostic value of eosinophilia in chronic graft-versus-host disease after nonmyeloablative hematopoietic cell transplantation. Biol Blood Marrow Transplant
Bjornsti MA, Houghton PJ. Lost in translation: Dysregulation of cap-dependent translation and cancer. Cancer Cell
Easton JB, Houghton PJ. MTOR and cancer therapy. Oncogene
Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS, et al.
FDA approval summary: Temsirolimus as treatment for advanced renal cell carcinoma. Oncologist
Pham PT, Pham PC, Danovitch GM, Ross DJ, Gritsch HA, Kendrick EA, et al.
Sirolimus-associated pulmonary toxicity. Transplantation
Champion L, Stern M, Israël-Biet D, Mamzer-Bruneel MF, Peraldi MN, Kreis H, et al.
Brief communication: Sirolimus-associated pneumonitis: 24 cases in renal transplant recipients. Ann Intern Med
Nozawa M, Ohzeki T, Tamada S, Hongo F, Anai S, Fujimoto K, et al.
Differences in adverse event profiles between everolimus and temsirolimus and the risk factors for non-infectious pneumonitis in advanced renal cell carcinoma. Int J Clin Oncol
Dabydeen DA, Jagannathan JP, Ramaiya N, Krajewski K, Schutz FA, Cho DC, et al.
Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: Incidence, radiographic findings and correlation with clinical outcome. Eur J Cancer
Molas-Ferrer G, Soy-Muner D, Anglada-Martínez H, Riu-Viladoms G, Estefanell-Tejero A, Ribas-Sala J, et al.
Interstitial pneumonitis as an adverse reaction to mTOR inhibitors. Nefrologia
Albiges L, Chamming's F, Duclos B, Stern M, Motzer RJ, Ravaud A, et al.
Incidence and management of mTOR inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma. Ann Oncol
Atkinson BJ, Cauley DH, Ng C, Millikan RE, Xiao L, Corn P, et al.
Mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: Predictors, management, and outcomes. BJU Int
Peddi PF, Shatsky RA, Hurvitz SA. Noninfectious pneumonitis with the use of mTOR inhibitors in breast cancer. Cancer Treat Rev
Cauley DH, Atkinson BJ, Ng CS, Millikan RE, Xiao L, Corn PG, et al
. mTOR inhibitor-associated noninfectious pneumonitis in patients with metastatic renal cell cancer: A single-center experience. J Clin Oncol
2013;31 15 Suppl: e15612.
White DA, Camus P, Endo M, Escudier B, Calvo E, Akaza H, et al.
Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al.
Phase 3 trial of everolimus for metastatic renal cell carcinoma: Final results and analysis of prognostic factors. Cancer
Nishino M, Boswell EN, Hatabu H, Ghobrial IM, Ramaiya NH. Drug-related pneumonitis during mammalian target of rapamycin inhibitor therapy: Radiographic pattern-based approach in Waldenström macroglobulinemia as a paradigm. Oncologist
Bourgier C, Massard C, Moldovan C, Soria JC, Deutsch E. Total recall of radiotherapy with mTOR inhibitors: A novel and potentially frequent side-effect? Ann Oncol
Clark D, Gauchan D, Ramaekers R, Norvell M, Copur MS. Radiation recall pneumonitis during systemic treatment with everolimus. Oncol Res
Paplomata E, Zelnak A, O'Regan R. Everolimus: Side effect profile and management of toxicities in breast cancer. Breast Cancer Res Treat
Seruga B, Gan HK, Knox JJ. Managing toxicities and optimal dosing of targeted drugs in advanced kidney cancer. Curr Oncol
2009;16 Suppl 1:S52–9.
Willemsen AE, Grutters JC, Gerritsen WR, van Erp NP, van Herpen CM, Tol J, et al.
MTOR inhibitor-induced interstitial lung disease in cancer patients: Comprehensive review and a practical management algorithm. Int J Cancer
Maloney DG, Grillo-López AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, et al.
IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood
Ansell SM. Brentuximab vedotin. Blood
Burton C, Kaczmarski R, Jan-Mohamed R. Interstitial pneumonitis related to rituximab therapy. N Engl J Med
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al.
CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med
Ennishi D, Terui Y, Yokoyama M, Mishima Y, Takahashi S, Takeuchi K, et al.
Increased incidence of interstitial pneumonia by CHOP combined with rituximab. Int J Hematol
Hadjinicolaou AV, Nisar MK, Parfrey H, Chilvers ER, Ostör AJ. Non-infectious pulmonary toxicity of rituximab: A systematic review. Rheumatology (Oxford)
Kanelli S, Ansell SM, Habermann TM, Inwards DJ, Tuinstra N, Witzig TE, et al.
Rituximab toxicity in patients with peripheral blood malignant B-cell lymphocytosis. Leuk Lymphoma
Katsuya H, Suzumiya J, Sasaki H, Ishitsuka K, Shibata T, Takamatsu Y, et al.
Addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy has a high risk of developing interstitial pneumonia in patients with non-Hodgkin lymphoma. Leuk Lymphoma
Liu X, Hong XN, Gu YJ, Wang BY, Luo ZG, Cao J, et al.
Interstitial pneumonitis during rituximab-containing chemotherapy for non-Hodgkin lymphoma. Leuk Lymphoma
Zhou T, Shen Q, Peng H, Chao T, Zhang L, Huang L, et al.
Incidence of interstitial pneumonitis in non-Hodgkin's lymphoma patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximab. Ann Hematol
Younes A, Connors JM, Park SI, Fanale M, O'Meara MM, Hunder NN, et al.
Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: A phase 1, open-label, dose-escalation study. Lancet Oncol
Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, et al.
Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med
Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, et al.
Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet
Sabet Y, Ramirez S, Rosell Cespedes E, Rensoli Velasquez M, Porres-Muñoz M, Gaur S, et al.
Severe acute pulmonary toxicity associated with brentuximab in a patient with refractory Hodgkin's lymphoma. Case Rep Pulmonol
Salesse S, Verfaillie CM. BCR/ABL: From molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Oncogene
Habeck M. FDA licences imatinib mesylate for CML. Lancet Oncol
Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George's respiratory questionnaire. Am Rev Respir Dis
Leoni V, Biondi A. Tyrosine kinase inhibitors in BCR-ABL positive acute lymphoblastic leukemia. Haematologica
Go SI, Lee WS, Lee GW, Kang JH, Kang MH, Lee JH, et al.
Nilotinib-induced interstitial lung disease. Int J Hematol
Jutant EM, Meignin V, Montani D, Tazi A, Rousselot P, Bergeron A, et al.
Bosutinib-related pneumonitis. Eur Respir J
2017;50. pii: 1700930.
Ohnishi K, Sakai F, Kudoh S, Ohno R. Twenty-seven cases of drug-induced interstitial lung disease associated with imatinib mesylate. Leukemia
Bergeron A, Réa D, Levy V, Picard C, Meignin V, Tamburini J, et al.
Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: A case series. Am J Respir Crit Care Med
Flynn R, Du J, Veenstra RG, Reichenbach DK, Panoskaltsis-Mortari A, Taylor PA, et al.
Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood
Go SW, Kim BK, Lee SH, Kim TJ, Huh JY, Lee JM, et al.
Successful rechallenge with imatinib in a patient with chronic myeloid leukemia who previously experienced imatinib mesylate induced pneumonitis. Tuberc Respir Dis (Seoul)
Delomas T, Darné C, Besson C. Lack of recurrence of imatinib-induced interstitial lung disease with nilotinib. Leuk Lymphoma
Weise AM, Gadgeel S. New options in the management of intractable ALK(+) metastatic non-small-cell lung cancer. Lung Cancer (Auckl)
Holla VR, Elamin YY, Bailey AM, Johnson AM, Litzenburger BC, Khotskaya YB, et al.
ALK: A tyrosine kinase target for cancer therapy. Cold Spring Harb Mol Case Stud
Sahu A, Prabhash K, Noronha V, Joshi A, Desai S. Crizotinib: A comprehensive review. South Asian J Cancer
Kazandjian D, Blumenthal GM, Chen HY, He K, Patel M, Justice R, et al.
FDA approval summary: Crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements. Oncologist
Khozin S, Blumenthal GM, Zhang L, Tang S, Brower M, Fox E, et al.
FDA approval: Ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. Clin Cancer Res
Larkins E, Blumenthal GM, Chen H, He K, Agarwal R, Gieser G, et al.
FDA approval: Alectinib for the treatment of metastatic, ALK-positive non-small cell lung cancer following crizotinib. Clin Cancer Res
Kim DW, Tiseo M, Ahn MJ, Reckamp KL, Hansen KH, Kim SW, et al.
Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: A randomized, multicenter phase II trial. J Clin Oncol
Yoneda KY, Scranton JR, Cadogan MA, Tassell V, Nadanaciva S, Wilner KD, et al.
Interstitial lung disease associated with crizotinib in patients with advanced non-small cell lung cancer: Independent review of four PROFILE trials. Clin Lung Cancer
Yanagisawa S, Inoue A, Koarai A, Ono M, Tamai T, Ichinose M, et al.
Successful crizotinib retreatment after crizotinib-induced interstitial lung disease. J Thorac Oncol
A case of chemical pulmonary disorder due to alectinib. Respirology
Ikeda S, Yoshioka H, Arita M, Sakai T, Sone N, Nishiyama A, et al.
Interstitial lung disease induced by alectinib (CH5424802/RO5424802). Jpn J Clin Oncol
Tamiya A, Okamoto I, Miyazaki M, Shimizu S, Kitaichi M, Nakagawa K, et al.
Severe acute interstitial lung disease after crizotinib therapy in a patient with EML4-ALK-positive non-small-cell lung cancer. J Clin Oncol
Mohamed AJ, Yu L, Bäckesjö CM, Vargas L, Faryal R, Aints A, et al.
Bruton's tyrosine kinase (Btk): Function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev
Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol
Chiorazzi N, Ferrarini M. B cell chronic lymphocytic leukemia: Lessons learned from studies of the B cell antigen receptor. Annu Rev Immunol
Maas A, Hendriks RW. Role of Bruton's tyrosine kinase in B cell development. Dev Immunol
Küppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer
Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med
Schwarzbich MA, Witzens-Harig M. Ibrutinib. Recent Results Cancer Res
Mullard A. BTK inhibitors get aboost. Nat Rev Drug Discov
de Claro RA, McGinn KM, Verdun N, Lee SL, Chiu HJ, Saber H, et al.
FDA approval: Ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clin Cancer Res
Raedler LA. Imbruvica (Ibrutinib):First drug approved for the treatment of patients with Waldenström's macroglobulinemia. Am Health Drug Benefits
Chalmers JD, Taylor JK, Mandal P, Choudhury G, Singanayagam A, Akram AR, et al.
Validation of the Infectious Diseases Society of America/American Thoratic Society minor criteria for Intensive Care Unit admission in community-acquired pneumonia patients without major criteria or contraindications to Intensive Care Unit care. Clin Infect Dis
Sibila O, Meduri GU, Mortensen EM, Anzueto A, Laserna E, Fernandez JF, et al.
Improving the 2007 Infectious Disease Society of America/American Thoracic Society severe community-acquired pneumonia criteria to predict Intensive Care Unit admission. J Crit Care
Mato AR, Islam P, Daniel C, Strelec L, Kaye AH, Brooks S, et al.
Ibrutinib-induced pneumonitis in patients with chronic lymphocytic leukemia. Blood
Samad R, Santamauro J, Feinstein M. Ibrutinib induced interstitial lung disease. Chest
Jungmann S, Ludwig WD, Schönfeld N, Blum TG, Großwendt C, Boch C, et al.
A patient with non-Hodgkin lymphoma and nonspecific interstitial pneumonia during ibrutinib therapy. Case Rep Oncol Med
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[Table 1], [Table 2], [Table 3]