Infiltrative lung diseases : Complications of novel antineoplastic agents in patients with hematological malignancies

1Dominican Hospital, Santa Cruz Pulmonary Medical Group, Santa Cruz, California; 2Thomas Jefferson University Hospital, Department of Pulmonary and Critical Care Medicine, Philadelphia, Pennsylvania, USA Correspondence: Dr Bobbak Vahid, 700 Fredric Street, Suite 203, Santa Cruz, California 95062, USA. Telephone 831-425-1906, fax 831-423-7579, e-mail bobbak_vahid@yahoo.com B Vahid, PE Marik. Infiltrative lung diseases: Complications of novel antineoplastic agents in patients with hematological malignancies. Can Respir J 2008;15(4):211-216.

P ulmonary involvement is a common and challenging con- dition in patients with hematological malignancies.Infiltrative lung diseases as a result of antineoplastic agentassociated pulmonary toxicity are being increasingly recognized as a cause of lung disease in patients with hematological malignancies.New agents are constantly being added to the list of available antineoplastic agents.Old medications with new indications (eg, thalidomide for multiple myeloma) may also cause pulmonary disease.Although pulmonary toxicity due to the older antineoplastic agents (bleomycin, busulfan, cyclophosphamide, methotrexate, melphalan, cytarabine and carmustatin) is well known, significant pulmonary toxicity may occur with the newer antineoplastic agents.The present article reviews the infiltrative lung diseases induced by novel antineoplastic agents in patients with hematological malignancies.Bone marrow transplantation and related pulmonary toxicities are not included.Various terms and definitions have been used in the literature to describe pulmonary complications of antineoplastic agents.To have a more unified understanding, we divided the antineoplastic agent-associated infiltrative lung diseases into eight groups based on clinical and pathological manifestations: nonspecific interstitial pneumonitis/fibrosis; organizing pneumonia (OP); desquamative interstitial pneumonia (DIP); eosinophilic pneumonia; granulomatous pneumonitis; noncardiogenic pulmonary edema (NCPE) and acute respiratory distress syndrome (ARDS); diffuse alveolar hemorrhage (DAH); and retinoic acid syndrome (Tables 1 and 2).Although the differentiation among these groups is arbitrary and the conditions may overlap, these definitions provide a useful framework for the present review.It is also important to emphasize that these patterns of lung injury for many antineoplastic agents have been described in limited case reports or small case series.On the other hand, patients with hematological malignancies often have multiple comorbidities and establishing a cause and effect relationship between specific agents and lung disease is sometimes a difficult task.

ANTINEOPLASTIC AGENT-ASSOCIATED INFILTRATIVE LUNG DISEASES Nonspecific interstitial pneumonitis/fibrosis
Pneumonitis is an inflammatory condition of the lungs that is characterized by alveolitis and infiltration of the lung interstitium.The etiology of interstitial pneumonitis includes noninfectious (eg, idiopathic, medications, inhalational exposures, collagen-vascular disorders) and infectious (bacterial, viral or fungal pneumonia) causes.Antineoplastic agents are known to cause interstitial pneumonitis (   The incidence of ANAP varies considerably and has been reported in 0.1% to 15% of treated patients in various phase II or phase III trials (Table 1) .Concurrent use of steroids does not necessarily prevent the development of ANAP, and severe cases of ANAP have been described with thalidomide, lenalidomide, rituximab, bortezomib and anthracyclines.Clinical symptoms range from mild dry cough and dyspnea on exertion to rapidly progressive disease and respiratory failure.Fever is a common finding.Skin rash and wheezing are less common, and when present, suggest a hypersensitivity reaction.Nonspecific systemic markers of inflammation including leukocytosis with neutrophilia, elevated erythrocyte sedimentation rate, and elevated C-reactive protein are common.Peripheral eosinophilia and abnormal liver transaminases are uncommon and suggest a hypersensitivity reaction .Common computed tomography scan patterns are diffuse or patchy ground-glass opacities, diffuse reticular and reticulonodular pattern, focal or patchy consolidation, and multiple pulmonary nodules.Bronchoscopy is helpful in evaluation of patients with suspected ANAP.Bronchoalveolar lavage (BAL) and protected microbiology brush can be used to evaluate for infections.BAL cytology may also show viral cytopathic effects.Hypercellular BAL with neutrophilia or lymphocytosis is a common finding.Lung biopsy either by transbronchial technique or videoassisted thoracic surgery can be extremely helpful to demonstrate the presence of pneumonitis and exclude alternative diagnoses.Pathology findings include nonspecific pneumonitis, acute or chronic inflammatory interstitial infiltrates, fibrosis, vasculitis and scattered organizing pneumonia .ANAP is diagnosed when clinical and radiographic manifestations are compatible with ANAP and other potential causes are excluded.The mainstay of management of ANAP is the cessation of the culprit agent.Corticosteroid treatment is guided by anecdotal data.Methylprednisolone 1 g/day for three days in patients with respiratory failure has been used.Lower doses of corticosteroids (methylprednisolone 60 mg every 6 h) may be considered in less severe cases of pneumonitis.Corticosteroid taper based on clinical response and improvement in oxygenation is a reasonable strategy (58).Other measures, including empirical treatment for infections until the culture results are available and maintaining euvolemic status, are also important in ANAP management.

OP
OP is a pathological diagnosis characterized by polypoid intraluminal plugs of proliferating fibroblasts and myofibroblasts within alveolar ducts and interstitial infiltrates.OP is a wellknown type of drug-induced lung disease.OP presents clinically with fever, cough, dyspnea and pulmonary infiltrates on chest imaging.Exclusion of infection and lung biopsy are necessary for definitive diagnosis.Anthracyclines, cladribine, interferonalpha, rituximab and thalidomide have been associated with OP.Cessation of culprit agent and systemic corticosteroids should result in rapid resolution of respiratory disease (21,(59)(60)(61)(62)(63)(64)(65)(66).
DIP DIP is a less common form of lung pathology.DIP is mostly seen in smokers with idiopathic interstitial pneumonitis.DIP is characterized by uniform filling of distal airspaces by numerous pigmented alveolar macrophages.Multinucleated cells, eosinophils and lymphocytes are also present.The macrophages have abundant cytoplasm with finely granular dusty brown pigment.DIP-like pathology has been described with cladribine, interferon-alpha and rituximab.Lung biopsy is necessary for diagnosis.Cessation of culprit agent and systemic corticosteroids are mainstays of therapy (21,67).

NCPE and ARDS
NCPE is a nonspecific term that is used to describe pulmonary edema not associated with heart failure.NCPE is caused by fluid retention and increased capillary leak caused by cytokine release.Pathology shows dilated lymphatic channels, alveolar septal edema, peribronchial edema, pleural effusion, pericardial effusion and occasionally ascites.Hydration with 5% dextrose that is commonly performed before and after administration of some antineoplastic agents (eg, pentostatin) may contribute to formation of pulmonary edema.Pentostatin is a potent adenosine deaminase inhibitor used in the treatment of hairy cell leukemia.Fatal pulmonary edema and respiratory distress have been observed after pentostatin therapy especially in combination with fludarabine, carmustatin, etoposide, rituximab and high-dose cyclophosphamide (76)(77)(78)(79)(80). Decitabine is a new demethylating agent indicated in the management of patients with myelodysplastic syndrome.In a phase III trial (81), an increased incidence of pulmonary edema was reported (6% versus 0% in the placebo group).Imatinib results in fluid retention and pulmonary edema.Imatinib inhibits platelet-derived growth factor, which regulates fluid absorption in the intestines (51).Dasatinib is associated with pulmonary edema in approximately 4% of treated patients.Fluid retention may also lead to pleural effusion, pericardial effusion and ascites (47).The role of steroids in the management of NCPE is unknown.Supportive care and diuresis are the main therapeutic strategies.ARDS as a severe type of NCPE has also been described as a potential complication of antineoplastic agents.Two types can be distinguished: lung injury and severe interstitial pneumonitis, and respiratory failure as a manifestation of infusionrelated reactions.Cyclosporine (82), all-trans retinoic acid (ATRA) (83), arsenic trioxide (84) and bortezomib (10) are associated with lung injury and diffuse alveolar damage that may present clinically as ARDS.Cyclosporine is used in the treatment of T-cell large granular lymphocyte leukemia.A high concentration of cyclosporine in pulmonary circulation after administration through a central line has been associated with development of lung injury and ARDS (82,(85)(86)(87).Severe pneumonitis resulting in ARDS can be seen with anagrelide (9), azacytidine (17), cladribine (21), interferon-alpha (18), procarbazine (33), rituximab (37) and tositumomab (19,20).Infusion-related reactions occur during or shortly after infusion of some antineoplastic agents (eg, monoclonal antibodies, anthracyclines).Clinical manifestations include fever, cough, dyspnea, wheezing, skin rash, vomiting and hypotension.Alemtuzumab and gemtuzumab ozogamicin infusionrelated reactions may also by complicated by pulmonary infiltrates and ARDS (88)(89)(90).Alemtuzumab is an anti-CD52 monoclonal antibody and is indicated in the treatment of chronic lymphocytic leukemia.Gemtuzumab ozogamicin is an anti-CD33 monoclonal antibody conjugated to a modified antitumour antibiotic, calicheamicin.This agent is active against CD33-positive acute myelogenous leukemia.Infusionrelated reactions due to cytokine release are common (33%).Severe cases of ARDS have been described within a day of the gemtuzumab ozogamicin 2 h infusion.Leukocyte counts above 60×10 9 /L has been observed in these patients.Reduction of peripheral blasts to below 30×10 9 /L with hydroxyurea or leukopheresis before gemtuzumab ozogamicin infusion may prevent this potentially fatal pulmonary complication (91,92).

DAH
DAH is characterized by hemorrhagic BAL return and presence of hemosiderin-laden macrophages in BAL.The clinical presentations are nonspecific and include fever, dyspnea and hemoptysis.ATRA, gemtuzumab and rituximab rarely induce DAH.High-dose steroids are used in the treatment of druginduced DAH (93)(94).
Chest imaging shows diffuse infiltrates, peripheral small nodules, consolidations or pulmonary edema.Pulmonary pathological findings include alveolar hemorrhage, pulmonary capillaritis, intra-alveolar myeloid cell infiltration, alveolar septal edema, diffuse alveolar damage and fibrinous exudates.ATRA and arsenic trioxide induce differentiation of APL cells to more mature cells in vitro and in vivo.This differentiation is thought to contribute to leukocytosis seen after initiation of the therapy.High peripheral leukocyte count was suggested as a possible risk factor for development of retinoic acid syndrome.This pharmacological cell differentiation may induce production and release of granulocyte-macrophage colony stimulating factor and cytokines like interleukin-1, tumour necrosis factor-alpha, interleukin-6 and interleukin-8.These cytokines have been suggested to contribute to pulmonary toxicity in retinoic acid syndrome.Prior corticosteroid therapy (eg, prednisone 30 mg) may reduce the risk for retinoic acid syndrome.Systemic corticosteroids such as dexamethasone are the mainstay of therapy (95)(96)(97)(98)(99)(100)(101)(102)(103)(104).
Vahid and MarikCan Respir J Vol 15 No 4 May/June 2008 212 Infiltrative lung diseases: Complications of novel antineoplastic agents Can Respir J Vol 15 No 4 May/June 2008 213 Vahid and MarikCan Respir J Vol 15 No 4 May/June 2008 214

TABLE 1
Agents associated with antineoplastic agent-associated pneumonitis