Cytarabine-related lung infiltrates on high resolution computerized tomography: a possible complication with benign outcome in leukemic patients

Abstract

Potentially fatal lung toxicity occurs in 12–20% of leukemic patients treated with cytarabine especially at intermediate to high doses, usually presenting as noncardiogenic pulmonary edema (NCPE). Anecdotally the association between cytarabine and the onset of bronchiolitis obliterans organizing pneumonia (BOOP) has been reported. We describe here three cases of patients affected by acute myeloid leukemia (AML) treated with chemotherapeutic regimens including high dose cytarabine, who developed early onset of fever, mild dyspnea, moderate hypoxemia on arterial blood gas analysis and lung infiltrates documented by high-resolution computerized tomography (HRCT), with a more indolent behaviour and a benign clinical outcome, compared with similar cases previously reported in the literature. Our cases widen the spectrum of clinical features of cytarabine-related toxicity in leukemic patients.

Cytosine arabinoside, a pyrimidine nucleoside analogue introduced into clinical regimens for cancer therapy in 1964, is still one of the most effective drugs for the treatment of adult acute leukemia. The toxicity of cytarabine can be represented by either minor side effects like exanthema, fever and elevation of hepatic enzymes, that are relatively frequent, but rarely represent therapeutic problems or by major adverse effects, including myelo-suppression, oral and gastrointestinal mucosal damage, keratoconjunctivitis and neurotoxicity, that can determine serious clinical problems, sometimes requiring the definitive interruption of treatment.1, 2

Several cancer therapeutic drugs are known to induce lung toxicity, which may result in a broad spectrum of clinico-pathologic syndromes with minor to severe consequences for the patient. Potentially fatal lung toxicity has been described in leukemia patients treated with cytarabine, especially at intermediate to high doses: this clinical entity, occurring in about 12–20% of patients, a median of 1–2 weeks (range 1–21 days) after chemotherapy, usually at initial course, has been defined as noncardiogenic pulmonary edema (NCPE).3– 11 It typically presents as a sub-acute syndrome characterised by severe dyspnea, cough, tachypnea, low grade fever, severe hypoxemia, crackles on thorax auscultation, and confluent alveolar consolidation on standard chest X-ray. Diagnosis of this drug-induced respiratory distress, also called acute lung injury, requires the exclusion of heart dysfunction and any infectious, metabolic or cancer-related causes.3–11 Anecdotally, the association between administration of cytarabine and the onset of bronchiolitis obliterans organizing pneumonia (BOOP), has been reported. BOOP is an uncommon fibrotic diffuse lung disorder, histopathologically defined as granulation tissue plugging into the lumens of small airways, extending, in a continuous fashion, into alveolar ducts and alveoli. It is generally characterised by subacute onset of respiratory symptoms resolving in the majority of cases (65–80%) with administration of steroids, but in other cases it may persist, with chronic and disabling cough and dyspnea, and may be life threatening, especially in the case of recurrence.12–16

We report here three cases of patients affected by acute myeloid leukemia (AML), treated with chemotherapeutic regimens including high dose cytarabine, who developed early onset of fever, mild dyspnea, moderate hypoxemia on arterial blood gas analysis, and lung infiltrates documented by high-resolution computerized tomography (HRCT). Issues of diagnosis and management of cytarabine related lung toxicity are discussed and differences in the clinical features between such cases and those reported in the literature are reviewed.