A 66-year-old male patient successfully treated with remission induction and consolidation chemotherapeu-tic regimens for acute myeloid leukemia (AML) with myelodysplasia-related changes according to the WHO classification [1] relapsed 5 months after autologous bone marrow transplantation. The patient, receiving prophylaxis with isoniazide for a latent tuberculosis infection documented by a Quantiferon-TB serologi-cal test, was admitted to our department in order to undergo a salvage chemotherapeutic regimen (FLAG) consisting of cytarabine (2 g/m2 on days +1 to +5), fludarabine (30 mg/m2 on days +1 to +3) and granu-locyte-colony stimulating factor (G-CSF, 5 mcg/kg/day from day −1 to day +5). At admission the patient was asymptomatic, and his physical examination was unremarkable. Moreover, the chest X-ray performed before starting chemotherapy was negative. On day +1 the patient showed mild dyspnea and bilateral inspira-tory crackles on chest auscultation, despite normal pO
2 on blood gas analysis. On day +2 after the admin-
istration of high-dose cytarabine had been started, he became febrile (temperature 38.4°C) (Fig. 61.1) and continued to show mild dyspnea in the absence of chest pain or cough. Blood tests were consistent with self-limiting disseminated intravascular coagulation in the absence of bleeding, probably due to leukemic cell lysis. Blood gas analysis on room air documented moderate hypoxemia (pO
2 62 mmHg), and chest
X-ray showed an area of consolidation in the left lower lobe and bilateral pleural effusions, especially on the left side (Fig. 61.2a). Chest high-resolution computerized tomography (HRCT) was performed on day +3 (Fig. 61.2b), confirming the presence of
Cytarabine-Induced Pulmonary Toxicity in Leukemic Patients
Fabio Forghieri, Leonardo Potenza, Monica Morselli, Monica Maccaferri, Giuseppe Torelli, and Mario Luppi
F. Forghieri, L. Potenza, M. Morselli, M. Maccaferri, G. Torelli, and M. Luppi (*) Department of Oncology, Hematology and Respiratory Diseases, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliera-Universitaria Policlinico, Via del Pozzo 71, 41100 Modena, Italy e-mail: [email protected]
61
Authors’ disclosures of potential conflict of interest: The authors indicated no potential conflict of interest.
bilateral pleural effusions and showing bilateral patchy consolidations in the lower lobes. The occurrence of respiratory symptoms in leukemic patients accompa-nied by lung infiltrates documented on either chest X-ray or HRCT may be attributed to either infectious or noninfectious causes [2–4]. The radiological find-ings disclosed in our patient are not pathognomonic for a specific process, so that an early and appropriate differential diagnosis is essential for clinical manage-ment. Patchy consolidations, with or without areas of ground-glass opacities, and pleural effusions, may be caused by several infectious agents [4], including bacteria, fungi, Pneumocystis jiroveci and, although rarely, viruses [4, 5]. An empirical antibiotic therapy with piperacillin-tazobactam and azithromycin was started in our patient, who was febrile and considered at high risk for systemic infections because of leuke-mia relapse, even though he was not neutropenic, with neutrophils being 4.6 × 109/L at that time point under treatment with G-CSF. Serological, cultural and molec-ular examinations (SCME) of biologic fluids (namely blood, urine, feces cultures, CMV and Galactomannan
antigenemia, and urinary Legionella antigen) did not disclose any infectious agent. Furthermore, the patient underwent bronchoscopy with bronchoalveolar lavage (BAL). BAL samples were not hemorrhagic, and their extensive microbiologic analyses showed negative results for the most common bacterial, fungal and viral pathogens. When an infectious agent is not detected, several other noninfectious causes of lung infiltrates should be considered and investigated in leukemic patients, such as pulmonary edema due to heart fail-ure [4], metabolic dysfunctions (namely renal failure, hypoalbuminemia and pancreatitis) [6], pulmonary leukostasis or leukemic infiltrates, even in the absence of leukocytosis or peripheral blastosis [7], alveolar hemorrhage and transfusion-related acute lung injury [4]. The above-mentioned causes of lung infiltrates were excluded in our patient (Table 61.1). From day +3 he became apyretic (Fig. 61.1), asymptomatic and blood gas analysis normalized, without stopping the administration of chemotherapy. A chest X-ray, performed 72 h later, showed complete resolution of the radiological features described above (Fig. 61.2c).
41
40
(Hours)
X-ray
Tem
per
atu
re (
°C) X-rayHRCT
39
38
37
36
35
8 16 24 32 40 48 56 64 72 80 88 96 104
112
120
128
136
144
Fig. 61.1 Fever chart of the leukemic patient treated with high-dose cytarabine. Graph shows onset and subsequent resolution of fever and the timing of radiological examinations (chest X-ray and HRCT) indicated by arrows. “O hours” indicates the start of administration of chemotherapy
Fig. 61.2 Radiological examinations in the leukemic patient receiving high-dose cytarabine. Early lung infiltrates (bilateral patchy consolidations in lower lobes and bilateral pleural effu-
sions) characterized by chest X-ray and HRCT (a, b); com-plete and spontaneous resolution in 72 h documented on chest X-ray (c)
73161 Cytarabine-Induced Pulmonary Toxicity in Leukemic Patients
The prompt resolution of the febrile condition, in the absence of disclosure of infectious agents by biologic fluid SCME, as well as the very early and complete disappearance of clinical symptoms and of radio-logical findings, as documented by subsequent chest X-ray, cannot be ascribed to the few days of empiri-cal antibiotic therapy and argue against an infectious etiology. Having excluded other noninfectious causes, the pulmonary symptoms and radiological features demonstrated by our patient 24 h after starting chemo-therapy were most likely induced by the administra-tion of high-dose cytarabine.
Cytarabine, a pyrimidine nucleoside analogue intro-duced 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 either by minor side effects like exan-thema, fever and elevation of hepatic enzymes, which are relatively frequent although rarely represent a ther-apeutic problem, or by major adverse effects, including myelosuppression, oral and gastrointestinal mucosal damage, keratoconjunctivitis and neurotoxicity, which can determine serious clinical problems, sometimes requiring the definitive interruption of treatment [8, 9].
Several cancer therapeutic drugs are known to induce pulmonary toxicity, which may result in a broad spectrum of clinico-pathologic syndromes with minor to severe consequences for the patient. Potentially fatal pulmonary toxicity has been described in leukemia patients treated with cytarabine, especially at interme-diate 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, has been defined as noncardiogenic pulmonary edema (NCPE) or acute lung injury [6, 10–19]. It typically presents as a sub-acute syndrome characterized by severe dyspnea,
cough, tachypnea, low grade fever, severe hypoxemia, crackles on chest auscultation and confluent alveolar consolidation on standard chest X-ray. NCPE is usu-ally characterized by abrupt onset of severe symptoms, which, if not fatal, can be reversed only with discon-tinuation of the administration of cytarabine and imme-diate start of intensive support treatment, including high-dose systemic steroids, mechanical ventilation and pressure support [6, 10–19]. Anecdotally, the asso-ciation between administration of cytarabine and the onset of organizing pneumonia (COP) has been reported in the literature [20, 21]. COP is an uncom-mon 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 charac-terized by the subacute onset of respiratory symptoms resolving in the majority of cases (65–80%) with the administration of steroids. The response to corticoster-oids is impressive, because clinical manifestations improve within 48 h, but complete resolution of radio-graphic pulmonary infiltrates takes several weeks. However, spontaneous, slow improvement only occa-sionally occurs, whereas in other cases, symptoms may persist with chronic and disabling cough and dyspnea and may be life threatening, especially in the case of recurrence [22–25].
We have recently widened the spectrum of clinical features of cytarabine-related pulmonary toxicity, report-ing on three leukemic patients who developed fever, mild dyspnea, moderate hypoxemia on blood gas analy-sis and lung infiltrates documented by either chest X-ray or HRCT 24 h after the administration of high-dose cytarabine [26]. The disappearance of symptoms and the complete resolution of radiological signs were obtained in 48–72 h. While the radiological signs resemble those
Patient age/diagnosis
SCME on biological fluids
Echocardiogram before starting chemotherapy (EF%)
ECG at presentation of symptoms
Renal function at presentation of symptoms, creatinine (mg/dL)
Albuminemia on the day before starting chemotherapy (g/dL)
Pancreatic enzymes (U/L)
66 years/ AML
Negative Normal (55%) Normal Normal (0.80) Normal (3.9) Amylase 16 lipase NA
Table 61.1 Clinical evaluation of possible causes of lung infiltrates (cardiac or metabolic dysfunctions, infectious agents) other than cytarabine in our leukemic patient
Normal values in our laboratory: creatinine 0.6–1.4 mg/dL for male, 0.6–1.2 mg/dL for female; albumin 3.5–5 g/dL; amylase 1–100 U/L; lipase 1–60 U/LSCME indicates serological, cultural and molecular examination of biologic fluids (blood, urine, feces, BAL cultures, CMV and Galactomannan antigenemia, urinary Legionella antigen), AML acute myeloid leukemia. EF% ejection fraction, ECG electrocardio-gram, NA not available
732 F. Forghieri et al.
Reference Patients presenting lung toxicity (N)
Median age (years) of patients (range)
Status of hemato-logic disease (N)
Cytarabine dosage Median time (days) of onset of symptoms from start of chemother-apy (range)
Clinical outcome (N)
Haupt et al. [10]
10 early; 18 late occurrence
39 (1–85) 28 REL Intermediate (7.5–30 mg/kg/day)
0–3; 4–30 28 Deaths (autoptic data)
Andersson et al. [11]
16 35 (16–68) 16 REL High (3 g/m2 every 12 h for 4–12 doses)
16 (2–21) 15 Recoveries, 1 deatha
Tham et al. [15]
15 29 (15–57) 15 first-line therapy
Intermediate (1 g/m2 every 12 h for 6 days); high (3 g/m2 every 12 h for 4 days )
16 (8–20) 13 Recoveries, 2 deathsa
Jehn et al. [16]
7 40 (17–64) 7 REL/REF Intermediate (1 g/m2 every 12 h for 6 days); high (3 g/m2 every 12 h for 4 days)
NA (1–14) 3 Recoveries, 4 deaths
Andersson et al. [12]
14 39 (22–66) 14 REL High (3 g/m2 every 6–12 h for 6–12 doses OR 3 g/m2 every 12 h for 2 doses, followed by 1.5 g/m2 over 24 h for 3–4 days)
8 (1–29) 4 Recoveries, 10 deaths
Shearer et al. [17]
5 NA (4–12) 5 REL Intermediate/high (1.0–1.5 g/m2 over 24 h for 5 days)
8 (3–38)b 2 Recoveries, 3 deaths
Salvucci et al. [14]
2 14, 31 1 PR High (4 g/day for 5 days) 1, 7 2 Recoveriesa
1 REL
Larouche et al. [18]
1 72 1 First-line therapy
Standard (200 mg/m2 over 24 h for 7 days)
3 1 Recoverya
Forghieri et al. [26]
3 53, 51, 66 2 First-line therapy
High (3 g/m2 every 12 h on day 1, 3, 5, 7 OR 2 g/m2 for 5 days)
1 3 Recoveriesa
1 REL
Yegln et al. [19]
1 17 First-line therapy
High (3 g/m2 every 12 h on days 2, 3)
4 1 Recoverya
Table 61.2 Revision of the clinical data available from cases of cytarabine-related lung toxicity reported in the literature
Patients affected with BOOP secondary to cytarabine administration were not included in this tableN number of cases, PR partial remission, REL relapsed, REF refractory, NA not availableaIndicates that some patients of the series received corticosteroidsbIndicates that one patient presented respiratory symptoms 38 days after the first course of cytarabine, but a second course had been already administered just before the onset of symptoms
typically detected in both NCPE and COP, which can be characterized by signs of alveolar or interstitial opacifi-cation, surrounded sometimes by ground-glass areas, and pleural effusions, our cases showed a more indolent behavior and a benign clinical outcome compared to cases previously reported in the literature. Of note, our patients developed a sudden onset of symptoms after starting to receive the drug, but, despite the severity of radiological findings, the symptoms rapidly improved
and were self-limiting, with only mild dyspnea and moderate hypoxemia on blood gas analysis [26].
Cytarabine-induced pulmonary toxicity is probably related to a cytokine-mediated mechanism involving tumor necrosis factor-alpha and platelet-activating fac-tor, which determine inflammatory response with alve-olar damage and increased vascular permeability [27]. Most of the reported patients were affected with relapsed leukemia (Table 61.2), so it cannot be
73361 Cytarabine-Induced Pulmonary Toxicity in Leukemic Patients
excluded that heavily pretreated patients could be more exposed to a possibly more severe pulmonary toxicity. From the review of the literature [6, 10–19, 26], cytar-abine-related pulmonary toxicity occurs more fre-quently in patients with relapsed leukemia (72 out of 92 reported cases) than in patients with “de novo” leu-kemia (20 out of 92 patients). In the former group, a more severe course, often fatal (46 out of 72), is observed; in the latter group, only 2 out of 20 patients died from lung toxicity. Of note, most of the reported patients underwent standard chest X-ray examinations, whereas the performance of HRCT at a very early phase would probably allow better characterization of severe radiological findings in the absence of a corre-sponding severity of the clinical symptoms. Thus, the incidence of cytarabine-related lung infiltrates may be underestimated so that the early performance of HRCT in leukemic patients treated with intermediate to high-dose cytarabine at onset of respiratory symptoms, even if of mild entity, should be recommended. Recently, mild dyspnea in a febrile context has been reported as an early complication of Ara C therapy, with diffuse bilateral centrilobular micronodules with upper lobe predominance [28].
Because the diagnosis of cytarabine-induced pul-monary toxicity in the setting of leukemic patients is an exercise of exclusion of several other causes of lung infiltrates, an aggressive diagnostic approach, includ-ing invasive procedures such as bronchoscopy with BAL and transbronchial biopsy sampling, unless con-traindicated, should be performed [4, 6]. Of note, the subsequent complete resolution of radiological find-ings should be promptly documented by either chest X-ray or HRCT as soon as the fever and the respiratory symptoms disappear.
As far as the therapeutic approach to patients with cytarabine-related pulmonary toxicity is concerned, it is not possible to define a formal management guide-line simply based on the scanty data reported from the literature. Decisions about temporary or definitive dis-continuation of cytarabine or about the introduction of systemic steroid therapy, which could lead to dramatic improvement and favorable outcomes, also in the most critical patients [6, 18, 19], should be based upon a careful evaluation of the clinical status (respiratory symptoms, fever, blood gas analysis and state of hema-tologic disease). The role of corticosteroids or any other therapeutic support in this clinical setting should be evaluated in clinical trials. However, the reported
high incidence of cytarabine-related lung toxicity in relapsed leukemia patients may suggest introducing pre-medication with low-dose dexamethasone in this patient subgroup. In conclusion, cytarabine-related toxicity should be considered among the possible causes of lung infiltrates in patients with hematologic malignancies.
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