Respiratory Medicine (1992) 86, 261-263
Case Report
Pulmonary toxicity and acute respiratory failure associated with fludarabine monophosphate G. C. KANE*,A. J. McMICHAEL,H. PATRICKAND A. J. ERSLEVt
Jefferson Medical College, Department of Medicine, Division of Pulmonary Medicine and Critical Care, and t the Cardeza Foundation, Philadelphia, Pennsylvania, U.S.A.
Introduction Fludarabine monophosphate is a novel nucleotide analog recently approved as a chemotherapeutic agent for the treatment of refractory chronic lymphocytic leukaemia (CLL) (1). Two case reports have suggested an association of fludarabine with interstitial pneumonitis occurring within weeks after the third course of intravenous fludarabine which responds to steroid therapy (2,3). We report a more severe life threatening case of fludarabine-associated pulmonary toxicity. This patient developed diffuse interstitial pneumonitis and hypoxaemic respiratory failure requiring mechanical ventilation 1 week after the first course of fludarabine monophosphate for refractory CLL. Case Report A 74-year-old man with a history of hypertension and hypothyroidism, was diagnosed with CLL 3 years previously after presenting with hepatosplenomegaly, anaemia and a white count of 117 000/11 -~ with 95% mature lymphocytes. Initial therapy with chlorambucil and prednisone produced a partial remission but subsequent therapy with cyclophosphamide, doxorubincin, vincristine and prednisone (CHOP) failed to achieve a response. Increased hepatosplenomegaly, worsening anaemia (haemoglobin 7.8 g dl -t) and thrombocytopenia (platelet count 45 000/11-1), and white count of 258000/A -~ were observed 2 months after the last dose of CHOP. Fludarabine monophosphate in an intravenous dose of 24 mg (m 2)daily for 5 days was begun. The patient initially Received 30 September 1991 and accepted in revised form 19December1991. *To whom correspondence should be addressed at: Department of Medicine, Division of Pulmonary Medicine and Critical Care, Thomas Jefferson University Hospital, 1025 Walnut Street, Room 804.Philadelphia, PA 19107,U.S.A. 0954-6111/92/030261+ 03 $03.00/0
tolerated this drug well, but 6 days after completing this first course of treatment a non-productive cough, fever and progressive dyspnoea developed and 1 week later the patient required hospitalization. On admission, medications included digoxin, atenolol, allopurinol, and Synthroid. There was no prior history of lung disease or tobacco use. Examination revealed a temperature of 38-4°C and diffuse crackles throughout both lung fields posteriorly. The white count was 28 300/A-t with 10% neutrophils and 90% lymphocytes. The haemoglobin was 9.7 g dl -~ and the platelet count 125 000/11- t. A room air arterial blood sample showed a pH of 7.48, PCO 2 35 mmHg and PO2 66 mmHg. The admission chest radiograph showed a diffuse bilateral reticulonodular infiltrate. The patient received broad spectrum antibiotic therapy without response. On the third hospital day, the patient required tracheal intubation and mechanical ventilation because of progressive hypoxaemia which failed to respond to high concentrations of inspired oxygen delivered by face mask. On the fourth day, bronchoscopy with bronchoalveolar lavage and brushings failed to demonstrate an infectious cause of the pneumonitis. On the fifth hospital day, an open lung biopsy was performed and showed patchy diffuse alveolar damage and exudation with atypical type II pneumocytes (Plate 1). All special stains and cultures for organisms including fungi, mycobacteria and Pneumocystis carinii were negative. After an infectious etiology was excluded by preliminary stains, high dose corticosteroids (methylprednisolone 60 mg intravenously every 6 h) were administered with clinical and radiographic improvement and weaning from mechanical ventilation within 48 h (hospital day 9). Subsequent chest radiographs showed clearing of the infiltrates and the patient was discharged from the hospital on low dose prednisone (hospital day 20). © 1992BaillirreTindall
262
G. C. Kane et al.
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Plate I Open lung biopsy specimen showing patchy areas ofdiffuse alveolar damage and alveolar exudation (atypical type 1I pneumocytes not shown in this low power view).
During the hospital stay the patient required 6 units of packed red cell transfusions and at discharge the white blood cell count was 16 800/t1-1 with 7% neutrophils and 93% lymphocytes. The discharge haemoglobin was 8.3 g dl- t and platelet count 65 000/tl- ~. Further courses of fludarabine were withheld. Discussion
This case, together with two previously published case reports and five other cases mentioned in abstract form in the drug literature, suggests that a syndrome of cough, fever, and dyspnoea may follow the use of fludarabine as monotherapy in refractory CLL in standard dosages (2-5). This patient demonstrated several features characteristic of drug-induced pulmonary disease. He presented with non-productive cough, fever, and dyspnoea and the chest radiograph demonstrated diffuse reticulonodular infiltrates. Initial diagnostic tests including bronchoscopy with bronchoalveolar lavage and ultimately open lung biopsy failed to reveal an infectious agent. The biopsy did reveal evidence of interstitial pneumonitis with thickened alveolar walls, alveolar exudation, and atypical type II pneumocytes (6). The specimen showed no evidence of vasculitis or granuloma formation. Finally, there was a dramatic response to corticosteroid therapy with clinical improvement and resolution of the radiographic abnormalities. Although this patient, as in previous reports, had received other chemotherapeutic agents with known pulmonary toxicity (chlorambucil and cyclophosphamide) up to 2 months prior to treatment with fludarabine, the sudden onset of symptoms 1 week
after infusion of fludarabine strongly suggests that ftudarabine caused the pulmonary injury (7,8). In this case the complication was life threatening and the patient required tracheal intubation and mechanical ventilation because of hypoxaemic respiratory failure. As in previous reports of fludarabine-related pulmonary disease, there was an excellent clinical response to corticosteroid therapy and the patient was weaned ~om mechanical ventilation and ultimately discharged from the hospital. The spectrum of fludarabine related pulmonary disease is broadened by this report. Previous reported cases occurred 8 days to 2 weeks after the third course of fludarabine in similar doses in patients who had also received prior chemotherapy (2,3). Our patient developed symptoms 1 week after the initial course of therapy. Both previous cases showed clinical response to high dose steroid therapy with resolution of symptoms and clearing of radiographic infiltrates consistent with this patient's response. In one patient, resumption offludarabine led to recurrent symptoms. None of the previously reported patients developed respiratory failure. This case also emphasizes the documented benefit of fludarabine monophosphate in refractory CLL. Although earlier treatment with chlorambucil and CHOP failed to control CLL in this patient, fludarabine was well tolerated and resulted in marked improvement in the white cell count and hepatosplenomegaly without worsening anaemia or thrombocytopenia. Despite the severity of the pulmonary toxicity suggested by this report, this side effect of fludarabine therapy appears to be rare based on the limited number of reported cases.
Fludarabine and pulmonary toxicity
We conclude that fludarabine therapy may be associated with pulmonary toxicity. The severity of pulmonary toxicity ranges from mild infammation which responds spontaneously to more severe cases complicated by respiratory failure. We recommend prompt high dose corticosteroid therapy for this syndrome after infectious etiologies of pneumonitis have been excluded.
Acknowledgements We thank Ms Nancy Axtman for assistance with preparation of the manuscript.
References I. Von Hoff DD. Phase I clinical trials with fludarabine phosphate. Sere Onco11990; 17 (suppl. 8): 33-38.
263
2. Hurst PG, Habib MP, Garewol H, Bluestein M, Paquin M, Greenburg BR. Pulmonary toxicity associated with fludarabine monophosphate, hlvest New Drugs 1987; 5: 207-210. 3. Cervantes F, Salgado C, Montserrat E, Rozman C. Fludarabine for prolymphocytic leukemia and risk of interstitial pneumonitis, Lancet 1990;336:1 I30, 4. Grever MR, Coltman CA Jr, Files JC et al, Fludarabine monophosphate in chronic lymphocytic leukemia. Blood 1986; 68: 223a (Abstract no. 771). 5. Mittleman A, Lichtman S, Budman D et al. Therapy of chronic lymphocytic leukemia (CLL) with fludarabine phosphate (FAMP). Blood 1988; 72:2502 (Abstract no. 909). 6. Dail DH, Hammar SP. Pulmonary Pathology. New York: Springer Verlag Inc., 1988; 512-514. 7. Rosenow EC III. The spectrum of drug induced pulmonary disease. Ann Intern Med 1972;77: 977-991. 8. Ginsberg SJ, Comis RL. Pulmonary toxicity of antineoplastic agents. Sere Onco11982; 9: 34-49.
Case Report
Pulmonary toxicity and acute respiratory failure associated with fludarabine monophosphate G. C. KANE*,A. J. McMICHAEL,H. PATRICKAND A. J. ERSLEVt
Jefferson Medical College, Department of Medicine, Division of Pulmonary Medicine and Critical Care, and t the Cardeza Foundation, Philadelphia, Pennsylvania, U.S.A.
Introduction Fludarabine monophosphate is a novel nucleotide analog recently approved as a chemotherapeutic agent for the treatment of refractory chronic lymphocytic leukaemia (CLL) (1). Two case reports have suggested an association of fludarabine with interstitial pneumonitis occurring within weeks after the third course of intravenous fludarabine which responds to steroid therapy (2,3). We report a more severe life threatening case of fludarabine-associated pulmonary toxicity. This patient developed diffuse interstitial pneumonitis and hypoxaemic respiratory failure requiring mechanical ventilation 1 week after the first course of fludarabine monophosphate for refractory CLL. Case Report A 74-year-old man with a history of hypertension and hypothyroidism, was diagnosed with CLL 3 years previously after presenting with hepatosplenomegaly, anaemia and a white count of 117 000/11 -~ with 95% mature lymphocytes. Initial therapy with chlorambucil and prednisone produced a partial remission but subsequent therapy with cyclophosphamide, doxorubincin, vincristine and prednisone (CHOP) failed to achieve a response. Increased hepatosplenomegaly, worsening anaemia (haemoglobin 7.8 g dl -t) and thrombocytopenia (platelet count 45 000/11-1), and white count of 258000/A -~ were observed 2 months after the last dose of CHOP. Fludarabine monophosphate in an intravenous dose of 24 mg (m 2)daily for 5 days was begun. The patient initially Received 30 September 1991 and accepted in revised form 19December1991. *To whom correspondence should be addressed at: Department of Medicine, Division of Pulmonary Medicine and Critical Care, Thomas Jefferson University Hospital, 1025 Walnut Street, Room 804.Philadelphia, PA 19107,U.S.A. 0954-6111/92/030261+ 03 $03.00/0
tolerated this drug well, but 6 days after completing this first course of treatment a non-productive cough, fever and progressive dyspnoea developed and 1 week later the patient required hospitalization. On admission, medications included digoxin, atenolol, allopurinol, and Synthroid. There was no prior history of lung disease or tobacco use. Examination revealed a temperature of 38-4°C and diffuse crackles throughout both lung fields posteriorly. The white count was 28 300/A-t with 10% neutrophils and 90% lymphocytes. The haemoglobin was 9.7 g dl -~ and the platelet count 125 000/11- t. A room air arterial blood sample showed a pH of 7.48, PCO 2 35 mmHg and PO2 66 mmHg. The admission chest radiograph showed a diffuse bilateral reticulonodular infiltrate. The patient received broad spectrum antibiotic therapy without response. On the third hospital day, the patient required tracheal intubation and mechanical ventilation because of progressive hypoxaemia which failed to respond to high concentrations of inspired oxygen delivered by face mask. On the fourth day, bronchoscopy with bronchoalveolar lavage and brushings failed to demonstrate an infectious cause of the pneumonitis. On the fifth hospital day, an open lung biopsy was performed and showed patchy diffuse alveolar damage and exudation with atypical type II pneumocytes (Plate 1). All special stains and cultures for organisms including fungi, mycobacteria and Pneumocystis carinii were negative. After an infectious etiology was excluded by preliminary stains, high dose corticosteroids (methylprednisolone 60 mg intravenously every 6 h) were administered with clinical and radiographic improvement and weaning from mechanical ventilation within 48 h (hospital day 9). Subsequent chest radiographs showed clearing of the infiltrates and the patient was discharged from the hospital on low dose prednisone (hospital day 20). © 1992BaillirreTindall
262
G. C. Kane et al.
1TM " .
.
~
"
•
},
.~
Plate I Open lung biopsy specimen showing patchy areas ofdiffuse alveolar damage and alveolar exudation (atypical type 1I pneumocytes not shown in this low power view).
During the hospital stay the patient required 6 units of packed red cell transfusions and at discharge the white blood cell count was 16 800/t1-1 with 7% neutrophils and 93% lymphocytes. The discharge haemoglobin was 8.3 g dl- t and platelet count 65 000/tl- ~. Further courses of fludarabine were withheld. Discussion
This case, together with two previously published case reports and five other cases mentioned in abstract form in the drug literature, suggests that a syndrome of cough, fever, and dyspnoea may follow the use of fludarabine as monotherapy in refractory CLL in standard dosages (2-5). This patient demonstrated several features characteristic of drug-induced pulmonary disease. He presented with non-productive cough, fever, and dyspnoea and the chest radiograph demonstrated diffuse reticulonodular infiltrates. Initial diagnostic tests including bronchoscopy with bronchoalveolar lavage and ultimately open lung biopsy failed to reveal an infectious agent. The biopsy did reveal evidence of interstitial pneumonitis with thickened alveolar walls, alveolar exudation, and atypical type II pneumocytes (6). The specimen showed no evidence of vasculitis or granuloma formation. Finally, there was a dramatic response to corticosteroid therapy with clinical improvement and resolution of the radiographic abnormalities. Although this patient, as in previous reports, had received other chemotherapeutic agents with known pulmonary toxicity (chlorambucil and cyclophosphamide) up to 2 months prior to treatment with fludarabine, the sudden onset of symptoms 1 week
after infusion of fludarabine strongly suggests that ftudarabine caused the pulmonary injury (7,8). In this case the complication was life threatening and the patient required tracheal intubation and mechanical ventilation because of hypoxaemic respiratory failure. As in previous reports of fludarabine-related pulmonary disease, there was an excellent clinical response to corticosteroid therapy and the patient was weaned ~om mechanical ventilation and ultimately discharged from the hospital. The spectrum of fludarabine related pulmonary disease is broadened by this report. Previous reported cases occurred 8 days to 2 weeks after the third course of fludarabine in similar doses in patients who had also received prior chemotherapy (2,3). Our patient developed symptoms 1 week after the initial course of therapy. Both previous cases showed clinical response to high dose steroid therapy with resolution of symptoms and clearing of radiographic infiltrates consistent with this patient's response. In one patient, resumption offludarabine led to recurrent symptoms. None of the previously reported patients developed respiratory failure. This case also emphasizes the documented benefit of fludarabine monophosphate in refractory CLL. Although earlier treatment with chlorambucil and CHOP failed to control CLL in this patient, fludarabine was well tolerated and resulted in marked improvement in the white cell count and hepatosplenomegaly without worsening anaemia or thrombocytopenia. Despite the severity of the pulmonary toxicity suggested by this report, this side effect of fludarabine therapy appears to be rare based on the limited number of reported cases.
Fludarabine and pulmonary toxicity
We conclude that fludarabine therapy may be associated with pulmonary toxicity. The severity of pulmonary toxicity ranges from mild infammation which responds spontaneously to more severe cases complicated by respiratory failure. We recommend prompt high dose corticosteroid therapy for this syndrome after infectious etiologies of pneumonitis have been excluded.
Acknowledgements We thank Ms Nancy Axtman for assistance with preparation of the manuscript.
References I. Von Hoff DD. Phase I clinical trials with fludarabine phosphate. Sere Onco11990; 17 (suppl. 8): 33-38.
263
2. Hurst PG, Habib MP, Garewol H, Bluestein M, Paquin M, Greenburg BR. Pulmonary toxicity associated with fludarabine monophosphate, hlvest New Drugs 1987; 5: 207-210. 3. Cervantes F, Salgado C, Montserrat E, Rozman C. Fludarabine for prolymphocytic leukemia and risk of interstitial pneumonitis, Lancet 1990;336:1 I30, 4. Grever MR, Coltman CA Jr, Files JC et al, Fludarabine monophosphate in chronic lymphocytic leukemia. Blood 1986; 68: 223a (Abstract no. 771). 5. Mittleman A, Lichtman S, Budman D et al. Therapy of chronic lymphocytic leukemia (CLL) with fludarabine phosphate (FAMP). Blood 1988; 72:2502 (Abstract no. 909). 6. Dail DH, Hammar SP. Pulmonary Pathology. New York: Springer Verlag Inc., 1988; 512-514. 7. Rosenow EC III. The spectrum of drug induced pulmonary disease. Ann Intern Med 1972;77: 977-991. 8. Ginsberg SJ, Comis RL. Pulmonary toxicity of antineoplastic agents. Sere Onco11982; 9: 34-49.
