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August (2) 2001, Volume 28, Number 4, Pages 399-403
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Post-transplant Complications
Pulmonary toxicity syndrome following CDEP (cyclophosphamide, dexamethasone, etoposide, cisplatin) chemotherapy
A Fassas1,a, I Gojo1, A Rapoport1, M Cottler-Fox1,a, B Meisenberg2, J C Papadimitriou2 and G Tricot1,a

1Department of Medicine, Division of Bone Marrow and Stem Cell Transplantation, Greenebaum Cancer Center, Baltimore, MD, USA

2Department of Pathology, University of Maryland, Baltimore, MD, USA

Correspondence to: Dr A Fassas, Myeloma and Transplantation Center, University of Arkansas for Medical Sciences, 4301 W Markham Street, Little Rock, AR, 72205, USA

aCurrent address: Myeloma and Transplantation Research Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA

Abstract

We report on three patients with multiple myeloma who developed drug-induced pneumonitis 1-2½ months following maintenance (post autologous transplantation) chemotherapy with CDEP (cyclophosphamide, dexamethasone, etoposide, cisplatin) and 6-20 months after exposure to carmustine (BCNU) 300 mg/m2, used in combination with melphalan 140 mg/m2, as pre-transplant conditioning regimen. All patients had either a proven (two) or suspected (one) fungal pneumonia and were treated with liposomal amphotericin B. Dyspnea, fever and cough were the prominent clinical symptoms, while air-space disease with ground glass appearance was seen radiographically. Histologic features typical for drug-induced lung injury were detected. All patients had a dramatic, clinical and radiographic response to a brief course of corticosteroids. Although CDEP-induced pneumonitis appears to be a rare complication, its early recognition and prompt treatment, as well as its possible association with preceding fungal infection may have important clinical implications. Bone Marrow Transplantation (2001) 28, 399-403.

Keywords

non-infective pulmonary toxicity; CDEP chemotherapy; fungal infection

Drug-induced pulmonary toxicity, not associated with infection, is a well-described complication of different chemotherapeutic agents. Among them, carmustine (BCNU), cyclophosphamide, bleomycin, busulphan, melphalan and total body irradiation have been implicated.1 Furthermore, combinations of various agents (even the ones rarely associated with the syndrome) may potentially lead to lung injury through drug interactions.2 Additionally, unrecognized host-drug interactions may contribute to the development of this pulmonary toxicity syndrome (PTS). This is further supported by the lack of correlation between severity of PTS in case of BCNU-based high-dose chemotherapy with age, tobacco use or baseline pulmonary function, suggesting that other factors play a role in PTS, in addition to chemotherapy exposure.3

From this perspective, it was intriguing to observe three patients, with a history of either proven (two) or suspected (one) fungal pneumonia, who developed typical clinical, radiographic and histologic features of PTS 5-11 weeks after treatment with CDEP (cyclophosphamide, dexamethasone, etoposide, cisplatin) chemotherapy, a fairly commonly used regimen which has not so far been associated with non-infective pulmonary toxicity. These patients had a dramatic response to a brief course of corticosteroids. There was no evidence of fungal infection at the time of PTS diagnosis.

Patients and methods

Between August 1997 and February 2000, 231 patients underwent autologous peripheral blood stem cell transplantation (APBSCT), at our institution, for a variety of hematologic malignancies (multiple myeloma, 87; non-Hodgkin lymphoma, 64; Hodgkin's disease, 11; others, 14) and solid tumors (breast carcinoma, 46; others, nine). In the vast majority (200 patients), the same conditioning regimen of BCNU at 300 mg/m2 and melphalan at 140 mg/m2 (BCNU/MEL) was applied, followed by post-transplant chemotherapy starting 3 months after the APBSCT and administered every 3 months ´ four courses during the year following transplant (or until disease relapse). The regimens used for the post-transplant chemotherapy were cyclophosphamide 300 mg/m2 by continuous i.v. infusion over 24 h for 4 days, dexamethasone 40 mg p.o. daily for 4 days, etoposide 30 mg/m2 by continuous i.v. infusion over 24 h for 4 days and cisplatin 15 mg/m2 by continuous i.v. infusion over 24 h for 4 days (CDEP), for courses 1 and 3, alternating with dexamethasone 40 mg p.o. daily for 4 days, taxol 135 mg/m2 by i.v. infusion over 6 h on day 2 and cisplatin 75 mg/m2 by i.v. infusion over 24 h on day 3 of the cycle, for courses 2 and 4. The feasibility and toxicity data on 50 patients with multiple myeloma treated with such an approach have been previously reported.4 Eight patients (4%) developed non-infective, pulmonary toxicity syndrome (seven lung-biopsy proven, one suspected). All had been exposed to BCNU during the pre-transplant conditioning. While in five patients the syndrome occurred in temporal proximity to BCNU exposure (32-98 days after administration), the remaining three patients experienced this complication 6-20 months following the pre-transplant conditioning and interestingly enough within 1-2½ months after treatment with CDEP. The clinical history of these patients is presented.

Patient 1

A 56-year-old man was diagnosed with nonsecretory multiple myeloma, stage II-A, in January 1999. He had a 20 pack-year history of smoking, but quit smoking approximately 17 years prior to diagnosis. Following two courses of pulse dexamethasone and mobilization chemotherapy consisting of cyclophosphamide 4500 mg/m2 and etoposide 2000 mg/m2 (CTX/VP16), he received APBSCT on 27 May 1999, after conditioning with BCNU/MEL. Delayed engraftment, despite an excellent collection of stem cells, prompted the infusion of additional stem cells on day +19, with ANC finally reaching 1500/mul on day +31. Evaluation for persistent neutropenic fevers revealed pulmonary nodules. Bronchoalveolar lavage (BAL) was negative for pathogens (Pneumocystis carinii pneumonia (PCP), Legionella, acid fast bacilli, viral and fungal pathogens). Empiric treatment with liposomal amphotericin B was initiated. A repeat bronchoscopy with BAL was performed for evaluation of hemoptysis on 6 August 1999; silver stains of cytologic specimens were positive for fungal elements consistent with aspergillus. Liposomal nystatin was introduced with improvement in the radiologic picture. Nystatin was discontinued in mid-November 1999, after no further change was documented by serial computed tomography (CT) scans. Of note, the patient remained severely anemic and thrombocytopenic during the entire post-transplant period, requiring frequent red cell and platelet transfusions. Despite the stormy post-transplant course and the good control of his disease (with bone marrow plasmacytosis 5%) maintenance chemotherapy consisting of CDEP was administered between 10 and 14 December 1999. Additional stem cells were infused at the completion of this chemotherapy. Prophylaxis with itraconazole was initiated, but no prophylaxis against PCP was given. On 10 January 2000, the patient presented with new onset dyspnea, malaise, non-productive cough and severe hypoxemia (PO2: 55 mmHg at room air). No blood products were transfused during the preceding 48 h. No fever was documented. Chest CT showed a new infiltrate (Figure 1a). Bronchoscopy showed scant clear secretions in otherwise normal airways. BAL failed to reveal any pathogens while the transbronchial biopsy was consistent with chemotherapy-induced pneumonitis. Rapid and dramatic symptomatic and objective improvement (as evidenced by resolution of dyspnea, weaning off supplemental oxygen, correction of hypoxemia and resolution of the radiographic picture) occurred after a brief course of oral corticosteroids. Due to the recent history of fungal pneumonia, a relatively low dose of methylprednisolone (total 24 mg/day) was chosen and symptoms recurred on fast tapering. Reinstitution of corticosteroids and much slower tapering led again to complete resolution of the symptoms. The patient experienced no subsequent reactivation of fungal pneumonia.

Patient 2

A 53-year-old woman, without prior history of smoking, was diagnosed with IgA kappa multiple myeloma, stage III-B, in March 1998. Following three courses of VAD and mobilization chemotherapy with CTX/VP16, she received APBSCT on 6 August 1998, after conditioning with BCNU/MEL. She achieved complete hematologic recovery and a partial remission of the myeloma. In November 1998, she was given CDEP chemotherapy, which was complicated by pneumonia with extensive bilateral infiltrates. Bronchoscopy with BAL was performed; cultures of the specimens grew Candida tropicalis only. The same pathogen, ie Candida tropicalis, was also identified in blood cultures. Further maintenance chemotherapy was therefore held. Relapsing disease in September 1999, prompted the administration of a second APBSCT on 14 October 1999, after conditioning with melphalan 200 mg/m2. Prophylaxis with itraconazole was initiated prior to the transplantation and continued over the next several months. No prophylaxis against PCP was given. Thalidomide was started after (timely) hematologic recovery. She achieved a complete remission (with <2% bone marrow plasmacytosis and undetectable monoclonal protein). On 20 January 2000, the patient received another course of CDEP chemotherapy. On 31 March 2000, she presented with fever, malaise, non-productive cough, dyspnea and mild hypoxemia (PO2: 84 mmHg at room air). No blood products were transfused during the preceding 48 h. Chest CT scan showed a diffuse ground glass pattern, predominantly involving the lower lungs (Figure 1b). Bronchoscopy showed moderate mucoid secretions in otherwise normal airways. No pathogens (Pneumocystis carinii pneumonia, Legionella, acid fast bacilli, viral and fungal pathogens) were identified by BAL and the transbronchial biopsy was consistent with chemotherapy-induced pneumonitis (Figure 2a, b). Corticosteroid treatment was initiated (total dose of methylprednisolone 60 mg/day, tapered over the next 3 weeks) with rapid resolution of the clinical symptomatology and normalization of the radiographic picture. The patient experienced no subsequent reactivation of fungal pneumonia.

Patient 3

A 65-year-old woman, without prior history of smoking, was diagnosed with IgA kappa multiple myeloma, stage III-A in January 1999. Following two courses of pulse dexamethasone and mobilization chemotherapy with CTX/VP16, she received APBSCT on 20 May 1999, after conditioning with BCNU/MEL. Her post-transplant course was complicated by Candida parapsilosis fungemia, Staphylococcus epidermidis and Enterococcus faecium bacteremia, Clostridium difficile colitis, cytomegalovirus reactivation (CMV antigenemia) and right lung pneumonia (for which she underwent bronchoscopy and BAL with negative results). Liposomal amphotericin B was given for 3 weeks along with appropriate antibacterial and antiviral coverage with resolution of fever and blood cultures becoming negative. Repeat chest radiographs were also clear. She achieved a near complete remission (with <2% bone marrow plasmacytosis and IgA only detectable by immunofixation). On 25 August 1999, she was given CDEP chemotherapy with good tolerance and timely hematologic recovery. No prophylaxis against PCP was given. On 16 November 1999, she presented with dyspnea, low grade fever and severe hypoxemia (PO2: 50 mmHg at room air). No blood products were transfused during the preceding 48 h. Chest CT scan showed extensive, diffuse air-space disease with a ground glass appearance (Figure 1c). Bronchoscopy showed scant mucopurulent secretions in otherwise normal airways. No pathogens (Pneumocystis carinii pneumonia, Legionella, acid fast bacilli, viral and fungal pathogens) were identified by BAL and the transbronchial biopsy was consistent with chemotherapy-induced pneumonitis (Figure 2c). Corticosteroid treatment was initiated (total dose of methylprednisolone 80 mg/day, tapered over the next 3 weeks) with dramatic resolution of the symptoms and the radiographic picture. The patient experienced no subsequent reactivation of fungal pneumonia.

Pathology

The findings in the transbronchial biopsies (Table 1) are young, connective tissue growth in the alveolar septa, enlargement and atypia of type II pneumocytes and accumulation of intra-alveolar edema and macrophages. A fifth feature, less consistently observed, was pulmonary arterial branch changes consisting of intimal edema and fibrosis and endothelial cell injury.

The results were assessed semiquantitatively by one of the authors (JCP). The grades assigned were 0-4+ (0, normal; 4+, most pathological).

In all three cases the presence of infectious agents (viruses, fungi) was ruled out with hematoxylin and eosin and special stains. The observed findings of pulmonary injury expressed by the pneumocyte II atypia, the accompanying young fibrosis and intra-alveolar accumulation of edematous fibroid and macrophages are - in the absence of any infectious etiology - compatible with drug toxicity.

Discussion

Three patients (1.5%) developed typical clinical radiographic and histologic features of PTS 5-11 weeks after treatment with CDEP (cyclophosphamide, dexamethasone, etoposide, cisplatin) chemotherapy. None had received prior radiation treatment for local disease control and only one had a limited, rather remote, exposure to tobacco. All patients had a remote (6 months) exposure to BCNU 300 mg/m2 and melphalan 140 mg/m2 with history of either proven (two) or suspected (one) fungal pneumonia. The clinical and radiographic picture resolved with a brief course of corticosteroids. No evidence of reactivation of fungal infection or transfusion-related lung toxicity was found.

It is possible that the PTS seen in our patients merely reflects a delayed BCNU toxic effect. Pulmonary toxicity attributed to BCNU has been reported up to 17 years post exposure.5 However, 23 out of 26 patients who developed idiopathic pneumonia syndrome following BCNU-based high-dose chemotherapy with autologous bone marrow transplantation (ABMT) for relapsed Hodgkin's disease, experienced symptoms during the first 6 months post-treatment (with the remaining three patients diagnosed between 6 and 12 months post-chemotherapy).6 In another report,3 26 women with breast cancer, who underwent ABMT after BCNU-based conditioning, developed pulmonary symptoms with a median onset of 10.3 weeks (range 2.4-16.6 weeks). Finally, in a retrospective study of 10 women with breast cancer and biopsy-proven pulmonary toxicity after high-dose BCNU, all became symptomatic at a mean time of 48 ± 14 days (range, 21-62 days) after the initiation of high-dose treatment.7 Furthermore, the dose of BCNU used in our treatment program was only 300 mg/m2, much lower than the dose used in the previously mentioned studies. Therefore, it is rather unlikely that a BCNU effect can explain the whole picture.

It may be also argued that the toxicity observed in our patients was caused by cyclophosphamide or etoposide. Several case reports of suspected cyclophosphamide-induced lung toxicity have been described.8 Both the timing of the reaction and the cumulative dose of the drug were widely variable. More importantly, however, in the overwhelming majority of related cases, confounding variables probably contributed to the lung findings. In a review from the Mayo Clinic,9 the authors identified only six patients, over a 20-year period, in whom cyclophosphamide was the only identifiable factor for lung toxicity. Most patients (5/6) developed late-onset pneumonitis that was frequently associated with pleural thickening and did not respond to corticosteroids, features not observed in our patients. Etoposide, administered orally for lung cancer management, has been implicated in causing drug-induced pneumonitis in two patients. In both reports (in Japanese), the clinical and pathologic features were similar to the ones described in our patients.

Pretreatment with BCNU may have 'primed' our patients for further lung injury by the following cyclophosphamide-based regimen. In a recent report10 standard induction chemotherapy with CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) produced asymptomatic pulmonary dysfunction in women with high-risk breast cancer (as evidenced by significant decrease in the diffusing capacity of the lungs for carbon monoxide (DLCO)). Further decrease in DLCO and subsequent PTS were observed with the BCNU-based pre-transplant conditioning regimen. Another study11 (with a design similar to ours) employed post-autologous transplantation 'maintenance' chemotherapy with paclitaxel in a group of 10 women with metastatic breast cancer. BCNU was used in the conditioning regimen at the dose of 450 mg/m2. No toxicity was reported with a median follow-up of 2 years post transplant. Although this 'priming' effect can not be ruled out (as no serial pulmonary function tests were performed in our patients), the low incidence of this complication makes this possibility less likely. From this point of view, it is also instructive that patient no. 2 did not have any appreciable decline in DLCO performed prior to her first and second transplantation and yet she developed the PTS following the administration of the CDEP course after her second APBSCT and >1½ years after exposure to BCNU.

Finally, the interesting possibility of a prior infectious 'priming' to PTS needs to be considered. Two of our patients (patients 1 and 2) had a history of proven pulmonary mycosis (which in the latter case deterred the administration of further maintenance chemotherapy). The third patient (patient 3) had pulmonary infiltrates in the context of Candida parapsilosis fungemia, for which she was treated with amphotericin B and promptly responded. It is highly unlikely that active infection was present at the time of PTS, given the stability of the clinical and radiographic picture at the time of chemotherapy administration, the failure to identify fungal (or other infectious) elements by BAL and the rapid improvement on corticosteroids. Therefore, it is possible that a preceding (albeit treated and well controlled) fungal pneumonia may somehow (in the setting of CDEP chemotherapy and remote BCNU exposure) have contributed to PTS. Alternatively, the antifungal treatment (liposomal amphotericin) which has good lung tissue penetration might be a factor in the subsequent development of the PTS (possibly interaction with the chemotherapy agents).

If the above-mentioned hypothesis is correct, it has to be emphasized that the presumption of the fungal etiology of the pulmonary symptoms and radiologic findings in patients with a similar clinical presentation needs to be avoided. Furthermore, transbronchial biopsy should always be encouraged.

In conclusion, non-infective pulmonary toxicity syndrome may rarely complicate the course of a commonly used chemotherapy regimen, such as CDEP, possibly in association with previous, treated, fungal pneumonia. Recognition of the syndrome, timely establishment of diagnosis and prompt treatment with steroids are essential for a favorable clinical outcome.

References

1 Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic therapy. Semin Oncol 1992; 19: 508-520, MEDLINE

2 Zimmerman MS, Ruckdeschel JC, Hussain M. Chemotherapy-induced interstitial pneumonitis during treatment of small cell anaplastic lung cancer. J Clin Oncol 1984; 2: 396-405, MEDLINE

3 Wilczynski SW, Erasmus JJ, Petros WP et al. Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer. Am J Respir Crit Care Med 1998; 157: 565-573, MEDLINE

4 Tricot G, Fassas A, Rapoport A et al. Post-transplantation (PT) intensive chemotherapy is feasible and results in prompt and complete hematologic recovery in patients with multiple myeloma and low grade lymphoma. ASH 1999; 1485: 332a (Abstr.),

5 O'Driscoll BR, Hasleton PS, Taylor PM et al. Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. New Engl J Med 1990; 323: 378-382, MEDLINE

6 Rubio C, Hill ME, Milan S et al. Idiopathic pneumonia syndrome after high-dose chemotherapy for relapsed Hodgkin's disease. Br J Cancer 1997; 75: 1044-1048, MEDLINE

7 Todd NW, Peters WP, Ost AH et al. Pulmonary drug toxicity in patients with primary breast cancer treated with high-dose combination chemotherapy and autologous bone marrow transplantation. Am Rev Respir Dis 1993; 147: 1264-1270, MEDLINE

8 Spector JI, Zimbler H, Ross JS. Early-onset cyclophosphamide-induced interstitial pneumonitis. JAMA 1979; 242: 2852-2854, MEDLINE

9 Malik SW, Myers JL, DeRemee RA, Specks U. Lung toxicity associated with cyclophosphamide use. Two distinct patterns. Am J Respir Crit Care Med 1996; 154: 1851-1856, MEDLINE

10 Bhalla KS, Wilczynski SW, Abushamaa AM et al. Pulmonary toxicity of induction chemotherapy prior to standard or high-dose chemotherapy with autologous hematopoietic support. Am J Respir Crit Care Med 2000; 161: 17-25, MEDLINE

11 Rahman Z, Kavanagh J, Champlin R et al. Chemotherapy immediately following autologous stem-cell transplantation in patients with advanced breast cancer. Clin Cancer Res 1998; 4: 2717-2721, MEDLINE

Figures

Figure 1 Improvement of pulmonary infiltrates following treatment with corticosteroids. Upper panel, pre-treatment; lower panel, post-treatment.

Figure 2 Histologic findings in lung biopsies of patient 2 (a, b) and patient 3 (c). All biopsies show thickening of the alveolar septa caused by interstitial fibrosis and chronic inflammation. The higher power magnification (b) shows the markedly hyperplastic and atypical pneumocytes type II (arrow). Intra-alveolar macrophages and edema are seen in different degrees in all cases. (Original magnification, ´ 10 a, c; ´ 40 b).

Tables

Table 1 Pathological findings in the transbronchial biopsies

Received 25 September 2000; accepted 15 May 2001
August (2) 2001, Volume 28, Number 4, Pages 399-403
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