Pulmonary toxicity following carmustine-based preparative ... - Nature

Bone Marrow Transplantation (2000) 25, 309–313  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt

Pulmonary toxicity following carmustine-based preparative regimens and autologous peripheral blood progenitor cell transplantation in hematological malignancies EP Alessandrino1, P Bernasconi1, A Colombo1, D Caldera1, G Martinelli1, P Vitulo2, L Malcovati1, C Nascimbene2, M Varettoni1, E Volpini2, C Klersy3 and C Bernasconi1 1

Centro Trapianti di Midollo Osseo, Istituto di Ematologia, 2Divisione di Pneumologia, 3Biometry-Scientific Direction IRCCS, Policlinico S Matteo, Pavia, Italy

Summary: Sixty-five patients with hematological malignancies (25 multiple myeloma, 18 Hodgkin’s disease, 22 non-Hodgkin’s lymphomas) who received a carmustine-based regimen followed by autologous PBPC transplantation, were studied retrospectively to evaluate the incidence of post-transplant non-infective pulmonary complications (NIPCs), risk factors predictive of NIPCs, and response to steroids. Carmustine (BCNU) given i.v. at a dose of 600 mg/m2 was combined with etoposide and cyclophosphamide in 40 patients (BCV regimen) and with etoposide and melphalan in 25 patients (BEM regimen). Seventeen of 65 patients (26%) had one episode of NIPCs. The median time to NIPCs was 90 days (52–289). Factors that increased the risk of developing NIPCs on multivariate analysis were female sex (P ⬍ 0.001) and BCV regimen (P ⬍ 0.05). All patients with NIPCs received prednisone at a dose of 1 mg/kg body weight for 10 days then tapered by 5 mg every two days; complete response to steroids was achieved in 15 of 17 patients; one unresponsive patient died of interstitial pneumonia. BCNU given at the dose of 600 mg/m2 is well tolerated when associated with melphalan and etoposide. In females and in patients receiving BCNU with cyclophosphamide, a BCNU dose reduction may be advisable. Bone Marrow Transplantation (2000) 25, 309–313. Keywords: carmustine; pulmonary toxicity; autologous peripheral blood progenitor cell transplantation

There is evidence that several agents used in the preparative regimens for both autologous and allogeneic bone marrow transplantation may induce lung injury without evidence of infection. Agents that have been implicated include carmustine (BCNU), busulphan, cyclophosphamide (CY), and total body irradiation.1 BCNU causes toxic lung reactions characterized by chronic interstitial fibrosis, cough, dyspnea and decrease in lung diffusing capacity; toxicity related to Correspondence: EP Alessandrino, Centro Trapianti di Midollo Osseo, Istituto di Ematologia, IRCCS Policlinico S Matteo, 27100 Pavia (I), Italy Received 15 May 1999; accepted 28 September 1999

the use of BCNU is suspected to be caused by damage to the glutathione system.2 BCNU has been included in highdose conditioning regimens for gliomas, breast cancer, Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma. Toxic pulmonary reactions have been recognized in as many as 16–64% of patients;3–13 onset generally occurs within 1 year of starting BCNU. Events occurring up to 17 years later have been reported.14 The drug seems to cause pulmonary damage in a dose-related manner:5,10,11 Phillips et al6 reported a 9.5% incidence of fatal pulmonary toxicity in patients receiving BCNU doses as high as 1.200 mg/m2 as a single agent; another report suggests no pulmonary toxicity at doses of less than 1000 mg/m2.7 The threshold dose for BCNU toxicity is still controversial: lung toxicity may occur at 600 mg/m2 when the drug is associated with other toxic agents like CY.1,15 This report deals with patients with hematological malignancies who received a carmustine-based preparative regimen; the drug was combined with cyclophosphamide and etoposide or with etoposide and melphalan and both regimens were followed by autologous peripheral blood progenitor cell (PBPC) transplantation. The aim of this retrospective analysis was to characterize the incidence of pulmonary toxicity in patients treated with two diverse carmustine-containing regimens, and also to determine predictive risk factors and response to steroid therapy. Methods The medical records of 65 patients undergoing autologous PBSC transplantation who had received a BCNU-containing preparative regimen were reviewed to assess the incidence of pulmonary complications occurring within 12 months from transplant and the risk factors for their development; response to steroid therapy was also evaluated. All data concerning the total dose of cyclophosphamide, bleomycine, history of radiation and mediastinal involvement, history of smoking, previous history of pneumonitis or other lung diseases were taken into account. Episodes of pulmonary toxicity occurring after the first 12 months were excluded. The study includes only patients with normal pulmonary function tests before transplant. All pulmonary complications occurring within 12 months from transplant were recorded. They were classified as fol-

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lows: (1) minor complications: reduction by 20% of singlebreath carbon monoxide diffusing capacity (DLCO) without any other sign or symptoms; (2) major complications: reduction of the above-reported parameter with symptoms (cough, dyspnea, fever) and signs (tachypnea, tachycardia, crackles or wheezes on auscultation) associated or not associated with evidence of interstitial pneumonia on chest radiograph. Patients with minor or major complications without evidence of bacterial, viral or fungal infection despite extensive examination, were classified as having non-infective pulmonary complication (NIPC). Patients with NIPC received prednisone therapy orally at a dose of 1 mg/kg body weight for 10 days, then tapered by 5 mg every other day. Preparative regimens Patients received as conditioning regimen a combination of BCNU, etoposide, melphalan (BEM regimen) or BCNU, etoposide and cyclophosphamide (BVC regimen). The BEM regimen was given to 25 patients with multiple myeloma: it consisted of BCNU 600 mg/m2/day on day −4, etoposide 1000 mg/m2/continous infusion on day −3, melphalan 200 mg/m2 on day −2. With the BVC regimen, BCNU was given at a dose of 600 mg/m2 on day −5; it was administered with etoposide administered at a dose of 1000 mg/m2 by 1 day continuous infusion on day −4 and with cyclophosphamide 4000 mg/m2 over 2 consecutive days (day −3 and day −2). Eighteen patients with HD and 22 with NHL received a transplant after the BVC regimen. On day 0 all patients received a minimum dose of 4 × 106/kg autologous CD34+ peripheral cells. Patients were nursed in single rooms with laminar flow. All patients received the same antiseptic and anti-fungal mouth care and irradiated blood product support. Pulmonary function evaluation Pulmonary function tests including spirometry and DLCO were performed before transplant in all patients. Patients were routinely followed monthly for 3 months and every 3 months thereafter. Patients with cough, fever, or chest tightness underwent post-transplant chest radiography and additional spirometry with DLCO. In some cases bronchoalveolar lavage (BAL) and trans-bronchial biopsy were performed; patients were selected for these procedures if they had major complications and gave their informed consent.

Kaplan–Meier estimates of pulmonary complications were computed and curves drawn for selected variables. A P value of 0.05 was considered statistically significant. Stata 5.0 (College Station, TX, USA) was used for computation.

Results Patients’ characteristics Sixty-five patients undergoing autologous PBPC transplantation who had received a BCNU-containing preparative regimen were identified. Their main characteristics are shown in Table 1. The median age was 40 years (range 13– 61). Thirty–three were male and 32 female. Thirteen had a history of smoking. Previous pulmonary complications were recorded in two cases; both had bacterial pneumonia. Eighteen patients with HD had received bleomycine together with adriamycin, vincristine and dacarbazine (ABVD scheme). Twenty-three patients had had mediastinal involvement and 12 of these had received radiotherapy to the mediastinum with a median dose of 35 Gy (range 25– 40 Gy). Twenty-five patients with MM received the BEM regimen, while 40 patients with advanced HD or NHL had the BCV regimen (Table 2). PBPC were mobilized by cyclophosphamide given at a dose of 4000 mg/m2 followed by G-CSF (5 ␮g/kg/day) in all cases. One or two leukapher-

Table 1

Main characteristics

Parameters

No. cases (%)

Total number of cases

65

Median age (years)

40 (13–61) years

Sex Male Female

33 (50.8) 32 (49.2)

Diagnosis NHL HD MM

22 (33.8) 18 (27.7) 25 (38.5)

Conditioning regimen BEM BCV

25 (38.5) 40 (61.5)

Smokers

13 (20)

Previous pulmonary complications Previous bleomycine therapy

2 (3.1) 18 (27.7)

Statistics

Mediastinal involvement at diagnosis

23 (35.4)

Descriptive statistics have been calculated for all variables. Data on patient ages, sex, diagnosis, previous radiation treatment, history of smoking, mediastinal involvement, mediastinal field radiotherapy, pretransplant pulmonary complications, previous treatment with bleomycine, and conditioning regimen were analyzed to assess by a Cox model their predictive value for the occurrence of noninfective pulmonary complications: all the potential risk factors (P ⬍ 0.1) identified on univariate analysis were included in a multivariate Cox model. In the event of collinearity, choice of variable was based on clinical importance.

Radiotherapy on mediastinal field Pulmonary complications

12 (18.5) 24 (36.9)

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Infection-related complications

7 (10.8)

Non-infection-related complications Major Minor

17 (26.1) 11 (16.9) 6 (9.2)

Median time of pulmonary complication and range (days)

90 (52–289)

NHL = non-Hodgkin’s lymphoma; HD = Hodgkin’s disease; MM = multiple myeloma; BEM = carmustine, etoposide, melphalan; BCV = carmustine, cyclosphosphamide, etoposide.

Pulmonary complications following carmustine-based regimens EP Alessandrino et al

Parameters

BCV regimen

BEM regimen

diagnosis appear to be significant prognostic factors on univariate analysis, while on multivariate analysis, conditioning regimen and sex are the only independent prognostic factors (Table 3) (Figure 1).

No. cases Age (median) years

40 36 (13–61)

25 50 (31–61)

Discussion

40 — 6 23 12 1 18

— 25 7 — — 1 —

17 3

7 4

14 10 4

3 1 2

0.53 (0.32–0.91)

0.15 (0.05–0.47)

Table 2

Pulmonary complications according to preparative regimen

Diagnosis HD/NHL MM Smoker Mediastinal involvement Radiotherapy Previous pulmonary complications Bleomycine therapy Post-transplant pulmonary complications Infection-related complications Non-infection related complications Major Minor Incidence of non-infective related complications (events per person per year observation) (95% confidence interval)

eses were performed to collect a minimum of 4 × 106/kg CD34-positive cells. Pulmonary complications Pulmonary complications occurring within 1 year from transplant occurred in 24 of 65 patients; seven had infection-related pulmonary complications, 17 non-infectious pulmonary complications (NIPCs) (Table 1). NIPCs were classified as major pulmonary complications in 11 patients; six patients only had a reduction of DLCO, classified as a minor complication. One NHL patient with major NIPCs died of acute respiratory distress on day +52 from transplant. The median time for pulmonary complication presentation was 90 days (range 52–289 ). Broncho-alveolar lavage was performed in seven cases; five underwent a transbronchial biopsy which showed evidence of interstitial pneumonia (two cases) and signs of lymphocytic alveolitis and septal fibrosis (three cases). The incidence of NIPCs given as event per person per year of observation was higher in patients receiving the BCV regimen (Table 2). All patients with major or minor complications started steroids at the dosage of 1 mg/kg day for 10 days which were then tapered by 5 mg every other day. Complete resolution was achieved in eight cases within 3 weeks, with improvement in functional tests, signs and symptoms. Response to treatment was reached at a median of 8 weeks in seven patients. One unresponsive patient died of interstitial pneumonia. Another patient had only slight improvement; he is still receiving steroids at the small dose of 0.1 mg/kg of prednisone on day +900 from transplant. Prognostic factors Results from univariate and multivariate analysis are summarized in Table 3. Age, sex, conditioning regimens and

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Cytotoxic chemotherapy and radiotherapy given as preparation for autologous hemopoietic stem cell transplantation have been associated with the development of NIPC.16 BCNU, increasingly used in several high-dose chemotherapy combinations, induces NIPC in as many as 15–42% of patients with HD, NHL or MM;5,9,10,17 its lung toxicity seems to increase with the total dose given and the toxicity threshold is higher in patients receiving the drug as a single agent than in those receiving BCNU along with cyclophosphamide or other chemotherapeutic agents.5–7,12,15 In the present study, 65 patients with hematological malignancies received BCNU at the dose of 600 mg/m2 together with etoposide and cyclophosphamide (BCV) in 40 cases and with melphalan and etoposide (BEM) in 25 cases. The higher incidence of major NIPC observed in patients treated with BCV compared with those who received BEM (35% vs 12%) supports the hypothesis that CY may augment the detrimental effect of BCNU on the lungs; comparable results were observed in breast cancer patients receiving BCNU associated with CY and cisplatin.3 In a dose toxicity study of 72 patients receiving a modified BEM regimen Ager et al5 observed that BCNU given at the dose of 600 mg/m2 to seven patients (five lymphomas, one ANLL, one MM), was associated with an unacceptable incidence of lung toxicity (42%); Rubio et al4 reported idiopathic pneumonia in 28% of patients with relapsed HD receiving a BEM regimen, while in our study patients receiving BEM had minimal lung toxicity; they all had MM. Diagnosis, previous chemotherapy and status at transplant may have a role in inducing NIPCs; in our study, however, multivariate analysis did not demonstrate the impact of diagnosis and previous chemotherapy in predicting NIPC (Table 3). Risk factors favoring NIPCs may be previous lung disease, a history of smoking,18 previous treatment with bleomycine or chest radiotherapy.19 In our study, however, none of these factors reached statistical significance (Table 3). BCV conditioning regimen and female sex were the only risk factors for the development of NIPC on multivariate analysis. The increased toxicity noticed in females has been previously reported; there is, however, no explanation for this fact;4,20 the use of oral contraceptive pills may perhaps be involved. Lung injury induced by BCNU can be reversed by steroids which may reduce symptoms and improve DLCO.18,21,22 Early reports, however, suggested no benefit.23 Jones and co-workers21 reported symptomatic improvement in 12 of 13 breast cancer patients treated with prednisone. Some authors advise immediate initiation of prednisone therapy to reduce need for long-term treatment and fatal outcome.22 In our study, patients received prednisone promptly at the onset of symptoms or at least when a reduction of DLCO was noticed. This approach induced Bone Marrow Transplantation

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Table 3

Risk factors for non-infective pulmonary complications With complication (%)

HR

95% CI

Model P value

14 (35) 3 (12) — 13 (40.6) 4 (12.9) 13 (40.6) 4 (12.1) 10 (23.8) 7 (30.4) 12 (22.6) 5 (41.7) 9 (40.9) 5 (27.8) 3 (12.0) 14 (35) 3 (12)

3.33

0.97–11.11

0.0321

0.96 3.33

0.92–0.99 1.1–10

0.0374 0.0209

4.54

1.49–14.29

0.0034

Univariate analysis Conditioning regimen

BCV BEM per year ⭐40 ⬎40 Female Male No Yes No Yes NHL HD MM Lymphoma Myeloma

Age Age class Sex Mediastinal involvement Radiotherapy Diagnosis

0.4595 1.45

Multivariate analysisa Model P value = 0.0003 Age Sex Conditioning regimen

per year Female vs male BCV vs BEM

0.55–3.80 0.17–1.41

0.2110

0.49 0.54 0.23 3.33

0.18–1.61 0.06–0.84 0.97–12.5

0.267 0.026 0.0321

HR

95% CI

0.98 7.14 4.17

0.94–1.02 2.17–25 1.04–16.67

0.274 0.001 0.043

HR = hazard ratio; 95% CI = 95% confidence interval. a Diagnosis has been omitted from the model due to collinearity with conditioning regimen.

ment and fatal complications; a reduction in BCNU dosage is probably advisable in females and in patients receiving BCNU along with cyclophosphamide where the incidence of NIPC was particularly high.

1.00

P = 0.04 0.75

0.50

References BCV

0.25 BEM 0.00 0

100

200

300

400

Days after transplant Figure 1 Actuarial probability of NIPCs according to different conditioning regimens.

response in 16 of 17 patients (94%). Despite the good results observed in our study, the lack of a control group renders the conclusions tentative. In some reports late administration of steroids may explain the high incidence of fatal NIPC.4,5 Prophylactic use of steroids concurrent with BCNU to prevent pulmonary toxicity or progression of toxicity is still debatable:6,7,24 its use should be tested in a randomised trial. In our study the main NIPC risk factors were BCV combination and female sex. Patients receiving high-dose BCNU should have close follow-up with frequent DLCO determinations to allow prompt initiation of steroid therapy which may be of value in reducing need for long-term treatBone Marrow Transplantation

1 Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic therapy. Semin Oncol 1992; 19: 508–520. 2 Stahl W, Eisenbrand G. Comparative study on the influence of two 2-chloroethylnitrosoureas with different carbamoylating potential towards glutathione and glutathione-related enzymes in different organs of the rat. Free Rad Res Comms 1991; 14: 271–278. 3 Cagnoni PJ, Nieto Y, Shpall EJ et al. High-dose chemotherapy with autologous hemopoietic progenitor-cell support as part of combined modality therapy in patients with inflammatory breast cancer. J Clin Oncol 1998; 16: 1661–1668. 4 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. 5 Ager S, Mahendra P, Richards EM et al. High dose carmustine, etoposide and melphalan (‘BEM’) with autologous stem cell transplantation: a dose–toxicity study. Bone Marrow Transplant 1996; 17: 335–340. 6 Phillips GL, Fay JW, Herzing GP et al. Intensive 1,3-bis(2chloroethyl)-1-nitrosourea (BCNU), NSC 436650 and cryopreserved autologous marrow transplantation for refractory cancer: a phase I–II study. Cancer 1983; 52: 1792–1802. 7 Selker RG, Jacobs SA, Moore PB et al. 1,3-bis(2-chloroethyl)1-nitrosourea (BCNU) induced pulmonary fibrosis. Neurosurgery 1980; 7: 560–565. 8 Wilczynski SW, Erasmus JJ, Petros WP et al. Delayed pul-

Pulmonary complications following carmustine-based regimens EP Alessandrino et al

9

10

11

12

13

14 15

monary toxicity syndrome following high dose chemotherapy and bone marrow transplantation for breast cancer. Am J Respir Crit Care Med, 1998; 157: 565–573. Reece DE, Connors JM, Spinelli JJ et al. Intensive therapy with cyclophosphamide, carmustine, etoposide, cisplatin and autologous bone marrow transplantation for Hodgkin’s disease in first relapse after combination chemotherapy. Blood 1994; 83: 1193–1199. Weaver CH, Appelbaum FR, Petersen FB et al. High dose cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation in patients with lymphoid malignancies who have received dose limiting radiation therapy. J Clin Oncol 1993; 11: 1329–1335. Wheeler C, Antin JH, Churchill WH et al. Cyclophosphamide, carmustine and etoposide with autologous bone marrow transplantation in refractory Hodgkin’s disease and non Hodgkin’s lymphoma: a dose finding study. J Clin Oncol 1990; 8: 648–656. Seiden MV, Elias A, Ayash L et al. Pulmonary toxicity associated with high dose chemotherapy in the treatment of solid tumors with autologous marrow transplant: an analysis of four chemotherapy regimen. Bone Marrow Transplant 1992; 10: 57–63. Chap L, Shpiner R, Levine N et al. Pulmonary toxicity of high dose chemotherapy for breast cancer: a non-invasive approach to diagnosis and treatment. Bone Marrow Transplant 1997; 20: 1063–1067. 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. Durant JR, Norgord MJ, Murad TM et al. Pulmonary toxicity associated with bis-chloroethyl nitrosourea (BCNU). Ann Intern Med 1979; 90: 191–194.

16 Quabeck K. The lung as a critical organ in marrow transplantation. Bone Marrow Transplant 1994; 14: S19–S28. 17 Valteau D, Hartmann O, Benhamou E et al. Nonbacterial nonfungal interstitial pneumonitis following autologous bone marrow transplantation in children treated with high dose chemotherapy without TBI. Transplantation 1988; 45: 737–740. 18 Demirer T, Weaver CH, Buckner CD et al. High dose cyclophosphamide, carmustine and etoposide followed by allogeneic bone marrow transplantation in patients with lymphoid malignancies who had received prior dose limiting radiation therapy. J Clin Oncol 1995; 13: 596–602. 19 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. 20 Lund MB, Kongerud J, Boe J et al. Cardiopulmonary sequelae after treatment for Hodgkin’s disease: increased risk in females? Ann Oncol 1996; 7: 257–264. 21 Jones RB, Matthes S, Shpall EJ et al. Acute lung injury following treatment with high dose cyclophosphamide, cisplatin, and carmustine: pharmacodynamic evaluation of carmustine. J Natl Cancer Inst 1993; 85: 640–647. 22 Kalaycioglu M, Kavuru M, Tuason L, Bolwell B. Empiric prednisone therapy for pulmonary toxic reaction after highdose chemotherapy containing carmustine (BCNU). Chest 1995; 107: 482–487. 23 Weiss RB, Poster DS, Penta JS. The nitrosoureas and pulmonary toxicity. Cancer Treat Rev 1981; 8: 111–125. 24 Aronin PA, Mahaley MS, Rudnick SA et al. Prediction of BCNU pulmonary toxicity in patients with malignant gliomas: assessment of risk factors. New Engl J Med 1980; 303: 183–188.

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