Clinical Investigations
Efficacy of total lymphoid irradiation for chronic allograft rejection following bilateral lung transplantation

Presented at the 39th annual meeting of the American Society of Therapeutic Radiology and Oncology, Orlando, FL, October 1997.
https://doi.org/10.1016/S0360-3016(98)00113-8Get rights and content

Abstract

Purpose: To assess the safety and efficacy of total lymphoid irradiation (TLI) in patients experiencing chronic rejection following bilateral lung transplantation (BLT).

Patients and Materials: Eleven patients received TLI for chronic allograft rejection (bronchiolitis obliterans syndrome) refractory to conventional treatment modalities. Radiation therapy (RT) was prescribed as 8 Gy delivered in 10 0.8-Gy fractions, 2 fractions/week, via mantle, paraaortic, and inverted-Y fields. Serial pre- and post-RT pulmonary function values, complete blood counts, and immunosuppressive augmentation requirements [use of methylprednisolone, murine anti-human mature T-cell monoclonal antibody (OKT3), polyclonal antithymocyte globulin (ATG), and tacrolimus] were monitored.

Results: In the 3 months preceding TLI, the average decrease in forced expiratory volume in 1 s (FEV1) was 34% (range 0–75%) and the median number of immunosuppression augmentations was 3 (range 0–5). Only 4 of 11 patients completed all 10 TLI treatment fractions. Reasons for discontinuation included progressive pulmonary decline (four patients), worsening pulmonary infection (two patients), and persistent thrombocytopenia (one patient). Seven of the 11 patients failed within 8 weeks of treatment cessation. One patient had unabated rejection and received bilateral living related-donor transplants; he is alive and well. Six patients died. Two of these deaths were due to pulmonary infection from organisms isolated prior to the start of RT; the other four deaths were from progressive pulmonary decline. The four remaining patients had durable positive responses to TLI (mean follow-up of 47 weeks; range 24–72). Comparing the 3 months preceding RT to the 3 months following treatment, these four patients had improvements in average FEV1 (40% decline vs. 1% improvement) and fewer median number of immunosuppressive augmentations (3.5 vs. 0). None of these patients has developed lymphoproliferative disease or has died. Features suggestive of a positive response to TLI included longer interval from transplant to RT, higher FEV1 at initiation of RT, and absence of preexisting pulmonary infection.

Conclusion: Total lymphoid irradiation for chronic allograft rejection refractory to conventional medical management following BLT was tolerable. A subset of patients experienced durable preservation of pulmonary function and decreased immunosuppressive requirements. Patients with rapidly progressive allograft rejection, low FEV1, or preexisting infection were least likely to benefit from irradiation. Early initiation of TLI for patients experiencing chronic allograft rejection following BLT may be warranted.

Introduction

The first human lung transplantation was performed by Dr. James Hardy in June 1963 (1). Between 1963 and 1974, 36 patients worldwide underwent lung transplantation, but only two survived longer than 1 month (2). These disappointing results continued until a new era in solid organ transplantation was ushered in with the introduction of cyclosporin in the early 1980s. Since 1981, over 4000 heart–lung and lung transplantations have been performed (3).

With refinements in immunosuppressive regimens and improvements in surgical techniques and medical management, 1-year survivorship now ranges between 70% and 93% 4, 5, 6. In one series, the greatest risk of death was in the first 100 days after transplantation, with a second period of moderately increased risk around 800 days (7). Mortality in the first postoperative month is primarily due to graft failure, infection, and other postoperative complications. Late deaths are primarily caused by chronic allograft rejection, or bronchiolitis obliterans syndrome (BOS) (8).

Up to two thirds of all lung transplantation patients develop BOS, a clinicopathologic syndrome of graft dysfunction that is characterized physiologically by airflow obstruction and histologically by bronchiolitis obliterans (9). Patients with evolving or established BOS are usually treated initially with corticosteroids and intensification of their maintenance immunosuppression regimen. Transient beneficial responses, usually defined as a decrease in the rate of forced expiratory volume in 1 s (FEV1) decline after treatment, have been achieved with azathioprine (10), antilymphocyte antibody preparations (ATG and OKT3) (11), methotrexate (12), aerosolized cyclosporin (13), and tacrolimus (14). Unfortunately, once BOS develops, it is rarely fully arrested by medical management.

Total lymphoid irradiation (TLI) impairs the immunologic reaction to allogeneic cells and has been used successfully to prevent renal (15) and cardiac 16, 17, 18, 19 allograft rejection following transplantation. A recent series from the United Kingdom has suggested that TLI can substantially reduce the rate of decline of pulmonary function in patients suffering chronic allograft rejection following heart–lung, single lung, and bilateral lung transplantation (20). The purpose of this study was to further assess the safety and efficacy of TLI in a series of patients experiencing BOS following bilateral lung transplantation (BLT).

Section snippets

Patients

Between March 1995, and September 1996, 11 patients (10 males and 1 female) received TLI for BOS refractory to conventional treatment, including intensification of maintenance immunosuppression (cyclosporine, azathioprine, and prednisone) and administration of methylprednisolone, OKT3, ATG, and/or tacrolimus. One patient (patient 1) received methotrexate; no patient underwent plasmapharesis or photopheresis. The diagnosis of BOS was established by the consensus criteria of the International

Results

Among all patients, in the 3 months preceding TLI, the average decrease in FEV1 was 34% (range 0–75%) and the median number of immunosuppression augmentations was 3 (range 0–5). At initiation of RT, average FEV1 was 1.4 l (range 0.77–2.28). Only 4 of 11 patients completed all 10 treatment fractions. Duration of TLI ranged from 16 to 42 days. Reasons for discontinuation included progressive pulmonary decline (four patients), worsening pulmonary infection (two patients), and persistent

Discussion

Chronic rejection, or BOS, remains the single most important limitation to better medium and long-term survival in lung transplantation recipients (22). Despite advances in immunosuppression, the prevalence of BOS remains high and the prognosis poor. Patients with advanced BOS suffer from severe pulmonary compromise and their respiratory tracts are often colonized with potential pathogens. Coupled with a high level of immunosuppression, these patients are at high risk for serious respiratory

Conclusions

Standard strategies for the management of emerging or established chronic lung allograft rejection, or BOS, rarely produce more than transient, partial arrests in pulmonary function decline. In this series, TLI for BOS refractory to conventional medical management following BLT was offered as a rescue treatment. TLI was found to be tolerable, with acute toxicity due to TLI essentially limited to transient bone marrow suppression. A subset of patients experienced a durable preservation of

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