Extracorporeal Photopheresis After Lung Transplantation: A 10-Year Single-Center Experience

Abstract

We report the largest single-center experience with extracorporeal photopheresis (ECP) for bronchiolitis obliterans syndrome (BOS) and recurrent acute rejection (AR) after lung transplantation. Lung transplant recipients undergoing ECP for BOS and recurrent AR were included (1997–2007). The rate of forced expiratory volume in 1 second (FEV₁) decline was used as the primary measure and graft survival post-ECP as the secondary measure of efficacy. Twenty-four transplant recipients were included (BOS, n=12; recurrent AR, n=12). In recipients with BOS, decline in FEV₁ was 112 mL/month before the start of ECP and 12 mL/month after 12 ECP cycles (P=0.011), mean (95% CI) change in rate of decline was 100 (28–171). Median patient survival was 7.0 (range, 3.0–13.6) years, median patient survival post-ECP 4.9 (range, 0.5–8.4) years. No ECP-related complications occurred. Extracorporeal photopheresis reduces the rate of lung function decline in recipients with BOS and is well tolerated. Furthermore, recipients with recurrent AR experience clinical stabilization. However, the underlying mechanism of ECP remains subject to further research.

Late allograft failure continues to be the Achilles’ heel of lung transplantation. The underlying mechanisms of this chronic graft deterioration are not fully understood (^{1, 2}). BO has been defined pathologically as the airway response to chronic lung allograft rejection that manifests physiologically as bronchiolitis obliterans syndrome (BOS) (¹). The current approach for BOS essentially comprises augmentation of immunosuppressant treatment, aiming to interrupt the allogenic response to the lung allograft. Nonetheless, therapies of BOS have been disappointing so far.

Extracorporeal photopheresis (ECP) has been proposed as a therapy option for lung transplant recipients with BOS. An initial report showed encouraging results suggesting that ECP may be a useful treatment option for BOS after lung transplantation (³). The role of ECP after lung transplantation for other indications such as recurrent acute rejection (AR) is even less clear. Moreover, the mechanisms by which ECP decreases immune response in transplant recipients remain unclear; however, regulatory T-cells are likely to play a major role.

In our center, ECP was implemented as therapy for lung transplant recipients with BOS, recurrent AR, and other indications in 1997. Our study reports the largest single-center experience with ECP.

All adult patients after primary lung transplantation who received ECP treatment at the University Hospital Zurich between 1997 and 2007 for BOS or recurrent AR were included.

Immunosuppressant treatment comprising cyclosporine A, azathioprine or mycophenolate mofetil, prednisolone, and induction therapy plus anti-infective prophylaxis was used according to our protocol (⁴). Posttransplant monitoring regime includes routine surveillance bronchoscopy and serial laboratory lung function tests.

Extracorporeal photopheresis was performed on 2 consecutive days (one treatment cycle) every 4 to 6 weeks. Extracorporeal photopheresis was performed using the UVAR XTS system (Therakos, Exton, PA) as approved by the FDA. Briefly, leukapheresis in the UVAR system is followed by photoactivation with 8-MOP and UVA irradiation, and subsequent reinfusion of irradiated cells over 3 to 4 hrs. During ECP, peripheral blood mononuclear cells are separated from the whole blood in a latham centrifuge at 2700g. Uvadex methoxsalen solution (Therakos) is added directly into the buffy coat bag before extracorporeal irradiation with UVA (1–2 J/m²) reducing systemic 8-MOP toxicity. The number of blood mononuclear cells exposed to 8-MOP and UVA during each procedure is usually 2% to 5% of the total circulating white cells (⁵).

The rate of decline of forced expiratory volume in 1 sec (FEV₁) was used as the primary measure and the allograft survival after completion of 12 cycles of ECP as the secondary measure of efficacy (post-ECP survival). Based on each patient’s serial lung function measurements, the rate of FEV₁ decline after transplantation was determined in milliliters per month, which is the average gradient between serial FEV₁ measures (mL) from baseline (best posttransplant value) and the FEV₁ result (mL) before initiation of ECP. Likewise, the rate of decline of FEV₁ (mL/month) after completion of 12 cycles of ECP was calculated based on serial FEV₁ results up to the end of the study period for all survivors or up to the last available FEV₁ measure of any deceased recipients. Individual patient’s survival was determined as total posttransplant survival and survival after completion of 12 cycles of ECP (post-ECP survival). Procedural complications were recorded.

Descriptive statistics was used. A paired Student’s t test was used to analyze the rate of decline of FEV₁ pre-ECP and post-ECP; P value less than 0.05 was considered statistically significant.

The local Research Ethics Committee granted approval for this study.

Twenty-four lung transplant recipients received ECP between 1997 and 2007 for BOS or recurrent AR, all of which were included in the study (Table 1).

TABLE 1: Patient demographics

All except two study patients, who were still undergoing their first 12 cycles of ECP at the end of the study period, completed 12 cycles of ECP treatment.

Twelve recipients underwent ECP treatment of BOS, the median time to BOS grade 1 was 29 (range, 5–83) months. Extracorporeal photopheresis therapy was started once severity of BOS worsened despite augmented immunosuppressant therapy. At the start of ECP treatment, five recipients were classified as BOS grade 1, two patients BOS grade 2, and five recipients BOS grade 3. In transplant recipients with BOS, decline in FEV₁ was 112 mL/month before ECP and 12 mL/month after completion of 12 cycles of ECP, P=0.011, mean (95% CI) change in rate of decline, 100 (range, 28–171) (Fig. 1). The ECP effect on absolute FEV₁ in this subgroup of patients was not significant.

FIGURE 1.: Change in rate of decline in forced expiratory volume in 1 second (FEV₁) (mL/month) (y-axis) before (pre-ECP) and after 12 cycles of extracorporeal photopheresis (post-ECP) in study patients with bronchiolitis obliterans syndrome (BOS) (n=12, P=0.011). Patient with BOS grade 1 (–); patient with BOS grade 2 (…); and patient with BOS grade 3 (- - -).

Twelve recipients underwent ECP for recurrent AR. None of these patients had BOS; therefore, no rate of FEV₁ decline could be determined. In this subgroup, all patients had more than or equal to two biopsy-proven episodes of AR (≥A2) before the start of ECP. All except one patient had follow-up transbronchial biopsies performed during their ECP treatment cycles; an episode of biopsy-proven AR (≥A2) occurred in only two of the recipients. All transplant recipients with recurrent AR underwent clinical stabilization after their 12 cycles of ECP treatment, none experienced BOS; mean (SD) FEV₁ pre-ECP 2.85 (0.8) and post-ECP 3.09 (0.87), P=0.48.

Extracorporeal photopheresis treatment was well tolerated by all patients. No adverse effects of ECP were recorded. The median patient survival of this study cohort (n=24) was 7.0 (range, 3.0–13.6) years, the median patient survival post-ECP was 4.9 (range, 0.5–8.4) years; however, two patients were retransplanted after completion of 12 cycles of ECP because of the progression of BOS. Four patients died during the 10-year study period; however, no patient died before completion of 12 cycles of ECP. The cause of death was BOS in all cases.

Our study demonstrates that ECP effectively reduces the rate of lung function decline in recipients with BOS and is well-tolerated. In none of the study patients, ECP therapy had to be terminated because of adverse events. Furthermore, recipients with recurrent AR experienced clinical stabilization.

Most treatments for BOS include the switch of agents of certain pharmacological classes (calcineurin inhibitor, antiproliferative agents); however, other therapy attempts such as total lymphoid irradiation (TLI) and plasmapheresis have been reported (^{6, 7}). In particular, the study by Fisher et al. reporting the safety and efficacy of TLI in lung transplant recipients with progressive BOS showed that TLI significantly reduces the rate of lung function decline in this retrospective single-center study. However, of 37 study patients, only 73% of the patients completed 80% or more of their planned TLI treatment regime and severe adverse effects occurred (bone marrow suppression, severe infections) (⁶).

Extracorporeal photopheresis is a cell-based immunomodulatory therapy first reported in the treatment of cutaneous T-cell lymphoma (⁸). In addition, its therapeutic value has been shown in other autoimmune and T-cell–mediated diseases such as rheumatoid arthritis (⁹), systemic sclerosis (¹⁰), and graft-versus-host disease (¹¹), aiming for a therapeutic strategy to induce tolerance to both solid organ and peripheral blood progenitor cell allografts. However, the immunomodulatory mechanisms of ECP in the host are not fully understood (¹²). In view of the fact that only 2% to 5% of the total circulating white cells are treated with ECP therapy, different immunomodulatory mechanisms have been postulated including the stimulation of cytokine release (IL-1, IL-6), which may then affect the whole immune cell population (¹³). Moreover, production of clone-specific suppressor T cells, induction of lymphocyte apoptosis, or alterations in the T-cell receptor may be possible pathways of the immunomodulatory activity of ECP (^{14, 15}). Immunomodulatory effects of ECP have been named transimmunization (¹⁶).

Our retrospective study has limitations. It was not a randomized controlled trial; therefore, unintentional bias may have impacted on patient outcome. The final decision to commence ECP in the individual case was taken at the clinician’s discretion. During the study period, all recipients were treated with a cyclosporine A–based immunosuppressant regime; however, changes occurred with regards to induction therapy and antiproliferative agents. Furthermore, even though this is the largest single-center experience to date, the sample size is small. Nevertheless, we were able to show a significant reduction in the rate of lung function decline in recipients with progressive BOS. We are unable to analyze the efficacy of ECP in subgroups of patients with different BOS grades because of their small sample size. Furthermore, we recognize that BOS is unlikely to present one pathological entity therefore, the clinical features of BOS are diverse including a more rapid onset early posttransplant or a slower progression later on. Because of this heterogeneity, the efficacy of ECP therapy in individual patients with BOS is likely to be different. In addition, the optimal timing of ECP within the clinical management of BOS is unclear. Recently, we have opted to commence ECP therapy early in our cohort of recipients with BOS. This seems logical as ECP would unlikely to be expected to reverse established fibroproliferation in the lung allograft and aberrant tissue repair of the small airways. In general, we support the continuation of ECP therapy beyond the initial 12 cycles in individual patients if clinical stabilization occurs, ideally long-term to maintain a good clinical outcome.

In conclusion, ECP reduces the rate of lung function decline in transplant recipients with progressive BOS. Furthermore, lung transplant recipients with recurrent AR reach clinical stabilization. Moreover, patients tolerate ECP therapy well. Extracorporeal photopheresis proved to be an effective therapy, with potential benefits beyond the limitations of current immunosuppressive agents in our hands.