Safety and Efficacy of Extracorporeal Photopheresis for Acute and Chronic Graft-Versus-Host-Disease

Introduction

Acute and chronic graft-versus-host disease (GVHD) remain severe complications of allogeneic hematopoietic cell transplantation (alloHCT). Corticosteroids and conventional intensified immunosuppressive therapy for steroid-refractory GVHD increase morbidity, mortality and relapses without improving survival. Extracorporeal photopheresis (ECP) has been introduced as an alternative treatment in many centers. We studied the safety and efficacy of extracorporeal photopheresis (ECP) as second or third line treatment in acute and chronic GvHD.

Methods

We enrolled consecutive patients that received ECP post alloHCT from 2003 to 2016. All patients with unrelated or haploidentical donors received thymoglobulin (ATG) 5mg/kg as prophylaxis. GVHD prophylaxis included cyclosporine-methotrexate in myeloablative and cyclosporine-mycophenolate mofetil in reduced toxicity or intensity regimens. ECP was commenced after assessment of response to 7 days of steroid treatment in acute (aGVHD): 2 sessions/week for 1 month, 1 session/2 weeks for 3 months, evaluation of response and 1 session/month for 6 months. In chronic (cGVHD), ECP was mostly administered as third line treatment with a similar protocol that was less intensified in the 1^st month (1 session/week).

Results

We studied 21 patients with acute, 81 with chronic and 7 with induced GVHD post Donor Lymphocyte Infusion (DLI) for relapsed disease. Only 2 patients with acute, 5 with chronic and 1 with induced GVHD received 4 or less ECP sessions because of severe GVHD-related morbidity and were excluded from further analysis. There were no ECP-related adverse events.

AGVHD was observed at day +18 (8-50) in 15 patients, late-onset at + 130 (110-160) in 4 patients. Skin, intestine and liver involvement was evident in 6 patients, skin and intestine in 9 and skin only in 4 patients. Seven patients were steroid-dependent and 12 steroid-refractory. ATG was administered simultaneously with ECP initiation in 8 refractory patients. The majority of patients presented partial (6), very good (9) or complete (1) response to ECP. Immunosuppression was reduced in 10/19 and ceased in 1. Clinically significant bacterial infections were found in 17 patients, fungal in 2 and viral in 15 patients. Cumulative incidence (CI) of cGVHD was 86.6 at 1-year. 1-year CI of aGVHD-related mortality was 17.6% and was associated with lack of response to ECP (p=0.026) and steroid-refractoriness (p<0.001). With a follow-up of 17.5 (1.8-58.3) months, 1-year overall survival (OS) was 52.5%. Improved OS was associated with response to ECP (0.032), number of ECP sessions (p=0.005), aGVHD grade (p=0.018) and reduction of immunosuppression (p=0.009). In the multivariate analysis, number of ECP sessions were independently associated with improved OS (p=0.037).

Regarding cGVHD, 52 patients presented with cutaneous sclerosis manifestations, 53 mucocutaneous disease, 31 liver, 37 visceral and 12 lung involvement. The majority of them (59/82) received mycophenolate mofetil, cyclosporine or ATG as a second line treatment and ECP as third line. Bacterial infections were observed in 26 patients, viral in 24 and fungal in 8 patients. Eligible for evaluation of response were 72 patients. Only 12 patients did not show response. Significantly higher rates of response presented in patients with cutaneous sclerosis manifestation (p=0.031) and later post-transplant GVHD diagnosis (p=0.001). With a follow-up of 68.1 (5.4-283.1) months, 5-year CI of cGVHD-related mortality was 24.1% and was associated only with number of ECP sessions (p=0.002). 5-year OS was 64.5% and was associated with HLA matching (p=0.030), cutaneous lesions (p=0.041), higher number of ECP sessions (p<0.001), later initiation of ECP post-transplant (p=0.004) and no relapse (p=0.027). In the multivariate analysis, cutaneous lesions (p=0.013), number of ECP (p<0.001) and days of ECP initiation post-transplant (p=0.015) predicted OS.

Conclusion

Our data indicate that ECP is safe and effective for both acute and chronic GVHD. Steroid-dependence in aGVHD and cutaneous manifestations in cGVHD predict improved survival with low toxicity. Therefore, ECP should be considered early in the course of GVHD, before significant irreversible end organ damage has been established. Optimal timing of intervention, frequency, duration and tapering schedule of ECP remain important unanswered questions.