Extracorporeal Photopheresis for First Line Treatment of Acute Graft Versus Host Disease
Authors: Malard Florent , Sestili Simona , Eder Sandra , Belhocine Ramdane , Ruggeri Annalisa , Battipaglia Giorgia , Brissot Eolia , Mediavilla Clemence , Dulery Remy , Mohty Mohamad 
Published: October 2019

Abstract
Background. Extracorporeal photopheresis (ECP) is increasingly used in the treatment of acute and chronic graft versus host disease (aGVHD). It is recognized as an immunomodulatory therapy that can decrease inflammation and allow for immune tolerance. Interesting results have obtained using ECP as salvage therapy in patients with steroid-refractory GVHD after failure of one or more lines of immunosuppressive therapy. With this background, we hypothesized that incorporation of ECP as part of first line treatment for aGVHD may improve response rate and avoid the development of steroid-refractory or steroid-dependent aGVHD, mainly in cases of aGVHD with predominant skin involvement.
Patients and methods. Forty consecutive patients who received ECP as part of their first line treatment of aGVHD with skin involvement between 2013 and 2016 were included in this single center analysis. 36 patients (90%) received granulocyte-colony stimulating factor mobilized PBSC as grafts, 3 patients (7.5%) received a bone marrow graft and one patient (2.5%) received an umbilical cord blood graft. Donor was a matched related one for 10 patients, haploidentical for 8 patients, matched unrelated for 16 patients and mismatched unrelated for 6 patients. 4 patients received a reduced intensity conditioning regimen and 36 a myeloablative reduced toxicity conditioning regimen. All patients received a combination of cyclosporine A (CsA) and mycophenolate mofetil for GVHD prophylaxis, except for patients with a matched related donor who received cyclosporine A alone. Patients transplanted with a haploidentical donor, received post-transplant cyclophosphamide (PTCy; 50mg/kg/d at d+3/d+5). ECP was initiated as soon as possible after the diagnosis of aGVHD with predominant skin involvement. The primary endpoint was to determine the best response achieved through the use of ECP for first line treatment of aGVHD.
Results. Median age was 57 (range, 22-66) years, with 28 male patients (49%). Diagnoses were myeloid (n=32) or lymphoid malignancies (n=8) and disease status at transplant was complete remission in 23 patients, partial remission in 8 patients, relapse/progression in 8 patients and untreated in 2 patients. Patients developed aGVHD at a median of 31 days after alloHCT (range, 11-129). 5 patients had late onset aGVHD and two patients developed aGVHD after DLI. None of them had an overlap syndrome. aGVHD grade was I in 13 patients, II in 18 patients and III-IV in 9 patients. All patients had skin involvement and 10 patients had gut (n=8) and/or liver (n=5) involvement. All patients, but one, were still receiving CsA at time of aGVHD diagnosis. Systemic corticosteroids were initiated in 29 patients, while 11 patients received only topical dermo-corticoids. ECP was initiated at a median of 9 days (range, 0-83) after the diagnosis of aGVHD. ECP was performed weekly for 26 patients and twice weekly for 14 patients. Overall response rate (ORR) was 80% after a median of 3 (range, 1-9) weeks of treatment, including 24 complete responses (CR, 60%), 6 very good partial responses (VGPR, 15%) and 2 partial responses (PR, 5%). According to aGVHD grade, in patients with grade I aGVHD, the ORR was 92%, including 11 CR and 1 VGPR. In patients with grade II aGVHD, the ORR was 83%, including 8 CR and 7 VGPR/PR. In patients with grade III-IV aGVHD, ORR was 55%, all of them being in CR. In responding patients, 1 patient presented a recurrence of aGVHD and 15 developed chronic GVHD, including 4 overlap syndromes. Median follow-up was 32 months (range, 22-58) among surviving patients. At 24 months after transplant, the OS and PFS rates were respectively 78% (95% CI, 61%-88%) and 56% (range, 39%-70%). The 2-years cumulative incidence of relapse was 33% (95% CI, 19%-49%) and the 2-years cumulative incidence of non-relapse mortality was 10% (95% CI, 3%-22%).
Conclusion. ECP is an effective and well-tolerated option for treatment of acute GVHD with predominant skin involvement with a 2 years cumulative incidence of NRM of 10% and an ORR of 80%. Best responses were seen in patients with grade I-II aGVHD, suggesting that ECP should be started as early as possible after the diagnosis of aGVHD. Incorporation of ECP as part of first line treatment for aGVHD may improve response rate and avoid the development of steroid-refractory aGVHD. Prospective randomized trial are warranted to evaluate ECP as adjuvant treatment for first line treatment of skin aGVHD.

Disclosures
Mohty: Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Consultancy, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Molmed: Consultancy; Servier: Consultancy; Amgen: Consultancy, Honoraria.