Prophylactic Extracorporeal Photopheresis for Gvhd Prevention after Reduced Intensity Conditioning and Allogeneic Stem Cell Transplantation from Identical Siblings and 10/10 HLA Unrelated Hematopoietic Stem Cells Donors
Authors: Michallet Mauricette , Sobh Mohamad , Praire Aline , Garban Frederic , Bulabois Claude Eric , Yakoub-Agha Ibrahim , Coiteux Valerie , Dulery Remy , Rohrlich Pierre-Simon , Legrand Faezeh , Clement Laurence , Morisset Stephane , Cannas Giovanna , Detrait Marie Y. , Barraco Fiorenza , Nicolini Franck E. , Hequet Olivier 
Published: October 2019

Abstract
Background:
Graft-versus-host disease (GVHD), and complications of its treatment, are the major causes of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and represent a limiting factor for transplantation in candidate patients. The pathophysiology of GVHD involves tissue damage, presentation of host antigen by host dendritic cells to donor T cells, and the activation and release of inflammatory cytokines. Even with the use of standard GVHD prophylaxis with calcineurin inhibitors and methotrexate, the incidence of acute and chronic forms of GVHD remains not negligible. Extracorporeal photopheresis (ECP) has shown very promising results in several immune-mediated disorders, including GVHD, with a direct impact on transplant-related mortality (TRM) rates and overall survival (OS).
Objective:
We performed this prospective multicenter phase 2 study to evaluate the safety and efficacy of prophylactic use of ECP early after allo-HSCT in patients with hematological malignancies.
Patients and methods:
Eligible patients were adults with hematological malignancy candidate for allo-HSCT, with controlled disease at transplantation and having a 10/10 HLA identical related or unrelated peripheral blood stem cells (PBSC) donor. All patients must have received a reduced intensity conditioning regimen consisting on Fludarabine (30 mg/m²/day, from day -5 to day -1), iv. Busulfan (0.8 mg/kg every 6 hours, from day -4 to day -3) and rabbit anti-thymocyte globulins (2,5 mg/kg, on day -2 and day -1). GVHD prophylaxis consisted on cyclosporine A (CsA) alone, associated to methotrexate in case of major ABO incompatibility; mycophenolate mofetil could be used instead of CsA in case of intolerance or toxicity. ECP was initiated at day 21 after transplantation, twice per week during the first two weeks and then once per week for the next four weeks, a total of 8 ECP courses had to be performed for each patient. ECP related toxicity and adverse events were evaluated according to NCI/NIH common toxicity criteria up to day 100 after transplantation. Transplantation outcomes have been assessed.
Results:
Between June 2009 and May 2014, a total of 20 patients were included in this study; 10 males and 10 females with a median age of 60 years (range: 47-66); 7 (35%) had acute myeloid leukemia (4 de novo and 3 secondary), 4 (20%) chronic lymphocytic leukemia, 3 (15%) Non-Hodgkin lymphoma, 2 (10%) multiple myeloma, 2 plasma cell leukemia and 2 myelodysplastic syndrome. At transplantation, 14 (70%) patients were in complete response, 2 patients in very good partial response and 4 patients in partial response; all patients received PBSC from 8 (40%) identical siblings and 12 (60%) 10/10 HLA unrelated donors. For sex matching, only 3 (15%) were female donors to male patients. The median number of injected CD34+ cells was 6.106/Kg (range: 2.7-10.4). After transplantation, all patients engrafted, 17 (85%) could achieve the full 8 ECP courses, one patient received 7 courses due to catheter dysfunction, one patient received 5 courses due to severe infection and one patient received only 4 courses due to early death. There were no unexpected adverse effects related to ECP. Among 11 (55%) patients evaluated for chimerism at day 100, all had full donor cells. Seven patients developed acute GVHD, all were resolutive, 3 grade I, 1 grade II, 1 grade III and 2 grade IV with a cumulative incidence of 20% (confidence interval: 11-29) for grade ≥ II. Only 4 patients experienced chronic GVHD, all limited and resolutive, with a cumulative incidence of 23% (confidence interval: 12-33) at 2 years. After a median follow-up of 21 months (range: 2-49), the probability of overall survival at 2 years was 84% (range: 75-93), the two years probability of progression-free survival was 78% (range: 68-88), and the cumulative incidence of transplant-related mortality was 11% (range: 4-18) at two years. At the last follow-up, 14 patients were alive in CR and without GVHD, 6 patients died (4 from relapse and 2 from GVHD after receiving DLI for relapse).
Conclusion:
This prospective phase 2 multicenter study demonstrated the safety of prophylactic ECP after allo-HSCT. We showed encouraging results with good potential in overall survival, very low GVHD incidence and no interference with GVL effect in view of low relapse rate after transplantation. Larger phase 3 study is now required to validate the benefit of this strategy.

Disclosures
No relevant conflicts of interest to declare.