Extracorporeal Photopheresis Using Theraflex ECP™ for Patients With Refractory Chronic Graft Versus Host Disease (cGVHD)

Inclusion Criteria:

• Patients must have chronic GVHD (cGVHD) occurring after any type of HSCtransplantation : with any type of donor (HLA-identical siblings or HLA-matched ormismatched family or unrelated donor); with any type of conditioning (full-intensity,reduced-intensity, nonmyeloablative, no conditioning); with any type of HSC (bonemarrow, PBSC, cord blood) or after donor lymphocyte infusion.

• Patients must have cGVHD primarily affecting at least one of the following organs:skin; oral mucosal; eye; liver; lung; joints; fascia. Gastro-intetinal (GI) cGVHDalone is not a sufficient inclusion criterion.

• Patients must have cGVHD that has already been treated with first-line systemictherapy for at least 1 month at effective doses. First-line systemic therapy must haveincluded at least prednisolone 1 mg/kg/day or equivalent. In case of formalcontraindication to steroid therapy, first-line systemic therapy must have includedtherapeutic doses of at least one of the following drugs: tacrolimus or ciclosporine (if patient not treated with a calcineurin inhibitor at onset of cGVHD), sirolimus,everolimus, mycophenolate mofetyl.

• Patients must require further salvage therapy for cGVHD because of eitherrefractoriness or contraindication/intolerance to current therapy. Need for salvage therapy is defined by any of the following criteria :

• the development of 1 or more new sites of disease while being treated for chronic GVHD

• progression of existing sites of disease while receiving treatment for chronic GVHD

• failure to improve despite at least 1 month of standard treatment for chronic GVHD,

• relapse/progression of cGVHD while tapering current treatment for cGVHD.

• Patients may have received any number of previous lines of treatment for cGVHD.

• Concomitant treatment with other immunosuppressors is allowed if they werestarted and maintained at constant dosage for at least one month before the startof ECP. Shorter delay can be accepted for patients with highly progressive GVHDrequiring salvage therapy.

• Signed informed consent.

• Any age.

• Weight > 15 Kg (because of leukapheresis). Weight <15 Kg is acceptable if asuitable method of leukapheresis has been developed and approved at site.

Exclusion Criteria:

• Patient has received any investigational agent for chronic GVHD in the past 4 weeks.

• Patient has started a new line of systemic therapy for cGVHD in the past 4 weeks.Shorter delay can be accepted for patients with highly progressive GVHD requiringsalvage therapy.

• Known sensitivity to psoralen compounds such as 8-methoxypsoralen

• Comorbidities that may result in photosensitivity (coexisting skin cancer orphotosensitive disease (such as porphyria, lupus, albinism…)

• Aphakia. MOP is contraindicated in patients with aphakia, because of the significantlyincreased risk of retinal damage due to the absence of lenses

• Known allergy to one of the components used in apheresis (e.g., heparin and citrate).

• History of heparin-induced thrombocytopenia or patients with serious coagulationdisorders.

• Unable to tolerate the apheresis procedure including extracorporeal volume shiftsbecause of uncompensated congestive heart failure, pulmonary edema, severe lungdisease, severe renal failure, hepatic encephalopathy, or any other reason.

• Bilirubin > 25 mg/L.

• Absolute neutrophil count < 1.0 x 109 / L despite use of growth factors

• Platelet count < 20 x 109 / L despite platelet transfusion

• HIV seropositivity.

• Uncontrolled infection

• Relapse or progression of the hematological malignancy.

• Eastern Cooperative Oncology Group (ECOG) score > 2.

• Pregnancy or breastfeeding

• Patient is a fertile man or woman who is unwilling to use contraceptive techniquesduring and for 12 months following treatment.

• Any serious illness with expected survival less than 6 months.

• Any clinically significant medical or other condition that in the investigator'sopinion could interfere with the administration of photopheresis or interpretation ofstudy results, or compromise the safety or wellbeing of the patient.