Synthetic PGI-2 (Iloprost) treatment in patients with resistant sclerodermic chronic GVHD (cGVHD) after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Scleroderma is a late manifestation of chronic GVHD, presenting as progressive tightness of the skin and hampering patients’ quality of life. Iloprost, a synthetic PGI-2, has been proving effective in the therapy of idiopathic systemic sclerosis, which has a similar pathogenesis to sclerodermic cGVHD. Materials (or patients) and methods: From 2001 to 2013 we observed 19 pts affected by diffuse or limited sclerodermic cGVHD. During the study period 353 allogeneic transplants were performed, 162 from HLA identical sibling and 191 from unrelated donor. The patients (9 AML, 3 MM, 4 ALL, 2 NHL and 1 MFI) were transplanted in 12 cases with classical conditioning regimen (FTBI 1200 cGy plus Cytoxan 120 mg/Kg or BusulfanCytoxan), in 7 cases with reduced intensity conditioning regimen. In 17/19 cases the donor was an HLA identical sibling. The source of stem cells was bone marrow in 3 cases and peripheral blood in 16 cases. Severe cGVHD with scleroderma was observed at a median of 21 months from HSCT (range 8-39), presenting as diffuse skin changes (tightness and thickening of the face, neck, hands, thorax, legs, feet and abdomen), cutaneous dyschromia, digital pitting scars and functional joint impairment. In 15 cases it was classified as de novo cGVHD. Most of the pts showed involvement of organs other than the skin: xerophthalmia in 13, xerostomia in 8 cases, liver in 5 pts, gastrointestinal tract in 4 and lung in 1 patient. In 4 pts these alterations were linked with itching and pain and in 4 cases diffuse scleroderma was associated with severe discomfort in tendons or muscles. In all cases cGVHD severely affected quality of life. The pts failed at least 2 immunosuppressive regimens including CSA, azathioprine, mycophenolate mofetil, steroids, repeated cycles of PUVA with little or no effect on the skin. Iloprost, 50 microgram a day over 8 hours IV continuous infusion for 5 days every month, was started after a median of 6 months from the appearance of scleroderma (range 6-13). Results: The drug was well-tolerated with no severe side effects: the most frequent side effect was mild hypotension and headache. In 15/19 cases we observed a significant clinical benefit after a median of 6 cycles (range 3-12). The Modified Rodnan Skin score, calculated before and after 1-year treatment, was 27 and 8, respectively. Iloprost courses were given in Outpatient Department for a median of 20 courses, the first 12 every month. All the 15 responsive pts received a maintenance therapy with 3-4 treatments a year. Further improvement was otherwise observed over the subsequent courses. At present, one patient not responsive to Iloprost has died because of sepsis. All the 15 responsive pts are alive in continuous complete remission, with satisfactory improvement of quality of life. Conclusion: In our study Iloprost seems to be one of the most effective drugs in reverting resistant/refractory sclerodermic cGVHD and in reducing the extension of the skin lesions. Improvements were observed in 15/19 pts (79%), after a median of 6 months of treatment. The Rodnan Skin Score is a practical and easy tool to assess skin involvement and to follow clinical outcome. It’s to be noted that the vast majority of the pts of this report received stem cells from an HLA identical sibling, even if in the same period the majority of transplants were done from unrelated donors.