Haploidentical hematopoietic stem cell transplantation in a myelofibrosis patient with primary graft failure

The prognosis of patients affected by myelofibrosis (MF) is usually dismal and allogeneic hematopoietic stem cell transplantation (HSCT) remains the only cure. The number of HSCTs in MF patients has recently increased. However, a major obstacle is still represented by primary graft failure (PGF). Currently there are no definitive guidelines for the treatment of PGF and a second HSCT can be performed only when an allogeneic donor is rapidly available. Herein we report on a MF patient with PGF after an unrelated HSCT, who was rescued by a non-myeloablative, unmanipulated, haploidentical HSCT that resulted in persistent engraftment and bone-marrow fibrosis regression, but not in a long-term disease control. Based on this experience we briefly review the role of different conditioning regimens and hematopoietic stem cell sources in the setting of HSCT for MF patients with PGF. The role of haploidentical donors in MF patients lacking HLAmatched relatives is also discussed

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\u2019 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\u2019s 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

Haploidentical hematopoietic stem cell transplantation in a myelofibrosis patient with primary graft failure

The prognosis of patients affected by myelofibrosis (MF) is usually dismal and allogeneic hematopoietic stem cell transplantation (HSCT) remains the only cure. The number of HSCTs in MF patients has recently increased. However, a major obstacle is still represented by primary graft failure (PGF). Currently there are no definitive guidelines for the treatment of PGF and a second HSCT can be performed only when an allogeneic donor is rapidly available. Herein we report on a MF patient with PGF after an unrelated HSCT, who was rescued by a non-myeloablative, unmanipulated, haploidentical HSCT that resulted in persistent engraftment and bone-marrow fibrosis regression, but not in a long-term disease control. Based on this experience we briefly review the role of different conditioning regimens and hematopoietic stem cell sources in the setting of HSCT for MF patients with PGF. The role of haploidentical donors in MF patients lacking HLAmatched relatives is also discussed

Mature CD10+ and immature CD10- neutrophils present in G-CSF-treated donors display opposite effects on T cells

The identification of discrete neutrophil populations, as well as the characterization of their immunoregulatory properties, is an emerging topic under extensive investigation. In such regard, the presence of circulating CD66b+ neutrophil populations, exerting either immunosuppressive or proinflammatory functions, has been described in several acute and chronic inflammatory conditions. However, due to the lack of specific markers, the precise phenotype and maturation status of these neutrophil populations remain unclear. Herein, we report that CD10, also known as common acute lymphoblastic leukemia antigen, neutral endopeptidase, or enkephalinase, can be used as a marker that, within heterogeneous populations of circulating CD66b+ neutrophils present in inflammatory conditions, clearly distinguishes the mature from the immature ones. Accordingly, we observed that the previously described immunosuppressive neutrophil population that appears in the circulation of granulocyte colony-stimulating factor (G-CSF)-treated donors (GDs) consists of mature CD66b+CD10+ neutrophils displaying an activated phenotype. These neutrophils inhibit proliferation and interferon \u3b3 (IFN\u3b3) production by T cells via a CD18-mediated contact-dependent arginase 1 release. By contrast, we found that immature CD66b+CD10- neutrophils, also present in GDs, display an immature morphology, promote T-cell survival, and enhance proliferation and IFN\u3b3 production by T cells. Altogether, our findings uncover that in GDs, circulating mature and immature neutrophils, distinguished by their differential CD10 expression, exert opposite immunoregulatory properties. Therefore, CD10 might be used as a phenotypic marker discriminating mature neutrophils from immature neutrophil populations present in patients with acute or chronic inflammatory conditions, as well as facilitating their isolation, to better define their specific immunoregulatory properties