Marco Sorio

Risk Factors for the Development of Secondary Malignancy After High-Dose Chemotherapy and Autograft, With or Without Rituximab: A 20-Year Retrospective Follow-Up Study in Patients With Lymphoma

PURPOSE High-dose chemotherapy with peripheral blood progenitor cell (PBPC) autograft is effective in high-risk lymphoma, particularly with the addition of rituximab; however, it is associated with risk of secondary malignancy. These issues have been addressed in a series of 1,347 patients with lymphoma treated with a high-dose sequential (HDS) program. PATIENTS AND METHODS A total of 1,024 patients with B-cell lymphoma, 234 patients with Hodgkins lymphoma, and 89 patients with T-cell lymphoma were treated with HDS between 1985 and 2005 at 11 Gruppo Italiano Terapie Innovative Linfomi centers. HDS was given as salvage treatment to 707 patients (52%); 655 patients (49%) received a modified HDS, with high-dose cytarabine and two consecutive PBPC harvests. Rituximab-supplemented HDS was given to 523 patients (39%). RESULTS At a median follow-up of 7 years, the median overall survival (OS) was 16.2 years; in B-cell lymphoma the OS was significantly superior with rituximab HDS compared to HDS alone. The cumulative incidence at 5 and 10 years of secondary myelodysplasia/acute leukemia (sMDS/AL) were 3.09% and 4.52%, respectively, that of solid tumors were 2.54% and 6.79%, respectively. Factors associated with sMDS/AL were male sex and use of the second harvest PBPC for the graft; factors found to be associated with solid tumor were advanced age, post-HDS radiotherapy, and rituximab addition to HDS. Despite the increased risk of solid tumors, rituximab addition to HDS was still associated with survival advantages. CONCLUSION This analysis has relevant implications for the design and use of intensive chemoimmunotherapy with autograft. In addition, it offers useful insights toward the understanding and prevention of tumor development.

Prolonged survival and low incidence of late toxic sequelae in advanced follicular lymphoma treated with a TBI-free autografting program: updated results of the multicenter consecutive GITMO trial

This study provides an updated report of the consecutive multicenter Gruppo Italiano Trapianto Midollo Osseo trial employing an intensified, purging-free, total body irradiation-free, high-dose sequential chemotherapy schedule with peripheral blood stem cell autograft (i-HDS) in advanced-stage follicular lymphoma (FL). Special interest has been devoted to late toxicities and outcome in terms of molecular status. Ninety-two untreated FL patients aged ⩽60 were enrolled by 20 Italian centers and evaluated on an intention-to-treat basis. Main findings are as follows: (1) 5.5-years overall survival projection of 80% (median follow-up: 68 months), with no differences related to age-adjusted IPI score; (2) 46 (50%) of 92 patients presently in continuous complete remission; (3) projected long-term progression-free survival exceeding 80% for patients collecting PCR-negative stem cell harvests or achieving molecular remission within the first 2 years from the end of therapy; (4) actuarial 5-years risk of developing secondary myelodysplasia and acute myeloid leukemia of 3.7%, with most of these events occurring in patients re-treated for recurrent lymphoma. These results demonstrate that i-HDS is feasible, effective and safe even in terms of long-term outcome. As the HDS schedule can be easily supplemented with Rituximab, it is one of the best options for random comparison with Rituximab-supplemented conventional chemotherapy.

Comparative Proteomic Analysis of Serum from Patients with Systemic Sclerosis and Sclerodermatous GVHD. Evidence of Defective Function of Factor H

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by immunological and vascular abnormalities. Until now, the cause of SSc remains unclear. Sclerodermatous graft-versus-host disease (ScGVHD) is one of the most severe complications following bone marrow transplantation (BMT) for haematological disorders. Since the first cases, the similarity of ScGVHD to SSc has been reported. However, both diseases could have different etiopathogeneses. The objective of this study was to identify new serum biomarkers involved in SSc and ScGVHD. Methodology Serum was obtained from patients with SSc and ScGVHD, patients without ScGVHD who received BMT for haematological disorders and healthy controls. Bi-dimensional electrophoresis (2D) was carried out to generate maps of serum proteins from patients and controls. The 2D maps underwent image analysis and differently expressed proteins were identified. Immuno-blot analysis and ELISA assay were used to validate the proteomic data. Hemolytic assay with sheep erythrocytes was performed to evaluate the capacity of Factor H (FH) to control complement activation on the cellular surface. FH binding to endothelial cells (ECs) was also analysed in order to assess possible dysfunctions of this protein. Principal Findings Fourteen differentially expressed proteins were identified. We detected pneumococcal antibody cross-reacting with double stranded DNA in serum of all bone marrow transplanted patients with ScGVHD. We documented higher levels of FH in serum of SSc and ScGVHD patients compared healthy controls and increased sheep erythrocytes lysis after incubation with serum of diffuse SSc patients. In addition, we observed that FH binding to ECs was reduced when we used serum from these patients. Conclusions The comparative proteomic analysis of serum from SSc and ScGVHD patients highlighted proteins involved in either promoting or maintaining an inflammatory state. We also found a defective function of Factor H, possibly associated with ECs damage.

The Local Complement Activation on Vascular Bed of Patients with Systemic Sclerosis: A Hypothesis-Generating Study

Objective The role of complement system in the pathogenesis of systemic sclerosis (SSc) has been debated during the last decade but an evident implication in this disease has never been found. We carried out an explorative study on SSc patients to evaluate the expression of soluble and local C5b-9 complement complex and its relation with a complement regulator, the Membrane Cofactor Protein (MCP, CD46) on skin vascular bed as target distinctive of SSc disease. We also analyzed two polymorphic variants in the complement activation gene cluster involving the MCP region. Methods C5b-9 plasma levels of SSc patients and healthy subjects were analyzed by ELISA assay. Archival skin biopsies of SSc patients and controls were subjected to immunofluorescence analysis to detect C5b-9 and MCP on vascular endothelial cells. The expression of MCP was validated by immunoblot analysis with specific antibody. Polymorphic variants in the MCP gene promoter were tested by a quantitative PCR technique-based allelic discrimination method. Results Even though circulating levels of C5b-9 did not differ between SSc and controls, C5b-9 deposition was detected in skin biopsies of SSc patients but not in healthy subjects. MCP was significantly lower in skin vessels of SSc patients than in healthy controls and was associated with the over-expression of two polymorphic variants in the MCP gene promoter, which has been related to more aggressive phenotypes in other immune-mediated diseases. Conclusions Our results firsty document the local complement activation with an abnormal expression of MCP in skin vessels of SSc patients, suggesting that a subset of SSc patients might be exposed to more severe organ complications and clinical evolution due to abnormal local complement activation.

The National Institutes of Health criteria for classification and scoring of chronic graft versus host disease: long-term follow-up of a single center series

Abstract We assessed the retrospective applicability and prognostic value of the National Institutes of Health (NIH) classification of chronic graft versus host disease (cGVHD) in 159 consecutive patients after allogeneic hematopoietic stem cell transplant (HSCT). Seventy-four patients (46.5%) were affected by late-acute GVHD (n = 19; 25.7%), classic cGVHD (n = 44; 59.4%) and overlap syndrome (n = 11; 14.9%). Overall, patients with NIH-defined cGVHD (i.e. classic cGVHD and overlap syndrome) had better 10-year overall survival (OS) as compared to patients without GVHD (76.9% vs. 47.4%, p = 0.0002) or with late-acute GVHD (47.4%, p = 0.001). Relapse mortality (RM) was lower in patients with NIH-defined cGVHD than in patients without GVHD (14.5% vs. 38.7%, p = 0.001), but comparable to that of late-acute type (19.4%, p = 0.31). Non-relapse mortality (NRM) was lower in patients with NIH-defined cGVHD as compared to late-acute GVHD (10.0% vs. 41.1%, p = 0.0005), as well as patients without GVHD (22.2%, p = 0.045). At multivariate analysis, NIH-defined cGVHD remained independently predictive for lower RM, but not for NRM. Thus, the new NIH classification identifies two subtypes of GVHD (late-acute and chronic) with different long-term outcomes and impact on RM and NRM.