isrctn.org Identifier: ISRCTN54371254.

Out of 690 allogeneic matched sibling donor transplants for multiple myeloma reported to the European Group for Blood and Marrow Transplantation (EBMT) registry, 334 were performed during the period 1983–93 (all with bone marrow) and 356 during 1994–98 [223 with bone marrow and 133 with peripheral blood stem cells (PBSCs)]. The median overall survival was 10 months for patients transplanted during the earlier time period and 50 months for patients transplanted with bone marrow during the later period. The use of PBSCs was associated with earlier engraftment but no significant survival benefit compared to bone marrow transplants during the same time period. The improvement in survival since 1994 was the result of a significant reduction in transplant‐related mortality, which was 38%, 21% and 25% at 6 months and 46%, 30% and 37% at 2 years during the earlier period, and the later period with bone marrow and PBSCs respectively. Reasons for the reduced transplant‐related mortality appeared to be fewer deaths owing to bacterial and fungal infections and interstitial pneumonitis, in turn a result of earlier transplantation and less prior chemotherapy. Better supportive treatment and more frequent use of cytokines may also play a role. The improvement in survival was not directly related to the increased use of PBSCs.

Minor histocompatibility antigens (mHAgs) constitute the targets of the graft-versus-leukemia response after HLA-identical allogeneic stem cell transplantation. Here, we have used genetic linkage analysis to identify a novel mHAg, designated lymphoid-restricted histocompatibility antigen-1 (LRH-1), which is encoded by the P2X5 gene and elicited an allogeneic CTL response in a patient with chronic myeloid leukemia after donor lymphocyte infusion. We demonstrate that immunogenicity for LRH-1 is due to differential protein expression in recipient and donor cells as a consequence of a homozygous frameshift polymorphism in the donor. Tetramer analysis showed that emergence of LRH-1-specific CD8 + cytotoxic T cells in peripheral blood and bone marrow correlated with complete remission of chronic myeloid leukemia. Furthermore, the restricted expression of LRH-1 in hematopoietic cells including leukemic CD34 + progenitor cells provides evidence of a role for LRH-1-specific CD8 + cytotoxic T cells in selective graft-versus-leukemia reactivity in the absence of severe graft-versus-host disease. These findings illustrate that the P2X5-encoded mHAg LRH-1 could be an attractive target for specific immunotherapy to treat hematological malignancies recurring after allogeneic stem cell transplantation.

Background-Systemic sclerosis (SSc, scleroderma) in either its diVuse or limited skin forms has a high mortality when vital organs are aVected. No treatment has been shown to influence the outcome or significantly aVect the skin score, though many forms of immunosuppression have been tried. Recent developments in haemopoietic stem cell transplantation (HSCT) have allowed the application of profound immunosuppression followed by HSCT, or rescue, to autoimmune diseases such as SSc. Methods-Results for 41 patients included in continuing multicentre open phase I/II studies using HSCT in the treatment of poor prognosis SSc are reported. Thirty seven patients had a predominantly diffuse skin form of the disease and four the limited form, with some clinical overlap. Median age was 41 years with a 5:1 female to male ratio. The skin score was >50% of maximum in 20/33 (61%) patients, with some lung disease attributable to SSc in 28/37 (76%), the forced vital capacity being <70% of the predicted value in 18/36 (50%). Pulmonary hypertension was described in 7/37 (19%) patients and renal disease in 5/37 (14%). The Scl-70 antibody was positive in 18/32 (56%) and the anticentromere antibody in 10% of evaluable patients. Peripheral blood stem cell mobilisation was performed with cyclophosphamide or granulocyte colony stimulating factor, alone or in combination. Thirty eight patients had ex vivo CD34 stem cell selection, with additional T cell depletion in seven. Seven conditioning regimens were used, but six of these used haemoimmunoablative doses of cyclophosphamide +/-anti-thymocyte globulin +/-total body irradiation. The median duration of follow up was 12 months (3-55). Results-An improvement in skin score of >25% after transplantation occurred in 20/29 (69%) evaluable patients, and deterioration in 2/29 (7%). Lung function did not change significantly after transplantation. One of five renal cases deteriorated but with no new occurrences of renal disease after HSCT, and the pulmonary hypertension did not progress in the evaluable cases. Disease progression was seen in 7/37 (19%) patients after HSCT with a median period of 67 (range 49-255) days. Eleven (27%) patients had died at census and seven (17%) deaths were considered to be related to the procedure (direct organ toxicity in four, haemorrhage in two, and infection/neutropenic fever in one). The cumulative probability of survival at one year was 73% (95% CI 58 to 88) by Kaplan-Meier analysis. Conclusion-Despite a higher procedure related mortality rate from HSCT in SSc compared with patients with breast cancer and non-Hodgkin's lymphoma, the marked impact on skin score, a surrogate marker of mortality, the trend towards stabilisation of lung involvement, and lack of other treatment alternatives justify further carefully designed studies. If future trials incorporate inclusion and exclusion criteria based on this preliminary experience, the predicted procedure related mortality should be around 10%.

PURPOSE: To determine the efficacy, toxicity, and long-term outcome and prognostic factors of donor lymphocyte infusions (DLI) in patients with relapsed multiple myeloma (MM) after allogeneic stem-cell transplantation (AlloSCT). MATERIALS AND METHODS: Twenty-seven patients received 52 DLI courses at a median of 30 months after the previous AlloSCT. Reinduction therapy was administered to 13 patients before DLI. RESULTS: Reinduction therapy was successful in eight of 13 patients. Fourteen patients (52%) responded to DLI, including six patients (22%) who achieved a complete remission (CR). Five patients responded after T-cell dose escalation in subsequent DLIs. Four patients experienced relapse or disease progression (three from partial response and one from CR). Five patients remain in remission more than 30 months after DLI. Major toxicity was acute and chronic graft-versus-host disease (GVHD), which was present in 55% and 26% of patients, respectively. Two patients died from bone marrow aplasia. Median overall survival of all patients was 18 months. Overall survival was 11 months for DLI-resistant patients and has not been reached for the responding patients. In two patients, sustained molecular remission was observed. The factors that were correlated with response to DLI were a T-cell dose of more than 1.108 cells/kg, response to reinduction therapy, and chemotherapy-sensitive disease before AlloSCT. CONCLUSION: These data confirm the potential and durable graft-versus-myeloma effect of DLI in patients with relapsed MM after AlloSCT. Future studies should be aimed at increasing response rates, especially in patients with chemoresistant disease, and reducing toxicity by limiting GVHD. Adjuvant DLI seems an attractive and promising approach for patients who do not achieve a molecular remission after AlloSCT.