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The optimal stem cell source for stem cell gene therapy has not been defined. Most gene transfer studies have used peripheral blood or marrow repopulating cells collected after administration of granulocyte colony-stimulating factor and stem cell factor (G-CSF/SCF). For clinical applications, however, growth factor administration may not be feasible. Thus, in the current study we used a competitive repopulation assay in the dog to directly compare transduction efficiency of steady-state marrow, G-CSF/SCF-primed marrow, and G-CSF/SCF-mobilized peripheral blood. Cells from all three sources were transduced, cryopreserved, and thawed together before infusion into myeloablated dogs. Gene marking in hematopoietic repopulating cells was assessed by polymerase chain reaction. While primed marrow resulted in the highest long-term marking levels, steady-state marrow was transduced at least as efficiently as mobilized peripheral blood in all three dogs. These results suggest that steady-state marrow may be an appropriate source for genetic modification of hematopoietic stem cells.

Despite prophylaxis with immunosuppressive drugs, severe graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality following allogeneic stem cell transplantation. T cell depletion of the graft has decreased incidence and severity of GVHD but has resulted in a higher incidence of graft failure and relapse. To reduce the risk of severe GVHD, but at the same time to maintain the graft-versus-tumor effect, we administered a fixed low number of 1 x 10(5) donor T cells per kilogram of body weight to recipients of CD34(+) cell-enriched allogeneic peripheral blood stem cells (PBSCs). Donor lymphocyte infusions (DLI) were then given in incremental doses when mixed chimerism persisted or signs of relapse occurred. A total of 23 patients receiving allografts from related and unrelated donors were treated according to this protocol after myeloablative or reduced intensity conditioning. One patient did not engraft and 3/20 evaluable patients developed acute (a) GVHD > or = grade II, with a corresponding estimated cumulative incidence of 15.6% (95% CI 0-30.5%). DLI (n = 13) induced aGVHD > or = II in 6 patients, but the severity of the syndrome was reduced. Overall GVHD-related mortality was low (13%). The probability of disease-free survival and overall survival at 2 years was 0.40 (95% CI 0.21-0.75) and 0.36 (95% CI 0.21-0.63). Progression-free survival and overall survival was significantly better in patients with acute or chronic myelogenous leukemia compared to patients with lymphoproliferative disorders (p = 0.002; p = 0.02). We conclude that the combination of allografts with a T cell content of about 1 x 10(5)/kg and escalating doses of DLI is a viable transplant strategy in patients with myeloid leukemias, which results in stable engraftment and a reduction of mortality from aGVHD.

Allogeneic stem cell transplantation (SCT) after reduced intensity conditioning (RIC) provides a new curative treatment option for patients usually not eligible for allogeneic SCT. Because the majority of patients lack HLA-identical sibling donors (SD), unrelated donor (UD) transplantation is performed increasingly. In this retrospective analysis, we have reviewed our experience with reduced-intensity conditioning regimens, comparing related and unrelated donors. From November, 1997, to February, 2002, 51 patients with hematological malignancies received allogeneic SCT after various RIC regimens. A total of 31 had a related donor, and the remaining 20 had an unrelated donor (UD). Both groups were comparable with respect to age and gender. We observed a trend toward higher rate of graft failure in the unrelated donor group with 11% compared to 3% in the related donor group (p = 0.55). The rate of acute graft-versus-host disease (GVHD) II-IV was 36% in the RD group versus 44% for the UD group; severe GVHD III-IV occurred in 26% and 22%, respectively. There were more serious infections in the unrelated donor group with 25% compared to 16%. Transplant-related mortality was 13% (RD group) versus 30% (UD group). At 21 months, progression-free survival was 30% in both groups. The Kaplan Meier estimate of overall survival was 40% (RD) and 30% (UD group). In summary, we found no statistically significant difference regarding progression free and overall survival, despite a trend for more graft failure and increased transplant-related complications associated with the use of stem cells from unrelated donors.

We analyzed effects of successive changes in prevention and treatment of chronic GVHD in 405 patients with aplastic anemia and refractory anemia given HLA-matched hematopoietic stem cell transplantation (HSCT) from 1970-1997. For analysis, patients were divided into group I, transplantations from 1970-1976; group II, 1977-1983; group III, 1984-1990; and group IV, 1991-1997. The overall incidence of chronic GVHD was 28%. Incidences of chronic GVHD for groups I through IV were 20%, 46%, 41%, and 22%, respectively, reflecting added buffy coat infusions in groups II and III. Five-year survival rates of patients with chronic GVHD for groups I through IV were 58%, 74%, 82%, and 76%, respectively (NS). Among group I patients, 50% were alive off immunosuppression, none were alive on immunosuppression, and 50% died. These figures were 76%, 0%, and 24% in group II; 80%, 10%, and 10% in group III; and 64%, 21%, and 14% in group IV patients. More serious infections and skin contractures were seen in group I than in groups II, III, and IV (P = .0001, .02, .01 and P =.0003, .001, .05, respectively). Lung complications, aseptic necroses, depression, and Karnofsky scores were comparable among groups. Gastrointestinal complications seemed less frequent among groups II through IV. Diabetes mellitus was more frequent in group IV than in groups I through III (P = .008). Secondary malignancies occurred in 33%, 6%, 3%, and 0% of patients in the 4 groups, respectively. In conclusion, over 28 years, chronic GVHD has remained challenging, with only slight improvements in quality of life. Decisive improvements in therapy and survival will have to await both a better understanding of the immunological events underlying chronic GVHD and better infection prevention and control.

Background: Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients.Methods/design: ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and--in absence of available stem cells from earlier harvesting--undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3(rd) (arm A + B) and the 5(th) lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS.Discussion: This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients.Trial Registration: ISRCTN16345835 (date of registration 2010-08-24). [ABSTRACT FROM AUTHOR]