BACKGROUND Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia. METHODS We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37). RESULTS The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P = 0.29), with an absolute difference of 5 percentage points (95% CI, −3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P = 0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P = 0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse. CONCLUSIONS We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute–National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.)

These findings indicate the feasibility of allogeneic hematopoietic transplantation with a nonablative preparative regimen to produce engraftment and GVL against lymphoid malignancies. The ability to induce remissions with donor lymphocyte infusion in patients with CLL, Richter's, and low-grade and intermediate-grade lymphoma is direct evidence of GVL activity against these diseases. This approach appears to be most promising in patients with chemotherapy-responsive disease and low tumor burden.

A reduced-intensity preparative regimen consisting of melphalan and a purine analog was evaluated for allogeneic transplantation in 86 patients who had a variety of hematologic malignancies and were considered poor candidates for conventional my-

The immune-mediated graft-versus-leukemia effect is important to prevent relapse after allogeneic progenitor cell transplantation. This process requires engraftment of donor immuno-competent cells. The objective of this study was to assess the feasibility of achieving engraftment of allogeneic peripheral blood or bone marrow progenitor cell after purine analog containing nonmyeloablative chemotherapy. Patients with advanced leukemia or myelodysplastic syndromes (MDS) who were not candidates for a conventional myeloablative therapy because of older age or organ dysfunction were eligible. All patients had an HLA-identical or one-antigen–mismatched related donor. Fifteen patients were treated (13 with acute myeloid leukemia and 2 with MDS). The median age was 59 years (range, 27 to 71 years). Twelve patients were either refractory to therapy or beyond first relapse. Eight patients received fludarabine at 30 mg/m2/d for 4 days with idarubicin at 12 mg/m2/d for 3 days and ara-c at 2 g/m2/d for 4 days (n = 7) or melphalan at 140 mg/m2/d (n = 1). Seven patients received 2-chloro-deoxyadenosine at 12 mg/m2/d for 5 days and ara-C 1 at g/m2/d for 5 days. Thirteen patients received allogeneic peripheral blood stem cells and 1 received bone marrow after chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methyl-prednisolone. Treatment was generally well tolerated, with only 1 death from multiorgan failure before receiving stem cells. Thirteen patients achieved a neutrophil count of greater than 0.5 × 109/L a median of 10 days postinfusion (range, 8 to 17 days). Ten patients achieved platelet counts of 20 × 109/L a median of 13 days after progenitor cell infusion (range, 7 to 78 days). Eight patients achieved complete remissions (bone marrow blasts were <5% with neutrophil recovery and platelet transfusion independence) that lasted a median of 60 days posttransplantation (range, 34 to 170+ days). Acute GVHD grade ≥2 occurred in 3 patients. Chimerism analysis of bone marrow cells in 6 of 8 patients achieving remission showed ≥90% donor cells between 14 and 30 days postinfusion, and 3 of 4 patients remaining in remission between 60 and 90 days continued to have ≥80% donor cells. We conclude that purine analog-containing nonmyeloablative regimens allow engraftment of HLA-compatible hematopoietic progenitor cells. This approach permits us to explore the graft-versus-leukemia effect without the toxicity of myeloablative therapy and warrants further study in patients with leukemia who are ineligible for conventional transplantation with myeloablative regimens either because of age or concurrent medical conditions.

Nonmyeloablative stem cell transplantation in patients with follicular lymphoma has been designed to exploit the graftversus-lymphoma immunity. The longterm effectiveness and toxicity of this strategy, however, is unknown. In this prospective study, we analyzed our 8-year experience. Patients received a conditioning regimen of fludarabine (30 mg/m 2 daily for 3 days), cyclophosphamide (750 mg/m 2 daily for 3 days), and rituximab (375 mg/m 2 for 1 day plus 1000 mg/m 2 for 3 days). They were then given an infusion of human leukocyte antigen-matched hematopoietic cells from related (n ‫؍‬ 45) or unrelated donors (n ‫؍‬ 2). Tacrolimus and methotrexate were used for graft-versushost disease (GVHD) prophylaxis. Fortyseven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively. All 18 patients who were tested and had evidence of JH/bcl-2 fusion transcripts in the bone marrow at study entry experienced continuous molecular remission. The incidence of grade 2-IV acute GVHD was 11%. Only 5 patients were still undergoing immunosuppressive therapy at the time of last follow-up. We believe that the described results are a step forward toward developing a curative strategy for recurrent follicular lymphoma. (Blood. 2008;111:5530-5536)

The incidence, characteristics, risk factors for, and impact of chronic graft-vs-host disease (GVHD) were evaluated in a consecutive series of 116 evaluable HLA-identical blood stem cell transplant recipients. Minimum follow-up was 18 months. Limited chronic GVHD occurred in 6% (95% confidence interval [CI], 0%-13%), and clinical extensive chronic GVHD in 71% (95% CI, 61%-80%). The cumulative incidence was 57% (95% CI, 48%-66%). In univariate analyses, GVHD prophylaxis other than tacrolimus and methotrexate, prior grades 2 to 4 acute GVHD, use of corticosteroids on day 100, and total nucleated cell dose were significant risk factors for clinical extensive chronic GVHD. On multivariate analysis, GVHD prophylaxis with tacrolimus and methotrexate was associated with a reduced risk of chronic GVHD (hazard ratio [HR], 0.35; P ‫؍‬ .001), whereas the risk was increased with prior acute GVHD (HR, 1.67; P ‫؍‬ .046). When adjusted for disease status at the time of transplantation, high-risk chronic GVHD had an adverse impact on overall mortality (HR, 6.6; P < .001) and treatment failure (HR, 5.2; P < .001) at 18 months. It was concluded that there is a substantial rate of chronic GVHD after HLA-identical allogeneic blood stem cell transplantation, that clinical factors may alter the risk of chronic GVHD, and that high-risk chronic GVHD adversely affects outcome. (Blood. 2001;98:1695-1700)

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Chronic graft-versus-host disease (GVHD) is a major limitation of successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photochemotherapy (ECP) has been tested extensively in small cohorts of patients with chronic GVHD. In this study, we retrospectively evaluated 71 patients with severe chronic GVHD treated with ECP. Response rate was 61% (n ‫؍‬ 43), and 14 patients had complete responses (CRs). The best responses were observed in skin, liver, oral mucosa, and eye. Factors affecting outcomes were assessed in the less heavily pretreated subgroup (n ‫؍‬ 63). Thrombocytopenia was associated with a lower response rate (P ‫؍‬ .04), and there was a trend toward a higher response rate in de novo chronic GVHD. At 6 months, a total of 27 (