Marrow fibrosis as a risk factor for posttransplantation outcome in patients with advanced myelodysplastic syndrome or acute myeloid leukemia with multilineage dysplasia.

Marrow fibrosis is considered a poor prognostic factor in patients with myelodysplastic syndrome (MDS). The affect of fibrosis on outcomes after hematopoietic cell transplantation (HCT) in patients with MDS has not been examined. We performed a retrospective analysis in 471 patients with MDS or acute myeloid leukemia with multilineage dysplasia arising from MDS, 113 with and 358 without marrow fibrosis, who received myeloablative allogeneic HCT. Post-HCT follow-up was 0.3-10 years (median, 3.6 years) for patients with, and 0.6-12 years (median, 5 years) for patients without fibrosis. Engraftment was significantly delayed in patients with fibrosis (hazard ratio [HR] = 0.4; P < .001). Overall, there were no significant differences in overall survival (OS), relapse-free survival (RFS), and nonrelapse mortality (NRM) between patients with and without fibrosis. However, among patients with advanced disease (int-2 or high-risk disease by the International Prognostic Scoring System), OS (P = .03), RFS (P = .04), and NRM (P = .04) were inferior when marrow fibrosis was present. Given that marrow fibrosis is a poor prognostic factor for patients with MDS, and that it does not appear to affect outcome of transplantation in patients with earlier-stage disease but has a negative impact on outcome for patients with advanced disease, patients with earlier-stage MDS and marrow fibrosis might be considered for HCT earlier than their disease stage would normally dictate.

Hematopoietic cell transplantation as curative therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia.

A total of 104 patients, aged 18 to 70 years, with a diagnosis of chronic idiopathic myelofibrosis (CIMF), polycythemia vera (PV), or essential thrombocythemia (ET) with marrow fibrosis were transplanted from allogeneic (56 related and 45 unrelated) or syngeneic (n = 3) donors. Busulfan (BU) or total body irradiation (TBI)-based myeloablative conditioning regimens were used in 95 patients, and a nonmyeloablative regimen of fludarabine plus TBI was used in 9 patients. The source of stem cells was bone marrow in 43 patients and peripheral blood in 61 patients. A total of 63 patients were alive at a follow-up of 1.3-15.2 years (median, 5.3 years), for an estimated 7-year actuarial survival rate of 61%. Eleven patients had recurrent/persistent disease, of whom 8 died. Nonrelapse mortality was 34% at 5 years. Patients conditioned with targeted BU (plasma levels 800-900 ng/mL) plus cyclophosphamide (tBUCY) had a higher probability of survival (68%) than other patients. Dupriez score, platelet count, patient age, and comorbidity score were statistically significantly associated with mortality in univariate models. In a multivariable regression model, use of tBUCY (P = .03), high platelet count at transplantation (P = .01 for PV/ET; P = .39 for other diagnoses), younger patient age (P = .04), and decreased comorbidity score (P = .03) remained statistically significant for improved survival. Our findings show that hematopoietic cell transplantation offers potentially curative treatment for patients with ICMF, PV, or ET.

Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties.

Current success in organ transplantation is dependent upon the use of calcineurin-inhibitor-based immunosuppressive regimens. Unfortunately, current immunotherapy targets molecules with ubiquitous expression resulting in devastating non-immune side effects. T-cell costimulation has been identified as a new potential immunosuppressive target. The best characterized pathway includes CD28, its homologue CTLA4 and their ligands CD80 and CD86. While an immunoglobulin fusion protein construct of CTLA4 suppressed rejection in rodents, it lacked efficacy in primate transplant models. In an attempt to increase the biologic potency of the parent molecule a novel, modified version of CTLA4-Ig, LEA29Y (belatacept), was constructed. Two amino acid substitutions (L104E and A29Y) gave rise to slower dissociation rates for both CD86 and CD80. The increased avidity resulted in a 10-fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre-clinical primate model. The use of immunoselective biologics may provide effective maintenance immunosuppression while avoiding the collateral toxicities associated with conventional immunsuppressants.