Avital Rand

Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan.

Reduced-intensity conditioning (RIC) regimens are increasingly used in allogeneic stem-cell transplantation (SCT). There are no data whether any of these regimens has advantage and in what setting. We retrospectively analyzed SCT outcomes in 151 patients given fludarabine-based RIC for various hematological malignancies; 72 conditioned with fludarabine and intravenous-busulfan (FB) and 79 with fludarabine and melphalan (FM). FM was more myelosuppressive. Grade III–IV organ toxicity occurred in 31 and 53% of FB and FM recipients (P=0.005) and acute graft-versus-host disease grade II–IV in 33 and 53%, respectively (P=0.01). Non- relapse mortality rate (NRM) was 16 and 40%, respectively (P=0.003). Active disease (HR 2.2, P=0.003) and prior autologous SCT (HR 1.7, P=0.04) predicted inferior overall survival (OS). Among patients transplanted in remission, OS was 72 and 36% after FB and FM, respectively (P=0.03) due to increased NRM with FM. Similarly, patients transplanted in active disease experienced higher NRM with FM, however lower relapse rates resulted in equivalent OS. In conclusion, there are marked differences in outcome between RIC regimens that are theoretically dose-equivalent. The FM regimen is more myelosuppressive and toxic but controls disease better. FB was associated with improved survival in patients transplanted in remission. These observations merit further study in prospective studies.

Genetic variations in the heparanase gene (HPSE) associate with increased risk of GVHD following allogeneic stem cell transplantation: effect of discrepancy between recipients and donors

Graft-versus-host disease (GVHD) is the most common cause of nonrelapse mortality and morbidity after hematopoietic stem cell transplantation (HSCT). The well-documented involvement of heparanase in the process of inflammation and autoimmunity led us to investigate an association between HPSE gene single-nucleotide polymorphisms (SNPs) and the risk of GVHD. The present study indicates a highly significant correlation of HPSE gene SNPs rs4693608 and rs4364254 and their combination with the risk of developing acute GVHD. Moreover, the study revealed that discrepancy between recipient and donor in these SNPs may elevate significantly the risk of acute GVHD. This association was statistically significant when the recipients possessed genotype combinations dictating higher levels of heparanase compared with their human leukocyte antigen (HLA)-matched donors. In addition, HPSE gene SNPs disclosed a correlation with extensive chronic GVHD, nonrelapse mortality, and overall survival. Our study indicates involvement of heparanase in the development of acute and extensive chronic GVHD. Moreover, it suggests a possible mechanism for the aggressive behavior of T lymphocytes leading to GVHD when the recipients possess genotype combinations that dictate high levels of heparanase mRNA compared with their HLA-matched donors expressing low levels of heparanase.

Ibritumomab tiuxetan (Zevalin) combined with reduced-intensity conditioning and allogeneic stem-cell transplantation (SCT) in patients with chemorefractory non-Hodgkin's lymphoma

Allogeneic SCT is an effective therapy for lymphoma. Reduced-intensity conditioning (RIC) reduces non-relapse mortality (NRM) associated with myeloablative conditioning but relapse rates are high when performed in active disease. This study was designed to explore the safety and outcome of ibritumomab tiuxetan (Zevalin) combined with RIC in patients with advanced lymphoma. The study included 12 patients, median age 54 years (37–62), with a median of four prior treatments (2–6) and active disease documented on PET–CT. Zevalin 0.4 mCi/kg was given on day −14 and fludarabine combined with BU (n=6) or melphalan (n=6) was started on day −6. GVHD prevention was tapered 3 months after SCT to augment the graft-versus-lymphoma effect. All patients engrafted, a median of 14 days after SCT. Eighty-three percent achieved CR/PR. With a median follow-up of 21 months (12–37), 2-year PFS is 33%. Only three patients relapsed; cumulative incidence 25%. NRM was 42%, predominantly due to acute GVHD. Zevalin–RIC is feasible with consistent engraftment, acceptable organ toxicity, but high rates of acute GVHD. The low incidence of relapse suggests augmented anti-lymphoma effect. Zevalin–RIC merits further study. Better results may be achieved in patients earlier in disease course and with longer duration of immune-suppression.

Fludarabine and treosulfan: A novel modified myeloablative regimen for allogeneic hematopoietic stem-cell transplantation with effective antileukemia activity in patients with acute myeloid leukemia and myelodysplastic syndromes

Allogeneic stem-cell transplantation (SCT) is potentially curative treatment for AML and MDS. New conditioning regimens are continuously explored trying to reduce toxicity while maintaining antileukemia effect. Treosulfan is an alkylating agent with in vitro cytotoxicity against leukemia as well as myeloablative and immunosuppressive properties when used in escalated doses. We explored a regimen of fludarabine (30 mg/m2×5) and treosulfan (12 gr/m2×3) in 24 patients, median age 55 years (range, 30 – 69), with AML (n = 19) or MDS (n = 5), not eligible for standard myeloablation. Donors were HLA-matched siblings (n = 11) or matched-unrelated (n = 13). Twenty-one patients engrafted within a median of 15 days. Extramedullary toxicity was relatively limited. The incidence of acute and chronic GVHD was 15% and 47%, respectively. With median follow-up of 19 months (range, 8 – 34), 16 patients are alive and 8 died (relapse-2, treatment-related-6). Two-year disease-free survival rate was 60% (95% CI, 39 – 81). The cumulative incidence of relapse was only 15% (95% CI, 5 – 44) while nonrelapse mortality rate was 25% (95% CI, 13 – 50). The fludarabine/treosulfan regimen can be considered a fully intensive, modified myeloablative regimen with effective antileukemia activity and acceptable toxicity in patients with AML/MDS not eligible for standard myeloablation, and merits further study in larger scale studies.