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Summary:We retrospectively compared the incidence and clinical characteristics of cGVHD in 37 allo-PBT recipients transplanted between July 1994 and October 1996 and 37 historical control allo-BMT recipients in a casecontrol study. All patients received a first unmanipulated transplant, graft from an HLA-identical sibling donor, with CsA-MTX GVHD prophylaxis and survived more than 100 days after transplant. PBT and BMT groups were well matched for age, grade of acute GVHD, male patients grafted from female donors, and phase of disease. The median CD34 + and CD3 + cell numbers infused in the PBT group were 5.2 × 10 6 /kg and 307 × 10 6 /kg, respectively. The median time to an ANC greater than 0.5 × 10 9 /l was 16 days (range 11-22) after PBT and 22 days (range 14-36) after BMT (P Ͻ 0.001). The median time to a platelet count greater than 20 × 10 9 /l was 15 days (range 6-43) after PBT and 28 days (range 12-68) after BMT (P Ͻ 0.001). Median follow-up was 12.3 months (range 5.4-30.3) and 58.7 months (range 4-122.3), for patients receiving PBT and BMT, respectively. Seventeen out of 37 (46%) PBT recipients, vs nine out of 37 (24%) BM recipients developed cGVHD. Actuarial probability of cGVHD at 1 year was 59% (95% CI, 39-79) in the PBT group vs 27% (95% CI, 12-42) in the BM group (P = 0.01). Cumulative incidence estimate of cGVHD was 51% and 25%, for patients receiving PBT and BMT respectively (P = 0.03). Clinical characteristics of cGVHD and response to therapy were similar in both groups, except for a higher incidence of de novo cGVHD in the PBT group. Our results suggest that as compared with BMT, PBT may result in an increased incidence of cGVHD.

Transfusion dependency seems to have a major prognostic impact in patients with myelodysplastic syndrome (MDS) (Malcovati L et al. J Clin Oncol2007;25:3503). Preliminary data also suggest that the development of iron overload could influence outcome (Malcovati L et al. J Clin Oncol2005;23:7594 and Garcia-Manero G et al. Leukemia2008;22:538), but small numbers have precluded a meaningful analysis of the prognostic value of this characteristic. The main aim of this study was to evaluate the independent prognostic value of transfusion dependency (as defined in WHO-based Prognostic Scoring System [WPSS]) and iron overload (defined as serum ferritin level >1,000 ng/mL) in a large series of 2,994 patients (median age, 74 yr) with de novo MDS according to FAB criteria (2,107 MDS according to WHO criteria). Complete transfusional history was available in 2,241 patients (835 transfusion dependent [TD] at diagnosis, 526 TD during follow-up, and 880 non-TD) and serum ferritin levels in 1,634. Karyotyping was successfully performed in 2,074 patients, who could then be classified by the International Prognostic Scoring System (IPSS) as low (861 patients), intermediate-1 (748), intermediate-2 (311), and high-risk (154). The numbers of patients in the five risk categories defined by the WPSS (available for 1,228 patients) were 257 (21%) in very low, 385 (31%) in low, 217 (18%) in intermediate, 271 (22%) in high, and 98 (8%) in very high, closely similar to those reported in the original WPSS series. Actuarial curves of overall survival (OS) and risk of evolution to acute myeloblastic leukemia (AML) were built by Kaplan-Meier method and differences between curves compared with log-rank tests. Multivariate analyses of OS and risk of evolution to AML were performed by Cox proportional hazards regression method, with development of transfusion dependency and iron overload entered as time-dependent covariates. Other variables included in the prognostic factor analyses were age, gender, hemoglobin level, absolute WBC, PMN, and platelet counts, proportion of blasts in blood and marrow, percentage of dysplastic features in the three different hematopoietic cell lines, cytogenetics according to IPSS cytogenetic risk subgroups, FAB and WHO classifications, ferritin, beta-2 microglobulin, erythropoietin, and LDH levels at diagnosis, and IPSS and WPSS risk categories. All the previous variables showed a statistically significant relationship with OS and/or AML risk on univariante analyses. Median OS for TD patients at diagnosis, TD patients during evolution, and non-TD patients was 19, 60, and 96 months, respectively (P<.0001). Multivariate analyses in a set of 902 cases with complete data confirmed that development of iron overload (1st variable selected to enter the model; hazard ratio [HR], 52.4; P<.0001) and transfusion dependency (2nd to enter; HR, 8.8; P<.0001) were strongly associated with OS and added significant independent prognostic information to that afforded by the IPSS and WPSS scores or by other characteristics with universally recognized prognostic value. Further, multivariate analyses of AML transformation risk showed that iron overload (1st to enter; HR, 6.6; P<.0001) and transfusion dependency (2nd to enter; HR, 3.5; P=.003) had also independent impact on that endpoint. These results demonstrate for the first time the independent prognostic value of development of iron overload on OS and AML risk in MDS, confirm the impact of transfusion dependency on those outcomes, and support that the inclusion of both variables in a new prognostic scoring system would add clinically relevant information. They also suggest that avoiding or reducing iron overload by an appropriate chelation therapy could improve OS and reduce the risk of AML transformation in MDS patients.

We investigated the effectiveness and tolerability of azacitidine in patients with World Health Organization-defined myelodysplastic syndromes, or acute myeloid leukemia with 20-30% bone marrow blasts. Patients were treated with azacitidine, with one of three dosage regimens: for 5 days (AZA 5); 7 days including a 2-day break (AZA 5-2-2); or 7 days (AZA 7); all 28-day cycles. Overall response rates were 39.4%, 67.9%, and 51.3%, respectively, and median overall survival (OS) durations were 13.2, 19.1, and 14.9 months. Neutropenia was the most common grade 3-4 adverse event. These results suggest better effectiveness-tolerability profiles for 7-day schedules.

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