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.
on behalf of the Spanish Society of Liver Transplantation and the Spanish Society of Thrombosis and Haemostasis*
Background We conducted an investigator-driven, multicenter, open label, randomized study to establish whether the source of factor VIII (FVIII) replacement (plasma-derived, pd; or recombinant, r) affects the rate of inhibitory alloantibodies in previously untreated patients (PUPs) with severe hemophilia A. Methods Between 2010 and 2014, 303 PUPs who provided consent through their tutors were screened at 42 participating sites in 14 countries from Africa, the Americas, Asia and Europe. The original aim was to screen 300 patients, randomize 270 (10% screening failure) and follow them for 50 exposure days (ED) or 3 years. Once the intended numbers were included, follow-up was terminated due to logistic and budgetary reasons. Screening criteria were age <6 yrs, plasma FVIII activity <1%, no previous treatment with FVIII concentrates, minimal exposure (less than 5 times) to blood components. Eligible patients were 1:1 block-randomized to a FVIII source class and exclusively treated with a single pd- or rFVIII product, that within each class was allocated on the basis of site licensing and availability. Patients were monitored for inhibitor onset at pre-established and frequent time intervals. Primary outcome was any FVIII inhibitor at titres ≥0.4 BU/ml as assayed centrally. High-titred inhibitors (peak levels >5 BU/ml) were a secondary outcome. Patients were censored at the end of the follow-up (50 EDs, 3 years or study end), at inhibitor development or drop-out. Kaplan-Meier and Cox regression survival analyses took into account as putative confounders FVIII gene mutations, ethnicity, hemophilia and inhibitor family history, previous blood component exposure, therapeutic regimen, age at first treatment and country site. Results Of 303 screened patients, 39 were screening failures, and 13 were excluded because 3 patients had received >5 treatments with blood components and 10 were not infused after randomization. The remaining 251 patients were analysed and 35 had truncated follow-up (25 dropout, 10 study termination). Patients were aged 0-81 months at randomization (median 14 months) and received between 1 and 50 infusions of FVIII concentrates (median 22). Of those who did not develop an inhibitor, over 70% had >20 ED. 76 patients developed an inhibitor, of which 50 were high-titred. The cumulative inhibitor incidence was 35.4% (95% confidence interval (CI95) 28.9-41.9%). 90% of inhibitors developed within 20 EDs, both for all and high-titre inhibitors. After randomization 125 patients received pdFVIII and 126 rFVIII. The putative confounders were equally divided between the two product class arms. There were 29 inhibitors (20 high-titred) in the group treated with the class of pdFVIII and 47 (30 high-titred) in those treated with rFVIII. The cumulative inhibitor incidence was 26.7% (CI95 18.3-35.1%) for pdFVIII and 44.5% (CI95 34.7-54.3%) for rFVIII (Figure). For high-titre inhibitors the cumulative incidence was 18.5% (CI95 12.1-26.9%) for pdFVIII and 28.4% (CI95 19.6-37.2%) for rFVIII. By univariate Cox regression analysis rFVIII was associated with an 87% higher incidence of inhibitors than pdFVIII (hazard ratio (HR) 1.87, CI95 1.18-2.97). For high-titre inhibitors the rate was 70% increased (HR 1.70, CI95 0.96-2.99). The associations did not materially change after adjustment for putative confounders: in adjusted models the rate remained 70-90% elevated for rFVIII vs pdFVIII. When analysis was restricted to sites that had not randomized patients to a second generation full length rFVIII or pdFVIII (n=131 patients, 25 inhibitors), the risk of other rFVIII concentrates vs pdFVIII was still twofold increased (HR 1.99, CI95 1.00-3.99). Conclusions The rFVIII product class was associated with a 1.87-fold higher incidence of inhibitors than the pdFVIII class. This difference remained even when second generation full length rFVIII concentrate was excluded from the analyses. The results of this randomized study have implications in the choice of product for management of PUPs, as inhibitor development remains a major challenge in the management of haemophilia A. (Funded by the Angelo Bianchi Bonomi Foundation, Italian Ministry of Health, Grifols, Kedrion and LFB - Registed at EudraCT 2009-001186-88). Figure 1. Figure 1. Disclosures Peyvandi: Octapharma: Other: Investigator; LFB, Kedrion, Novonordisk, Bayer, Roche, CSL Behring.: Consultancy, Honoraria, Research Funding. Mannucci:Novonordisk, Grifols, Kedrion, Bayer, Biotest, Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Karimi:Octapharma: Other: Investigator. Young:Baxter, Grifols: Consultancy, Honoraria. Santagostino:Roche: Speakers Bureau; Bayer: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Octapharma: Speakers Bureau; Biotest: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Speakers Bureau; Biogen/Sobi: Speakers Bureau; CSL Behring: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Mancuso:Baxter, Pfizer, CSL Behring, Baxter, Sobi/Biotest: Consultancy; Novo Nordisk, Bayer: Speakers Bureau. Mahlangu:Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bonanad:Baxalta: Research Funding. Ewing:Baxter, Novo Nordisk, Grifols, Bayer, Kedrion: Honoraria. Owaidah:King abdulaziz city for science, Novo Nordisk, Bayer: Honoraria, Research Funding. Kobrinsky:Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Sanofi: Speakers Bureau; Kedrion Biopharma: Membership on an entity's Board of Directors or advisory committees. Kavakli:Baxter: Other: advisory board member and received educational and investigational support; Bayer: Other: advisory board member and received educational and investigational support; Novo Nordisk: Other: advisory board member and received educational and investigational support; Pfizer: Other: advisory board member and received educational and investigational support; Bio Products Laboratory: Other: received educational and investigational support; CSL Behring: Other: received educational and investigational support; Octapharma: Other: received educational and investigational support. Manco-Johnson:Baxter, bayer, biogen, CSL Behring, NovoNordish: Honoraria. Neme:Novo Nordisk and Pfizer: Other: fees for speaking. Wicklund:NovoNordisk, Bayer, Baxter (now Baxalta), Biogen-Idec, CSL-Behring, National Hemophilia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zulfikar:Eczacýbaþý-Baxter, Pfizer, Novo Nordisk: Consultancy, Honoraria, Research Funding.
Introduction: Haemoassist TM 2 is an electronic system designed for people with bleeding disorders and their physicians to record prophylactic infusions and treatment of bleeds. It aims to improve adherence by permitting reminders and accuracy of documentation by facilitating real-time reporting. Aim: To assess documentation quality and adherence to prophylactic regimens in patients with haemophilia A, haemophilia B or von Willebrand disease who are using Haemoassist TM 2. Methods: Ten centres enrolled consecutive patients, who had been using Haemoassist TM 2 for ≥ 3 months (Cohort 1, 'quality of documentation'). Of these, patients who had a specified prophylactic regimen in Haemoassist TM 2 for ≥ 3 months were eligible for inclusion in Cohort 2 ('adherence to prophylaxis'). Results: Cohort 1 comprised 796 patients (71% with severe haemophilia A; median 20.5 months of Haemoassist TM 2 use). The most common method of documentation for patients was using the mobile app; the median time between infusion and documentation was 4 hours using the app, compared with 85 hours using a web portal on a stationery device. The median total annualised number of infusions was consistent in the first and last 3 months of documentation (128; IQR: 70-184 and 120; IQR 64-176, respectively). Cohort 2 comprised 202 patients (79% severe haemophilia A; median of 13 months on prophylactic regimen in Haemoassist TM 2). The rate of adherence to prophylaxis was 83%; median deviation between planned and actual infusion time was ± 2 hours. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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