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Introduction: Transfusional hemosiderosis is common in myelodysplastic syndromes (MDS). There are multiple retrospective analyses demonstrating a survival benefit associated with iron chelation therapy (ICT) in lower risk, transfusion dependent (TD) MDS patients. However, these studies are limited by their retrospective nature, potential for bias and by the use of risk scores at diagnosis rather than at the onset of TD. Since January 2012 the Canadian MDS Registry has prospectively collected disease and patient-related data on MDS patients including comorbidity (Charlson and MDS-CI), frailty (Rockwood clinical frailty scale) and disability [Lawton Brody Instrumental Activities of Daily Living (sIADL)]. We compared characteristics and clinical outcomes of lower risk TD MDS patients who received ICT to non chelated TD patients, adjusting for MDS and patient-related factors. Methods: Only patients who remained International Prognostic Scoring System (IPSS) low or intermediate (int)-1 risk at the time of first TD were included with MDS and patient-related factors analyzed at first TD rather than at MDS diagnosis or registry enrollment. Univariate and multivariate Cox proportional hazard models were used to determine significant predictive factors for overall survival (OS) and the model with the highest R2 was selected. Results: 219 Low (n=69)/Int-1 (n=149) risk MDS patients at the time of first TD were included. Median age was 73 [interquartile range (IQR 65,80)] with a median time from diagnosis until TD of 7 months (IQR 1,28). 60% were male with a median ECOG of 1 and median blast of 3% (IQR 1,4). By WHO classification, 39% and 37% had unilineage and multilineage dysplasia respectively, 11% CMML and 13% had excess blasts. By IPSS-revised (R), very low, low, intermediate, high and very high risk groups were 12%, 34%, 38%, 15% and 0.5%, respectively. Seventy (32%) patients received ICT with desferrioxamine (n=6), deferasirox (n=56) or both (n=8). At the time of first TD, chelated patients were younger, had higher ferritins and had lower IPSS-R risk scores (Table 1). Importantly, frailty, comorbidity, and disability scores did not differ. At a median follow up of 2.7 (IQR 2.2-3.3) years from diagnosis, OS was 6.1(IQR 4.5-7.5) years. OS was significantly improved among MDS patients treated with ICT as compared to those without (median 8.62 vs. 4.38 years, respectively, p = 0.0005, Figure 1.) By univariate analysis, age, ICT, IPSS, IPSS-R, MDS-CI, frailty, karyotype, time from diagnosis until TD, and disability were associated with improved OS. By multivariate analysis, ICT, age at TD and IPSS-R at TD were independently predictive of OS (Table 2). Conclusions: Adjusting for patient and disease related factors at the time of TD, ICT remains predictive of improved OS in patients with low/int-1 risk MDS who become TD. The adjustment for patient-related factors and analysis from TD rather than MDS diagnosis, diminishes the impact of selection bias that may have favored ICT patients in past analyses and lends additional support to the role for ICT in lower risk MDS. | Factors at Time of TD Median (IQR) | Without Iron Chelation (n=149) | With Iron Chelation (n=70) | p-value | | --------------------------------------------------------------------------------------------------- | --------------------------------------------------------------------- | ------------------------------------------------------------------- | ------- | | Age (y) | 75 (67,81) | 69 (62,75) | 0.0008 | | Ferritin (ug/L) | 664 (346,1118) n=92 | 1201 (883,1691) n=44

Background: Osteonecrosis (ON) is a prevalent (30-50% by age 30) yet underdiagnosed complication in patients with sickle cell disease (SCD), commonly affecting the femoral and humeral head. SCD ON is progressive resulting in chronic intractable pain and disability. Various imaging modalities are available for the diagnosis of ON and a number of staging methods have been proposed to classify its severity. Numerous surgical and non-surgical treatments exist for different stages of ON. There is a lack of consensus on how to best investigate, classify and treat patients with SCD ON. A previous systematic review included only 1 randomized controlled trial (RCT) but the majority of the literature are non-randomized studies. Objectives: To systematically review and summarize the available evidence from randomized and non-randomized studies with regard to the classification, diagnosis, treatment options and outcome of ON of the hips in SCD adults. Methods: Searches were conducted using the following search concepts: (sickle cell disease OR sickle cell anemia OR hemoglobin SC disease) AND (osteonecrosis OR avascular necrosis OR bone and joint complications) NOT Bisphosphonate-Associated Osteonecrosis of the Jaw. Related terms were also searched in order to maximize sensitivity. MEDLINE, Embase, CINAHL, Current Controlled Trials, and Cochrane Central Register of Controlled Trials were queried. Two independent reviewers (DM-A and AP) excluded abstracts based on pre-defined criteria. A third reviewer (KK) resolved all conflicts. Full-text of included abstracts were translated to English as needed, extracted by DM-A, AP, KK and YP and screened based on the inclusion/exclusion criteria. Two assessors (DM-A and KK) independently assessed trial quality of extracted data. Study limitations (risk of bias) and confidence in effect estimates (quality of evidence) were assessed using the Newcastle-Ottawa Quality Assessment Scale for cohort studies. Results and Discussion: 25 studies (1 RCT, 1 case-control, 10 prospective and 13 retrospective studies) were included from 544 unique citations (kappa=0.82). A total of 2,640 participants (median number of patients/study 34, range 10-1,031) with mean age of participants in each study between 19 and 40 years. Majority were HbSS (n=1,888), followed by 302 HbSC, 98 HbS/thalassemia, 27 sickle cell trait, 22 unspecified SCD genotype and 1 HbS/hereditary persistence of fetal hemoglobin. The male to female distribution was equal. Mean duration of follow-up was between 3 and 19 years. Majority (n=12) of the studies included symptomatic patients only. Nine studies used x-rays only to identify ON and 9 used x-ray with CT and/or MRI. Classification of ON between studies was heterogeneous (Ficat and Arlet: 3, Steinberg: 4, Ficat: 4, Mitchell 1987: 1, Arlet: 1, no classification scheme: 12). Treatment modalities used were extremely diverse. Of the 22 studies that described an intervention: 11 used hip arthroplasty only, 1 with cement injection only, 1 with core decompression only, and 9 used a combination of surgical and non-surgical interventions. There was also tremendous heterogeneity with the outcomes reported which precluded the conduct of any meta-analysis. The revision rate after hip arthroplasty, cement injection, and core decompression were 21% (range 3-40%), 13%, and 12% respectively. Median difference in Harris Hip Score post-hip arthroplasty was 52 (range 44-58), and 25 post-cement injection. The median rate of prosthesis infection post-hip arthroplasty was 5.5% (range 2-34%). Summary statistics were not possible on other outcome measurements since they were used in single study. Risk of bias in all the studies was moderate to high. Conclusion: The heterogeneity in diagnosing, classifying and treating ON makes the development of a consensus guideline difficult. Ficat and Arlet, Steinberg, and Ficat were the most common method in ON staging. Hip arthroplasty alone or in combination with non-surgical interventions were the most commonly used treatment options. Although hip arthroplasty offers post-surgical pain relief, it is associated with high rates of revision. The paucity of RCT and the high risk of bias with the existing non-randomized studies highlight the importance of developing prospective controlled studies examining existing and novel therapies using a unified approach in determining the severity of ON and outcome measures. Disclosures Kuo: Novartis Canada: Honoraria, Other: Advisory Board; Alexion Pharmaceuticals: Honoraria, Other: Advisory Board.