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Background: The incorporation of patient-reported outcomes with traditional disease risk classification, was found to strengthen survival prediction in patients with myelodysplastic syndromes (MDS). A recently reported model, FA-IPSS(h), found that patients' reported fatigue, assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30), among higher-risk IPSS population, further stratifies them into distinct sub-groups with different survival outcomes (Efficace et al, 2018). Compared to the IPSS, the revised IPSS (IPSS-R) is more refined in prognostic assessment and an IPSS-R score of > 3.5 may identify higher risk disease (Pfeilstocker et al, 2016). The Edmonton Symptom Self Assessment Scale (ESAS) Global Fatigue Scale (GFS), is a single-item fatigue rating scale (0-10, with 10 being the highest degree), which has been previously recommended by the National Comprehensive Cancer Network to screen for fatigue in all cancer populations. Aims: (1) to validate the FA-IPSS(h), among the Canadian MDS registry (2) investigate whether a modified index, integrating higher risk by IPSS-R with patient reported fatigue according to the GFS, is able to identify individual subgroups with divergent overall survival (OS). Methods: All adult patients diagnosed with MDS with an IPSS-R score >3.5 within 6 months before the date of registration were eligible for this analysis. Fatigue was assessed both by the QLQ-C30 questionnaire and the GFS. Frailty was assessed by the Canadian Study of Health and Aging (CSHA) 9 point Rockwood clinical frailty scale. Survival was calculated using standard Kaplan-Meier analysis. Results: This analysis included 331 patients. Median age was 73 years (range, 30-98 years), 65.7% were male, median blast % was 6% (range, 0-30), median IPSS-R score was 5.2 (range, 3.5-10) and 55% had high and intermediate-2 (Int-2) IPSS risk, 68% had high and very high IPSS-R risk disease, 66% were exposed to a hypomethylating agent. Median fatigue scores increased with Rockwood frailty scores. The median QLQ-C30 fatigue score was 33 (interquartile range (IQR), 22-55.6) and 4 (IQR, 2-6) by the GFS with 59% recording high fatigue (>4). At a median follow-up of 17 months (IQR, 9-30 months), 233 deaths were observed. The actuarial median OS was 19.3 months (95% CI, 16.5-21.7). We applied the FA-IPSS(h) using QLQ-C30 fatigue cutoffs of 45 (figure 1a) and found a significant difference in OS (p3.5 + Low Fatigue (3.5 + High Fatigue (≥45) (n=96). We found a significant difference in OS between these 2 groups, median OS 19.5 months (95% CI, 17.2-24.3) in group A versus 15.2 months (95% CI, 11.9-22.0) in group B (p=0.02) (figure 1b). We found similar results with these refinements, using the QLQ-C30 cutoff of 33 (the median in our patient population) (p4), was able to distinguish OS using the IPSS (p3.5 (p=0.005) (figure 1d). Conclusions: We were able to externally validate the FA-IPSS (h) using a threshold QLQ-C30 fatigue score of 45, as originally described and 33 (Canadian median), using both the IPSS and IPSS-R (score >3.5) classifications to define higher risk MDS. The easier to deploy ESAS GFS score of >4 further discriminates survival using the IPSS and IPSS-R. This emphasizes the power of self-reported fatigue at refining OS predictions in higher risk MDS and further bolsters the importance of considering patient related outcomes in global assessments. Disclosures Geddes: Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Keating:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees. Leber:Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leitch:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exjade: Speakers Bureau. Shamy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Storring:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nevill:Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Delage:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Elemary:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chodirker:Hoffman Laroche: Honoraria. Buckstein:Novartis: Honoraria; Celgene: Research Funding; Takeda: Research Funding; Celgene: Honoraria; Astex: Honoraria.

Background Myelodysplastic syndromes (MDS) are characterized by frequent mutations in RNA splicing factor genes. Protein arginine methyltransferase 5 (PRMT5) regulates the activity of the splicing machinery through methylation of key spliceosome proteins. PRMT5 inhibitors have demonstrated preferential killing of acute myeloid leukemia cells with splicing factor mutations. JNJ-64619178 is a potent, selective, oral PRMT5 inhibitor that causes accumulation of splicing abnormalities in preclinical models. It is hypothesized that inhibition of PRMT5 by JNJ-64619178 may target splicing factor gene mutant MDS clones, leading to recovery of normal hematopoiesis. Here we present Part 2 of a phase 1 study of JNJ-64619178 evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of JNJ-64619178 in adult patients (pts) with lower risk MDS (International Prognostic Scoring System [IPSS] score Low or Intermediate-1) who are red blood cell (RBC) transfusion-dependent and relapsed or refractory to erythropoiesis-stimulating agent (ESA) treatment. Methods Dosing was initiated at 2 mg, 14 days on/7 days off (intermittent) on a 21-day cycle, a tolerable dose from the ongoing dose escalation in solid tumors and lymphomas in Part 1. Confirmation of tolerability followed a modified 3+3 design with de-escalation allowed based on the totality of the data. Enrollment was expanded at the selected, tolerable dose level to further evaluate safety, PK, PD, and preliminary clinical activity. Results As of 29 May 2021, 21 pts were enrolled. Median age was 71 (range 52-85). Revised IPSS score was Very Low (10%), Low (71%) or Intermediate (19%). Pts had a median of 1 prior line of therapy post-ESA (range 0-4), including lenalidomide (33%), hypomethylating agents (29%), and luspatercept (19%). SF3B1 mutations were identified in 71% of pts. Median treatment duration was 3.1 months (range 0.03-6.37). No dose-limiting toxicities were observed. While the 2 mg intermittent starting dose was tolerable, lower dose schedules of 1 mg intermittent and 0.5 mg continuous (once daily [QD]) dosing were evaluated to reduce myelosuppression, and enrollment was expanded at 0.5 mg QD (n=13 pts). Fifteen pts (71%) experienced ≥1 treatment emergent adverse event (TEAE) that was considered related to the study agent (TRAE). TRAE in >10% of pts were thrombocytopenia (52%), neutropenia (48%), anemia (19%), and dysgeusia (14%). Grade 3 or higher TRAE were reported for 57% of pts. Grade 3 or higher TRAE worsening from baseline in >1 pt were neutropenia (29%); anemia and thrombocytopenia (19.0% each); and diarrhea (9%). TEAEs contributed to treatment interruption, dose reduction, and treatment discontinuation in 57%, 14%, and 19% of pts, respectively. Anemia, thrombocytopenia, and neutropenia were the only TRAE leading to treatment modification in >1 pt. Hematologic toxicities were dose-dependent and reversible. Grade ≥3 thrombocytopenia and neutropenia were observed, respectively, in 67% and 50% of pts at 2 mg intermittent versus 0% and 31% at 0.5 mg QD. Serious AE considered possibly related to JNJ-64619178 by the investigator included 1 pt with Grade 3 anemia and 1 pt with Grade 1 atrial fibrillation, Grade 3 cardiac troponin I increase, and Grade 5 cardiac failure (>30 days from last dose). One other death of unknown cause was not considered related to treatment. Comparison of the multiple dose C trough across all dose levels suggests a dose-dependent increase in JNJ-64619178 plasma concentration. Robust target engagement, as measured by plasma symmetric dimethylarginine, was achieved at all dose levels. Serial analysis of variant allele frequency of clonal mutations in a subset of pts did not show significant reductions from baseline in peripheral blood or bone marrow. No pts experienced objective response or hematologic improvement according to International Working Group criteria, RBC transfusion independence, or meaningful reduction in transfusion requirements. Conclusion JNJ-64619178 demonstrated primarily hematologic toxicity in pts with transfusion-dependent lower-risk MDS, which was manageable at the selected expansion dose. Despite robust target engagement, clinical activity was not observed, and enrollment was stopped. The role of PRMT5 in MDS and the differential impact of PRMT5 inhibition on normal and malignant hematopoiesis require further study. Disclosures Platzbecker: Novartis: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria. Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Brunner: Agios: Consultancy; Keros Therapeutics: Consultancy; Aprea: Research Funding; AstraZeneca: Research Funding; GSK: Research Funding; Acceleron: Consultancy; Janssen: Research Funding; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Morillo: Janssen: Honoraria; Abbvie: Honoraria; Takeda: Honoraria. Patel: Acerta Pharma: Research Funding; Curis: Research Funding; Clovis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aileron Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Effector Therapeutics: Research Funding; Eli Lilly: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Evelo Biosciences: Research Funding; Jacobio: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jounce Therapeutics: Research Funding; Klus Pharma: Research Funding; Kymab: Research Funding; Loxo Oncology: Research Funding; LSK Biopartners: Research Funding; Lycera: Research Funding; Mabspace: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Millennium Pharmaceuticals: Research Funding; Mirati Therapeutics: Research Funding; ModernaTX: Research Funding; ORIC Pharmaceuticals: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Phoenix Molecular Designs: Research Funding; Placon Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; Prelude Therapeutics: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Revolution Medicines: Research Funding; Ribon Therapeutics: Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; Stemline Therapeutics: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Tesaro: Research Funding; TopAlliance: Research Funding; Vedanta: Research Funding; Verastem: Research Funding; Vigeo: Research Funding; Xencor: Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Daiichi Sankyo: Research Funding; Cyteir Therapeutics: Research Funding; Ciclomed: Research Funding; Checkpoint Therapeutics: Research Funding; Calithera: Research Funding; Boehringer Ingelheim: Research Funding; Bicycle Therapeutics: Research Funding; AstraZeneca: Research Funding; Artios Pharma: Research Funding; Agenus: Research Funding; Florida Cancer Specialists: Research Funding; BioNTech: Research Funding; Incyte: Research Funding; Forma Therapeutics: Research Funding; Ignyta: Research Funding; Hutchinson MediPharma: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Hengrui: Research Funding; H3 Biomedicine: Research Funding; GlaxoSmithKline: Research Funding. Germing: Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Lavie: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Fees for lectures; Roche: Other: Fees for lectures; Novartis: Other: Fees for lectures; Takeda: Consultancy. Lauring: Janssen Research and Development: Current Employment; Johnson and Johnson: Current holder of stock options in a privately-held company. Mistry: Janssen: Current Employment, Current equity holder in publicly-traded company.

Intro: Iron overload (IO) reflected by elevated serum ferritins is associated with increased mortality in patients with myelodysplastic syndromes (MDS) with a threshold effect seen above 1000 ug/ml (Malcovati, JCO 2005). Ferritin is elevated due to transfusions, inflammation and ineffective erythropoiesis but is an imperfect metric of true iron overload. Elevated levels of oxidatively damaging non-transferrin bound iron (NTBI) and labile plasma iron (LBI) are not easily measured but correlate with transferrin saturation (TSAT) >70% and >80% respectively (de Swart, Haematological 2018). The relationship of TSAT with ferritin and MDS-related clinical outcomes has not been well-characterized. Objectives: We aimed to describe temporal trends in TSAT according to transfusion dependence and to determine if elevated TSAT correlates with ferritin levels, and/or predicts for clinical outcomes such as survival, infectious death and cardiac death in patients with MDS. Methods: Adult patients enrolled in the Canadian national MDS registry over 11.5 years and 15 centers were evaluated retrospectively. Mean, median and ranges for ferritin and TSAT were calculated at six (+/- 3) month intervals. General linear mixed model analysis with repeated measures per subject was used to evaluate changes in ferritin and TSAT over time. Transfusion density (TD) was calculated at landmark year 1 and 2 and was defined as the total number of units transfused/months elapsed since commencing transfusion dependence, with TD-low and TD-high defined as above or below median. Log-rank tests were used to detect survival differences among three transfusion groups (transfusion independent [TI], TD-low and TD-high), among three TSAT groups (TSAT 80% at enrolment), and among three ferritin groups (≤500ug/mL, 501-1000ug/mL and >1000ug/mL at enrolment). Results: A total of 718 patients from the MDS-CAN registry were included in the analysis. Patient characteristics including demographics, clinical and laboratory characteristics are summarized in Table 1. With a median follow up of 2.1 years, actuarial OS was 2.4 years. 17% developed AML and 61% of patients have died. AML, progressive disease, infection, cardiac causes, bleeding accounted for 26%, 20%, 19%, 9.6% and 6.34% of known causes of death respectively. 56% experienced infections (median 2/patient), 7% experienced a cardiac event and 43% were hospitalized at least once. Ferritin and TSAT were moderately correlated over time (r=0.63, p < 0.0001) (Figure 1A) with only 39% of all ferritins >1000ug/mL associating with a TSAT of >80%. The relationship between the 2337 serum ferritins (recorded over 42 months) and TSAT is shown in Figure 1B. Among all patients, ferritin significantly increased from enrolment up to 42 months (p Conclusion: Among a cohort of predominantly low-intermediate risk MDS patients, TSAT correlated only moderately with serum ferritins. TD patients, and in particular high transfusion-burden TD patients have inferior clinical outcomes compared to TI or low-transfusion burden TD patients. Further analyses to probe these relationships are ongoing including the effect of TSAT and iron chelation therapy on infectious deaths, and a multivariate analysis adjusting for other covariates. Disclosures Geddes: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Keating:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Leber:Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shamy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Storring:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nevill:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria. Delage:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Elemary:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chodirker:Hoffman Laroche: Honoraria. Leitch:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exjade: Speakers Bureau. Buckstein:Astex: Honoraria; Celgene: Honoraria; Takeda: Research Funding; Celgene: Research Funding; Novartis: Honoraria.

Background: More than 50% of patients with myelodysplastic syndrome (MDS) become transfusion dependent (TD) during the course of their disease and 25-30% present as TD at diagnosis. While TD is more common in IPSS/IPSS-R higher risk patients and is associated with inferior overall survival, it is unclear if achievement of transfusion independence (TI) for even short periods of time is associated with improved overall survival (OS). Objectives: Evaluate the impact of intermittent transfusion dependence and independence on OS in MDS patients and compare the OS with patients persistently TD or TI. Determine the optimal TI duration or ratio that translates into improved overall survival and the impact of developing transfusion dependence or acquiring transfusion independence after diagnosis. Methods: We extracted the detailed clinical and transfusion records of patients followed since 2010 in the national MDS registry of Canada (MDS-CAN) and assigned patients into 4 categories: TI continuous (TIcont), TD continuous (TDcont), TI followed by TD (TI/TD) and TD followed by TI (TD/TI) at any time. TD was defined as receiving at least 1 unit of packed red blood cells (PRBC) within an 8-week period for a consecutive 16 weeks. The ratio of time spent TI to total follow up period was calculated for each patient. Survival was compared between groups and an ROC curve was attempted to define the optimal ratio of TI/follow-up that translated into an overall survival benefit. Results: This study evaluated 544 patients with a median follow up of 19 months (95% CI 18-22 and actuarial OS of 28 months (95% CI 24-31). 254 (46%) were TIcont, 96 (18%) TDcont, 136 (25%) TI/TD (median time to TD 7.4 months, interquartile range (IQR) 4-19) and 58 (11%) TD/TI (median time to TI 6 months (IQR 4-10) lasting a cumulative13 months (IQR 7-29). Baseline characteristics comparing these groups are in table 1. Patients TDcont and TD/TI had higher risk IPSS/IPSS-R scores, more unfavourable karyotypes, a greater degree of frailty, higher ferritin and levels of fatigue and more deficits in instrumental activities of daily living at enrollment. 57% of TI/TD patients remained TD while 43 % converted back to TI for variable lengths of time. Among the TD/TI patients, 46% remained transfusion independent (median TI duration 12 mos, IQR 6-21) while 53% converted back to TD (median TI duration 12 mos, IQR 6-29). The TI ratio was 0.7 +/-0.4 overall. The receiver operating curve could not identify a threshold ratio or duration of transfusion independence that predicted with good sensitivity and specificity overall survival. In the 304 patients with IPSS-R very low, low and intermediate risk scores, 168 (55%) were TIcont, 27 (9%) TDcont, 81(27%) were TI/TD and 28 (9%) were TD/TI. In lower risk TI/TD patients, the development of TD within the first 6, 6-12, 12-24 and >24 mos from enrollment was associated with progressively worse OS (25, 50, 45 and 86 mos respectively, p=.0025) (figure 1a). In the 58 TD/TI patients, OS did not differ if the achievement of TI occurred < 6, 6-12 or >12 mos from enrollment (p=0.3). Of all 48 TD/TI patients with an overall survival that exceeded 12 months, there were no significant differences in OS if the duration of transfusion independence lasted a minimum of 16, 24 or 48 weeks (p=0.45). The actuarial OS for the 4 transfusion categories were 39 months (TIcont), 35 months (TI/TD), 29 months (TD/TI) and 10 months (TDcont), p Conclusion: This study validates the extremely poor prognosis associated with persistent transfusion dependence. While only 38% of patients TD at diagnosis achieve transfusion independence at any point, the achievement of transfusion independence (even if intermittent) is associated with an improved overall survival that is similar to TIcont and TI/TD within the first 2 years of follow up. For patients with TD who achieved TI, we were unable to determine a TI duration or ratio that translated into a survival benefit. While the achievement of transfusion independence may simply reflect response to therapy or better disease biology, our data suggest that we should strive for the acquisition and/or maintenance of transfusion independence as it may be a surrogate for improved overall survival. The impact of achieving or losing TI on health related quality of life is being analyzed. Disclosures Buckstein: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Geddes:Alexion: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Sabloff:Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Canada: Research Funding; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Keating:Novartis: Honoraria; Seattle Genetics: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees. Leber:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leitch:Alexion: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Otsuka: Honoraria; AbbVie: Research Funding; Celgene Corporation: Honoraria, Research Funding. Yee:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding. St-Hilaire:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Finn:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Ipsen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Boehringer Ingelheim: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nevill:Paladin Labs: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Storring:Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Shamy:Amgen: Membership on an entity's Board of Directors or advisory committees; Abbie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding. Banerji:LLSC: Research Funding; Research Manitoba: Research Funding; CCMF: Research Funding; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; CIHR: Research Funding; CancerCare Manitoba/University of Manitoba: Employment; CAPhO: Honoraria; BIOGEN: Other: Licensing fee; Dana-Farber Cancer Institute: Other: Licencing fee; Janssen: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Licensing fee, Research Funding. Delage:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wells:Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Introduction: Patients with lower-risk (LR) MDS, defined as very low-, low-, and intermediate-risk by the Revised International Prognostic Scoring System (IPSS-R), have a reduced risk of progressing to acute myeloid leukemia compared with higher-risk patients, but a shortened overall survival (OS) compared with age-matched controls. MDS patients with RS have a better prognosis than those without RS, but may experience extended periods of RBC transfusion dependence. RBC transfusion dependence is associated with reduced OS in patients with LR-MDS, but studies focusing on RBC transfusion dependence and OS in RS+ MDS patients are lacking. To address this gap, data from the Canadian MDS Registry were used to assess the relationship between RBC transfusion dependence patterns and OS in this patient population. Methods: Patients with a diagnosis of RS+ MDS who were identified as transfusion dependent (TD) in the Canadian MDS Registry from 2008 to 2019 were included. Patients were considered TD if they received ≥ 1 RBC transfusion in at least one 8-week cycle. A sensitivity analysis was conducted wherein patients were considered TD if they received ≥ 1 RBC transfusion for 2 consecutive 8-week cycles. Patients were considered persistently TD (PTD) if they were TD throughout follow-up, or intermittently TD (ITD) if they were transfusion independent for periods of ≥ 8 weeks after an initial onset of TD. Covariates that were assessed included age, sex, IPSS-R risk score at enrollment, Eastern Cooperative Oncology Group performance status score at enrollment, ferritin level at first TD onset, Charlson Comorbidity Index at first TD onset, and receipt of iron chelation and anemia-treating therapies at first TD onset. Cox proportional hazards regression was used to test the association between PTD and mortality risk. Treatment patterns during follow-up were also examined. Results: Between 2008 and 2019, 191 patients had a diagnosis of RS+ MDS, of which 107 required ≥ 1 RBC transfusion over at least one 8-week cycle during follow-up. Of the 107 patients who received ≥ 1 RBC transfusion, 71 had ≥ 2 assessments for transfusion dependence and complete data on all outcomes and covariates, 36 (50.7%) of whom were classified as PTD (Table 1). Compared with ITD patients, PTD patients were older (mean age ± standard deviation [SD]: 75.11 ± 8.34 vs 69.59 ± 13.33 years) and had higher IPSS-R risk (17% of PTD patients were intermediate- or higher-risk compared with 3% of ITD patients). Median OS from first TD onset was 18.7 months (95% confidence interval [CI] 11.3-46.9) for PTD patients, compared with 48.7 months (95% CI 39.0-not evaluable) for ITD patients (Figure). After adjusting for baseline covariates, being PTD was associated with significantly greater mortality risk than being ITD (hazard ratio [HR] 2.24, 95% CI 1.18-4.25). Similar results were observed for the sensitivity analysis requiring ≥ 1 RBC transfusion for 2 consecutive 8-week cycles prior to the onset of TD (HR 2.18, 95% CI 1.13-4.21). Compared with ITD patients, PTD patients were less likely to receive iron chelation therapies (42% vs 54%), erythropoiesis-stimulating agents (25% vs 40%), and lenalidomide (14% vs 20%) during follow-up (Table 2). Conclusions: In this study, we extracted Canadian MDS Registry data on RBC transfusions and OS for MDS patients with RS+ MDS. More than half (50.7%) of the identified cohort became TD during follow-up. Among those who received RBC transfusions, PTD patients had significantly shorter OS and increased mortality risk compared with ITD patients, and RBC transfusion dependence independently predicted inferior outcomes. These conclusions are consistent with previous findings on the relationship between RBC transfusions and OS in all patients with LR-MDS. Disclosures Buckstein: Takeda: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Leber:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sabloff:Pfizer Canada:: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. Leitch:Novartis: Honoraria, Research Funding, Speakers Bureau; Otsuka: Honoraria; Alexion: Research Funding; AbbVie: Research Funding; Celgene Corporation: Honoraria, Research Funding. St. Hilaire:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Finn:Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Ipsen: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: 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, Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Banerji:Janssen: Consultancy, Honoraria, Research Funding; Research Manitoba: Research Funding; CAPhO: Honoraria; BIOGEN: Other: Licensing fee; CancerCare Manitoba/University of Manitoba: Employment; CIHR: Research Funding; Dana-Farber Cancer Institute: Other: Licencing fee; CCMF: Research Funding; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; LLSC: Research Funding; Roche: Honoraria, Licensing fee, Research Funding. Liu:Celgene Corporation: Employment. Tang:Celgene Corporation: Employment, Equity Ownership. Westcott:Celgene Corporation: Employment, Equity Ownership. Huang:Celgene Corporation: Employment. Wang:Cornerstone Research Group: Employment. Cameron:Cornerstone Research Group: Employment, Equity Ownership. Morison:Celgene Corporation: Employment. Spin:Cornerstone Research Group: Employment.

Background: Hypomethylating agents (HMAs) can confer transfusion independence and prolong overall survival (OS) in patients with myelodysplastic syndromes (MDS), but response rates are < 50% and depend on sustained administration. In Ontario, 33% of higher risk MDS patients receive < 4 cycles AZA and have very short survival. Identifying the patients unsuitable for HMAs and the factors predictive of overall survival (OS)/leukemia free survival (LFS) would be of value. MDS-CAN, the national MDS registry prospectively evaluates patient-related factors in addition to disease factors in MDS, MDS/MPN, and oligoblastic AML patients. Objective: Determine the factors predictive of OS/LFS and the completion of ≥ 4 cycles of HMA, with particular focus on frailty and comorbidity. Methods: All patients who had received HMAs (azacytidine (AZA), decitabine, guadecitabine, ASTX727) were eligible. Frailty was assessed using the Rockwood clinical frailty scale (CFS) and the frailty index (FI) comprised of 42 deficits we previously developed. The MDS-FI was calculated using baseline measurements of comorbidities, laboratory values, Lawton Brody instrumental activities of daily living (LB-IADL), quality of life (EQ-5D), and 3 physical fitness tests. Patients who had ≤ 13 missing variables on the MDS-FI were included. Kaplan-Meier (KM) OS curves were calculated from treatment start date to death or last follow up. Univariable and multivariable analysis was done to identify significant predictors of OS, LFS and the receipt of ≥ 4 cycles of HMA. Results: There were 422 patients treated with an HMA (94% AZA). FI scores could be calculated in 188 patients and CFS in 169 patients. Among the 188 patients, the median age at HMA start was 73 years old (IQR 67, 79), time from diagnosis was 10 months (IQR 2, 28), 66% of patients were high/intermediate-2 risk IPSS, and 72% were high/very high risk IPSS-R. 40% were transfusion dependent, 30% had poor/very poor cytogenetics, and 10% had oligoblastic AML. Median number of HMA cycles was 7 and 76% completed ≥ 4 cycles. The median follow up was 12 months (IQR 7, 25). 19% of patients developed AML. Actuarial median OS was 17 months (95% CI: 13-20) with 50% of deaths due to AML or progressive disease. The MDS-FI score was grouped into categories of 1, 2, and 3 (scores ≤0.2, 0.2-3, and >3, respectively), with a median score of 0.3 (IQR 0.2, 0.3). The median scores for the clinical frailty scale (CFS), Charlson comorbidity index (CCI), and MDS-specific comorbidity index (CI) were 3 (IQR 2, 4), 1 (IQR 0, 2), and 0 (IQR 0, 2) respectively. 21% of patients had cardiac comorbidity(s), 53% had ≥ 1 disability (LB-IADL), and 76% had ≥ 1 impaired symptoms or function on the EQ5D, the most common being usual activities (45%) and pain/discomfort (44%). On physical testing, 56%, 30% and 88% had partial or full deficits in grip strength, 4 meter walk and the 10x chair stand tests compared with age/sex matched reference standards. Those who completed ≥ 4 cycles of AZA compared with those that did not were more likely to be younger (73 vs 78 years old, p=0.002), have lower risk disease (IPSS-R very low/low/intermediate: 29 versus 13%, p=0.044), have lower comorbidity (MDS-CI score: 0 vs 1, p=0.006), lower frailty scores (CFS: 2 versus 3, p=0.008) and performed better on grip strength (31 vs 26 kg, p=0.021) and the 10x chair stand test (28 vs 30s, p=0.045). Predictive factors from univariate analysis are presented on Table 1. There was a trend towards receiving fewer HMA cycles if patients fell within higher FI categories (8 vs 7 vs 5 cycles, p=NS). OS declined with increasing FI categories (p=0.002, Fig 1a). In subgroup analysis by IPSS or IPSS-R score, the FI further stratified the OS of patients with IPSS high/intermediate-2 (p=0.001, Fig 1b) and IPSS-R very high/high risk groups (p=0.002, Fig 1c). The best multivariate model for OS included IPSS (p=0.001), LDH (p=0.001), and MDS-CI (p Conclusions: Frailty and comorbidity provide important prognostic information for clinical outcomes in MDS patients receiving hypomethylating agents. The evaluation of patient characteristics in addition to disease parameters should be an integral part of clinical decision-making. Disclosures Wells: Alexion: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Rockwood:Alzheimer Society of Canada: Research Funding; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Canadian consortium on neurodegeneration in aging and nutricia: Membership on an entity's Board of Directors or advisory committees; Foundation Family Fund: Research Funding; Pfizer: Research Funding; Capital Health research support: Research Funding; Sanofi: Research Funding; CIHR: Research Funding; Nova Scotia Health research foundation: Research Funding. Geddes:Celgene: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sabloff:Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Keating:Sanofi: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Novartis: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. Leber:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leitch:Celgene Corporation: Honoraria, Research Funding; Otsuka: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Alexion: Research Funding; AbbVie: Research Funding. Yee:Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding. St-Hilaire:Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Finn:Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ipsen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Storring:Novartis: Honoraria, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Nevill:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Paladin Labs: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shamy:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Banerji:Roche: Honoraria, Licensing fee, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; LLSC: Research Funding; Research Manitoba: Research Funding; CCMF: Research Funding; CancerCare Manitoba/University of Manitoba: Employment; CAPhO: Honoraria; BIOGEN: Other: Licensing fee; Dana-Farber Cancer Institute: Other: Licencing fee; Abbvie: Consultancy, Honoraria; CIHR: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria. Delage:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Buckstein:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding.

Background: Health-Related Quality of life (HRQoL) is diminished in patients with myelodysplastic syndrome (MDS). We have previously shown that HRQoL remains stable over time and low hemoglobin, transfusion dependence (TD) and age > 65 years impact QoL1. Here, we present an updated larger data set with longer follow up and consider the impact of baseline characteristics and treatments received on patient-related outcomes. Methods: MDS-CAN is a prospective database active in 15 centers across Canada, enrolling patients since April 2012. In addition to disease and patient-related characteristics, we measure HRQoL at baseline and every 6 months using the EORTC-QLQ-C30, EQ-5D, and a global fatigue scale (GFS). We examined the impact of disease related factors (IPSS, IPSS-R, karyotype, TD), patient factors (ECOG, age, gender, co-morbidity (Charlson index), frailty (Rockwood scale), disability (Lawton-Brody Independent Activities of Daily Living), and treatments received at any time (azacitidine (AZA), lenalidomide, erythropoietin-stimulating agents (ESA), iron chelation) on QoL scores. AZA-treated patients were divided into responders (where documented) or deriving benefit (if > 6 cycles) vs. non-responders. Wilcoxon rank-sum or Kruskal-Wallis nonparametric tests were used to compare scores among subgroups. Changes in QoL were assessed with a linear mixed model to account for time- dependent covariates such as TD, risk scores and treatment. Results: 594 patients were enrolled a median of 2.2 months post diagnosis (IQR: 0.8, 4.8) with a median age of 73 years , 63% male gender and performance status (ECOG) of 0-1 in 90%. IPSS scores were low/int-1 in 73% and IPSS-R scores were very low (9%), low (30%), intermediate (27%), high (20%) and very high (14% of patients). 31% were transfusion dependent at enrolment. Treatments received at any time included AZA (38%), lenalidomide (9.8%), ESA (35%) and iron chelation (12%). At a median follow up of 17 months, 329 patients (55%) died with cause of death reported as AML in 22%. Baseline assessment: Mean EQ-5D global score for the cohort was 0.75 ± 0.25 and did not significantly change over time (Figure 1). Patients with high IPSS, high/very high IPSS-R, TD, lower hemoglobin, higher ECOG, increased comorbidity, frailty and disability were more likely to have lower EQ-5D/QLQ C30 scores (inferior QoL) and higher fatigue (GFS). Age was not significantly related to QoL. Interestingly, female gender was associated with inferior QoL by EQ-5D and GFS (Figure 2). Patients scoring in the lowest quartiles for physical performance tests (grip, 4 metre walk and 10x chair sit-stand tests) also had inferior QoL scores. QoL over time: By linear mixed modelling, we did not find significant differences in QoL over time in patients treated with or without AZA, lenalidomide, or ESAs measured by the EQ-5D instrument. Iron chelation was associated with lower scores (p=0.003) although this may simply be a surrogate for transfusion dependence which is associated with inferior QoL. AZA responding/deriving benefit patients had higher QoL scores from baseline and decreased fatigue compared with those not responding or not deriving benefit (Figure 3) measured by the QLQ-C30 and GFS instruments. Patients with the highest IPSS/IPSS-R risk groups had significantly inferior QoL over time. In conclusion, this study demonstrates that HRQoL remains fairly stable over time in MDS and implementation of treatment is not at the detriment of patient related outcomes. Patients treated with AZA who respond or remain on drug for > 6 months maintain higher QoL scores over time. Disease (IPSS, IPSS-R, hemoglobin, transfusion dependence) and patient-related factors (ECOG, gender, comorbidities, disability, frailty) are associated with reduced HRQoL. The prospective assessment of QoL using a validated MDS-specific QoL instrument (QUALMS) and disease course is underway. 1 Buckstein, R., Alibhai, S.M., Lam, A., et al. The health-related quality of life of MDS patients is impaired and most predicted by transfusion dependence, hemoglobin and age. Leukemia Research. May 2011 Vol 35, Supplement 1, Pages S55-56. Disclosures Wells: Alexion Pharmaceuticals, Inc.: Honoraria, Other: Travel Support , Research Funding; Novartis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Geddes:Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zhu:Janssen: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding. Sabloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Keating:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leitch:Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; AbbVie: Research Funding. Yee:Celgene, Novartis, Otsuka: Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, GSK, Onconova, Genentech/Roche: Research Funding. St-Hilaire:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shamy:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Elemary:Roche: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Delage:Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rockwood:Pfizer: Research Funding; Lundbeck: Membership on an entity's Board of Directors or advisory committees; CHIR: Research Funding; Nova Scotia Health research foundation: Research Funding; Sanofi: Research Funding; Capital Health research support: Research Funding; Canadian consortium on neurodegeneration in aging and nutricia: Membership on an entity's Board of Directors or advisory committees; Alzheimer Society of Canada: Research Funding; Foundation Family Fund: Research Funding. Banerji:Teva: Other: Unrestricted grant received in the past; Gilead: Other: Unrestricted grant received in the past; Abbvie: Other: Unrestricted grant received in the past; Roche: Other: Unrestricted grant received in the past; Janssen: Other: Unrestricted grant received in the past. Buckstein:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background : We previously presented that selected quality of life (QOL) domains in MDS patients are impaired compared with age-matched controls and most impacted by hemoglobin (Hgb) level, transfusion dependence, frailty and comorbidity in an initial cohort of 236 patients from a Canadian MDS registry (Buckstein R. et al, Abstract 699, ASH 2012 and Abstract 2500, ASH 2009). The optimal Hgb threshold associated with improved QOL may vary according to health states that may fluctuate for any given patient. With longer follow up and greater sample size, we now examine the impact of Hgb levels on QOL in transfusion dependent (TD) versus independent (TI) patients and according to IPSS-R risk scores. Methods:Since 2008, we have prospectively assessed QOL in all patients registered in the Canadian national MDS registry using the instruments EORTC QLQ-C30, FACT-F, global fatigue scale (GFS) and EQ-5D, at enrollment and every 4-6 months. These QOL data are paired with disease specific and laboratory information at the same time intervals. Each patient could provide multiple QOL measurements at different time points. Clinically significant score differences were considered 10 points for the EORTC, 0.08 for the EQ-5D and 4 for the FACT F. General linear regression analysis was applied to search for a significant relationship between physical and social functioning, dyspnea, fatigue and QOL with Hgb, according to transfusion dependence, IPSS and IPSS-R measured categorically. To account for multiple comparisons among 5 Hgb categories, Bonferroni adjusted p-value < .01 was considered statistically significant. Results: 689 patients from 15 Canadian sites completed their first QOL assessment at a median time of 7.8 (IQR 2.7-23) months from MDS diagnosis. The median time from MDS diagnosis to death or last follow-up was 2.5 years (IQR 1.2-4.9). The median Hgb at enrollment was 100 g/L (IQR 86-113) and the distribution of risk scores included: very low (13%); low (35%); intermediate (28%); high (15%); and very high (10%). 27% of patients were TD at enrollment and 54% were TD at any time. The median number of QOL assessments per patient completed was 3 (IQR 2-6) with 547 patients completing at least 2, 424 at least 3 and 335 at least 4 serial QOL measurements at a median time interval of 17 weeks (IQR 13-25). When examined by Hgb thresholds, mean physical functioning, dyspnea, fatigue (QLQ-C30 and GFS) and global QOL improved with increasing Hgb. QOL symptom and function scores were clinically and statistically significantly superior in TI versus TD patients (table 1). The optimal discriminating Hgb threshold for improved symptom and function scores was 100 g/L for patients that were TI or with IPSS-R very low, low and intermediate risk MDS; and 90 g/L for high and very high risk disease (table 2). No discriminating threshold was found in TD patients. Conclusions: In the largest reported serial cross sectional population based assessment of QOL in MDS patients, we confirm that higher Hgb and transfusion independence have significant impact on QOL, symptoms and self-reported function and should be considered important surrogate endpoints for clinical improvement. Disclosures Buckstein: Novartis: Honoraria; Celgene: Honoraria, Research Funding. Wells:Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: advisory board; Novartis: Honoraria, Other: advisory board; Alexion: Honoraria, Other: Advisory board. Zhu:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Geddes:Celgene: Other: Advisory Board, Research Funding. Sabloff:Gilead: Research Funding; Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Lundbeck: Research Funding. Leber:BMS Canada: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Keating:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Storring:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Leitch:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. St-Hilaire:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Membership on an entity's Board of Directors or advisory committees. Nevill:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shamy:Celgene: Honoraria, Other: Advisory board; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Delage:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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: Among Chronic Lymphocytic Leukemia (CLL) patients (pts), 4-10% are diagnosed with autoimmune cytopenias (AC) at some point during the course of their disease. This is less common than cytopenias related to bone marrow infiltration (10-20%). Infiltrative cytopenias (IC) are clearly a poor prognostic factor. However, the effect of AC on survival and prognosis of CLL pts remains understudied. Objectives: To determine the prevalence of AC and IC among CLL pts and their effect on overall survival (OS) and time to first treatment (TTFT) compared to patients without cytopenia. Furthermore, the effect of different treatment modalities including chemotherapy and chemo-immunotherapy on the disease course was evaluated in patients with AC. Methods: A population-based retrospective analysis through an electronic search of pts within the Providence Health Care CLL database between 1978 and 2013 was carried out. The diagnostic criteria for autoimmune hemolytic anemia (AIHA) were positive direct antiglobulin test and laboratory evidence of hemolysis, for immune thrombocytopenia (ITP) the exclusion of other etiologies of thrombocytopenia and for pure red cell aplasia (PRCA) anemia with low reticulocyte count and bone marrow evidence of decreased erythropoiesis. Infiltrative cytopenia diagnosis was confirmed by bone marrow biopsy based on lymphocyte percentage and cellularity. Anemia was defined as hemoglobin Results: Among 754 pts with CLL, 80 (10.6%) developed cytopenias (anemia and thrombocytopenia). Of those, 50 (6.6%) had IC and 30 (4%) had AC. There was no significant difference between the 2 groups in terms of age, gender, hemoglobin, platelets, LDH, WBC and lymphocyte count at diagnosis. The time to development of cytopenias for the IC and AC groups was similar with median of 3 and 4 years (yrs) from diagnosis, respectively. Within the AC group 16 pts had AIHA, 8 had ITP, 5 had both (Evan's Syndrome) and 1 had PRCA. The median OS was 12.2 yrs (5.9–18.3) and 13 yrs (1.6-24.3) for IC and AC, respectively (p=0.260). However, when compared to CLL pts without cytopenias (median not reached), the AC group had worse OS (p< 0.005) (Fig 1). For the IC and AC groups, the median TTFT was 6.5 yrs (4.5-8.5) and 8.2 yrs (4.1–12.3), respectively (p=0.191). For the CLL pts without cytopenias TTFT was 8.1 yrs (2-12.2), similar to the AC group (p=0.88) (Fig 2). For AC pts, the OS was not significantly different based on treatment received: alkylator based therapy vs. chemo-immunotherapy (p= 0.885). The effect of concomitant hypo-gammaglobulinemia on OS and treatment outcome was studied.Of the 30 pts with AC, 26 had a serum protein electrophoresis done. Of those, 10 (38.5%) had normal results and 16 (61.5%) had low gammaglobulin levels (IgG< 6 g/L); the mean OS was 18.1 yrs and 15.7 yrs respectively (median not reached), (P=0.433). Conclusion: The prognosis of pts with autoimmune and infiltrative cytopenias was similar.However, CLL pts with AC had worse OS compared to those without cytopenias. There was no significant difference in TTFT between AC and IC or when compared to CLL pts without cytopenias. For the AC group, neither treatment with chemotherapy vs. chemo-immunotherapy nor having concomitant hypo-gammaglobulinemia had an effect on outcome. To our knowledge, there are limited population based studies addressing the importance of determining the etiology of cytopenias in CLL pts and the effect of AC on survival. CLL immune complications need to be studied further especially in the context of novel agents and their effects on immune reconstitution. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Introduction: MDS is a disease of the elderly; yet, the impact of clinical frailty (an age-related vulnerability state created by a multidimensional loss of reserves) and patient-reported outcomes on overall survival (OS) are unknown. Rockwood et al. have developed a simple 9-point clinical frailty scale (CFS) that correlated highly with the risk of death, institutionalization, worsening health and hospital use (Rockwood K., CMAJ 2005). In a prospective, national MDS registry, participants have undergone annual evaluations with the following: (a) 3 geriatric physical performance tests, (b) Charlson (CCI) and Della Porta comorbidity index (DP-CCI) scores, (c) graded frailty using the Rockwood CFS, (d) disability assessments with the Lawton Brody SIADL, and (e) QOL using the EORTC QLQ C-30 and the EQ-5D. The results of these frailty assessments and the effects of these patient-related factors and reported outcomes on OS, in addition to the IPSS/revised IPSS, will be presented. Methods: Overall survival was measured from time to enrollment. Results from physical performance tests were divided into quintiles with higher scores indicating better performance. We used univariate and multivariable Cox proportional hazard model to determine significant predictive factors of overall survival (OS). The variables considered included age, IPSS, R-IPSS, ferritin, LDH, transfusion dependence, hemoglobin (hgb), ECOG, frailty, CCI and DP-CCI, grip strength, 4 M walk test, stand-sit test, modified short physical performance battery (SPPB), Lawton Brody SIADL, time from diagnosis and selected QOL domains including the EQ-5D summary score, EORTC physical functioning, dyspnea and fatigue scores. Results: 453 MDS patients (pts) have been consented and enrolled locally since January 2008 (n=231) and nationally since January 2012 (n=222). Median time from diagnosis was 5.8 mos (IQR 1.4-21). Median age was 73 y (range, 26-95 y), 65% were male and the R-IPSS scores were very low (14%), low (46%), intermediate (24%), high (10%) and very high (6%). Thirty-three % of pts were transfusion dependent at enrollment. Median CCI and DP-CCI scores were 1 (0-12) and 0 (0-6) respectively with 18% and 24% falling into the highest category scores. Median frailty scale score (n=346) was 3 (1-9) with 25% having scores indicating moderate (4-5) or severe (6-9) frailty. The CCI and DP-CCI strongly correlated (r=0.6; p< .0001) with each other, while frailty significantly but modestly correlated with them (r=0.3-0.35, p2, p=.03) and EORTC fatigue (p=.01) as summarized in Table 1 below. A frailty score > 3 predicted for worse survival (figure 1: 2 year OS 68.5% vs. 83.8%) and further refined survival within the R-IPSS categories (Figure 2). Frailty was also the single most predictive factor for OS from the start of azacitidine therapy (not shown). Conclusions: Patient-related factors such as frailty and comorbidity (that evaluate physiologic reserve and global fitness) should be considered in addition to traditional MDS prognostic indices. Abstract 165. Table. Independent Covariate Predictive factors at baseline Coefficient SE p -value HR 95% CI of HR R2 (%) Time from diagnosis (months) * 0.0335 0.1076 0.7557 1.034 0.837 1.277 17.29% R-IPSS (5 categories) Figure 1 Overall survival by Frailty (n=346) Figure 1. Overall survival by Frailty (n=346) Figure 2 Overall Survival by Frailty and R-IPSS Figure 2. Overall Survival by Frailty and R-IPSS Disclosures Buckstein: Celgene Canada: Research Funding. Wells:Celgene: Honoraria, Other, Research Funding; Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding. Leitch:Alexion: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Educational Grant Other, Honoraria, Research Funding. Shamy:Celgene: Honoraria, Other.

Abstract 3203 Background: Patients with transfusion dependent (TD) hemoglobinopathies are at risk of endocrinopathies and bone disease due to iron overload (IOL). Vitamin D is involved in regulation of calcium homeostasis, bone health and other clinical endpoints. Vitamin D deficiency is a common manifestation of patients with transfusional IOL; the mechanism remains unclear. Vitamin D hydroxylation occurs in the liver; whether liver IOL interferes with this step has not to date been addressed. This study investigates an association between liver iron concentration (LIC) and vitamin D levels in patients with TD hemoglobinopathies. Methods: Patients with TD b thalassemia major (TM), hemoglobin Eb TM (Eβ TM), and congenital dyserythropoetic anaemia (CDA) attending the Inherited Bleeding and Red Blood Cell Disorder Program at the adult (St. Paul's Hospital) or pediatric (BC Children's Hospital) programs in Vancouver, Canada were included if they had an assessment of LIC done by magnetic resonance imaging (MRI) and 25-hydroxyvitamin D3 (25 OH D3) levels between January 2009 and the 31st of December 2011. The analysis was restricted to patients >16 years of age to minimize confounding due to body mass. Clinical data collected included: gender, ethnicity, type of iron chelation therapy (ICT) and vitamin D and calcium supplementation. Laboratory data included: serum ferritin level, 25 OH D3, phosphorus (PO4), ionized calcium (Ca2+), parathyroid hormone (PTH) and thyroid stimulating hormone (TSH). Vitamin D insufficiency was: 25 OH D3 level 7 mg/gmDW severe. Cardiac IOL was: >20 ms, normal; 14–20 ms, mild; 8–15 ms, moderate; Results: 26 patients with TD: βTM, n=21; Eβ TM, n=3; and CDA, n=2 were included, 21 adults and 5 from the pediatric program. Patients characteristics were: median age 24 (range 16–51) years and 11 (42.3%) were male. Ethnicities were: Asian, 11 (42.3%); Indian, 6 (23%); unclear ethnicity, 5 (19.2%); Middle Eastern, 3 (11.5%); and Caucasian, 1 (3.8%). The mean amount of blood received annually was 9633.9 (4677–14,508) mls/year. All patients were receiving ICT: deferasirox (DFX), 16 (61.5%); desferrioxamine (DFO), 8 (30.8%); and combination DFX+DFO, 2 (7.7%). 15 (57.7%) patients received vitamin D and calcium supplementation in variable doses and formulations. Median 25 OH D3 was 66.5 (18–125) nmol/L and vitamin D deficiency/insufficiency occurred in 15 (57.7%) patients: 5 mg/gDW, and vitamin D level Conclusion: In this single center study of patients with transfusion dependent hemoglobinopathies, we found a significant association between LIC ≥5 mg/gDW and vitamin D level Disclosures: Ezzat: Novartis: Honoraria. Leitch:Novartis: Honoraria, Speakers Bureau, participated in advisory boards Other.

Abstract 4677 Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening form of microangiopathic hemolysis that can be associated with HIV infection, and has previously been reported to be associated with low CD4 counts. The existing literature on HIV-TTP is very small and largely made up of small case series generated through databases of patients with HIV. As a result, reports have tended to focus on HIV parameters with limited information available regarding the presentation, management and outcome of the TTP itself. We conducted a retrospective review of TTP cases referred to the pheresis units St. Michael’s Hospital and Vancouver General Hospital in Vancouver between July 1993 and May 2011. Ten cases of HIV associated TTP were identified (8 male; 2 female). Median age at presentation was 38 years. One patient had been previously diagnosed and treated for TTP at a different institution. Average duration of HIV infection prior to TTP diagnosis was 5 years (range 0 to 11). Median CD4 count at TTP diagnosis was 79 × 106/ml (range 2 to 326). Median platelet count at presentation was 14 × 106/ml (range 5 to 233), median haemoglobin was 74 g/L (range 61 to 133), all patients had an LDH > 2x the upper limit of normal, and all for whom data was available (8/10) had fragmentation on blood film. Creatinine was elevated in 9 of 10 patients. ADAMTS13 was assessed in 3 of 10 patients and was deficient in one. Five of 10 patients had fever. At presentation, 6 of 10 patients had neurological symptoms (most commonly seizures and/or confusion), but none suffered permanent neurological deficits. All patients were treated with plasmapheresis and received a median of 16 exchanges (2-56). Four patients received concurrent steroids, two patients received IVIG, and one patient received pheresis, steroids IVIG, vincristine and rituximab. Eight of 10 patients achieved complete remissions, one patient achieved a partial response, and one died on treatment. Four of the responding patients subsequently relapsed (0.6 to 13.8 months after the initial episode of TTP); two achieved second remissions, and two died on treatment. In conclusion, our series of HIV associated-TTP confirms previous reports that HIV-TTP tends to occur in patients with CD4 counts less than 200. Complete remissions can be achieved with standard management. However, based on our small series, relapses may be more common and mortality greater than in the general TTP population. Disclosures: Leitch: Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Abstract 1732 Background: Several retrospective analyses suggest that transfusional iron overload portends inferior survival in lower risk MDS and that iron chelation therapy (ICT) is associated with improved survival in this group of patients. However an analysis of 126 patients with RARS from the Mayo Clinic showed no association between elevated ferritin level at diagnosis or transfusion burden on overall survival (OS). We performed a retrospective analysis of 268 MDS patients seen at our center to determine whether an association between transfusional iron overload or receiving iron chelation therapy (ICT) and survival differed between RARS and other lower risk MDS. Methods: Patients were identified from the clinical database of the hematology practice. Patients with a diagnosis (dx) of MDS confirmed by bone marrow biopsy (bmbx) were included. Clinical and laboratory data were collected by retrospective chart review. Survival analyses were performed using SPSS version 19. Results: 268 patients with a bmbx confirmed diagnosis of MDS by WHO or FAB criteria were identified. The following patients were excluded: uncertain IPSS score, n=35; intermediate-2 risk, n=33; high risk, n=16; RAEB-t, n=3; concomitant diagnosis of advanced stage non-Hodgkin lymphoma of uncertain type, n=1. The remaining 182 patients had the following characteristics: median age 69.5 (range 30–94) years and 109 (69.9%) were male. Specific MDS dx were: RA, n=27; RARS, n=53; RCMD, n=34; RAEB, n=15; MDS-U, n=22; hypocellular MDS, n=6; 5Q- syndrome, n=6; CMML, n=21. IPSS scores for all patients were: intermediate-1, n=101; low, n=74; uncertain (but IPSS score not >1.0), n=7. The marrow blast count was 6–9 x109/L in 4 patients and 1000ng/mL was not significant in this analysis (P=not significant [NS]). In a multivariate analysis (MVA), the following factors remained significant for OS: specific MDS dx; IPSS score; receiving ICT; specific MDS rx; and AML transformation (P Conclusions: These results suggest an association between receiving iron chelation therapy and survival in lower IPSS risk MDS, in keeping with prior analyses. However, the association between ICT and OS in non-RARS MDS appeared to be stronger than in RARS, in keeping with data from Mayo suggesting transfusional iron overload may not have a major association with outcome in RARS. The median follow-up in the current study was just over 2 years, and median duration of ICT only 10.5 months; longer follow-up may be needed in RARS to determine whether ICT is potentially beneficial in this subgroup of patients with a relatively long expected survival. As with all retrospective analyses, these results must be considered hypothesis generating, and prospective trials are needed for firm conclusions to be drawn. Disclosures: Leitch: Novartis Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Iron chelation agents for the treatment of transfusional iron overload in MDS. Vickars:Novartis Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 4437 This multi-center, open-label, single-arm study evaluated the safety and efficacy of nilotinib in patients with imatinib resistant/intolerant chronic myeloid leukemia (CML) in blast crisis, accelerated phase and chronic phase. This study provided expanded access to nilotinib prior to commercial availability. Methods: Patients received nilotinib orally at a dose of 400 mg twice daily. Adverse events were monitored throughout the study and assessments of cardiac, hematology and blood chemistry were performed every 3 months at a minimum. The efficacy assessments were performed every 6 months at a minimum and comprised of cytogenetic analysis of bone marrow, evaluation of extramedullary disease, and cancer related symptoms. Results: Sixty-five patients were enrolled in the study. The median age was 56 (range 21–85) years; 50.8% were male, and 89.2% Caucasian. The majority of patients (92.3%) were in chronic phase; 3.1% and 4.6% of the patients were in blast crisis and accelerated phase respectively. Twenty-five (38.5%) patients were imatinib-resistant, thirty-seven (56.9%) imatinib-intolerant and three (4.6%) both imatinib-resistant and -intolerant. The overall median duration of treatment with nilotinib was 27.2 (range 0.3 – 48.8) months. Thirty-six patients (55.4%) were still on treatment at study end. The main reasons for discontinuation were adverse events (16.9%) and unsatisfactory therapeutic effect (12.3%). Treatment related adverse events reported in at least 10% of patients, irrespective of severity, included rash (23.1%), pruritus (20%), fatigue (18.5%), muscle spasms (15.4%), headache (16.9%), alopecia (13.8%), abdominal pain (10.8%) and lipase elevation (10.8%). Grade 3 and 4 adverse events reported in at least 5% of patients, irrespective of study drug relationship, included thrombocytopenia (12.3 %), anemia (6.2%), neutropenia (6.2%) and lipase elevation (6.2%). Three patients (4.6%) discontinued due to cardiac disorders including tachycardia (1), myocardial infarction (1), and palpitations (1). Clinically significant abnormal ECG results were uncommon and mostly transient. There was no evidence of toxicity to a major organ system. One patient died within 28 days after study discontinuation due to progression of recently diagnosed multiple myeloma and chronic obstructive pulmonary disease deterioration not suspected to be related to study drug. Thirty patients received treatment for at least 30 months with nilotinib on study. At month 30, 14 (82.4%) of 17 patients who underwent a bone marrow aspirate achieved a complete cytogenetic response. Seven of these fourteen patients (50%) had never previously achieved complete cytogenetic response with imatinib. Conclusions: This phase IIIB trial provided nilotinib to 65 patients with imatinib-resistant or -intolerant chronic CML in all phases on expanded access for 44 months, allowing evaluation of its safety profile. Nilotinib treatment was reasonably well-tolerated with an overall safety profile similar to that reported in previous studies, without the occurrence of unexpected adverse events. Real-time quantitative RT-PCR of BCR-ABL mRNA levels was not a study endpoint but is used routinely in Canada to monitor patients in complete cytogenetic response instead of cytogenetic assessments which likely explains the low compliance with cytogenetic assessments in this study. Disclosures: Turner: Novartis Pharmaceuticals Canada: Research Funding, Speakers Bureau. Leber:Novartis Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hasegawa:Novartis Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Leitch:Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Bence-Bruckler:Novartis Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Sandeep:Novartis Pharmaceuticals: Honoraria. Laneuville:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Woo:Novartis Pharmaceuticals Canada Inc.: Employment. Beauparlant:Novartis Pharmaceuticals Canada Inc: Employment. Lipton:Novartis Pharmaceuticals Canada Inc: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Abstract 5280 BACKGROUND: Deferasirox is an oral iron chelator that has become available in recent years. The long term tolerability profile of deferasirox is still being evaluated, however a common side effect is skin rash, which may occur in up to 10% of patients. This is usually mild to moderate and resolves with continued treatment. More severe rash may require interruption of therapy and reintroduction of deferasirox at a lower dose followed by gradual dose escalation. A short course of corticosteroids may be used. Occasional cases of angioedema have been reported for which cessation of deferasirox is recommended but re-introduction is difficult. We report three patients with hypersensitivity to deferasirox, two manifested as NCI CTC grade 3-skin rash and one as grade 1-skin rash. All were able to tolerate deferasirox following desensitization. METHODS: Two patients with β thalassaemia major and one with congenital sideroblastic anemia, all with transfusional iron overload, experienced skin rash to deferasirox and received a desensitization protocol, given orally as follows: Solution 1 (deferasirox 1.25 mg/ml): 1 ml given days 1–3 2 ml given days 4–6 5 ml given days 7–9 Followed by Solution 2 (deferasirox 12.5 mg/ml) 1 ml given days 10–12 2 ml given days 13–15 5 ml given days 16–18 The dose of deferasirox was subsequently increased by 125 mg/day every week until the desired dose was reached. RESULTS: Case 1: A 23 year-old female with b thalassaemia major, non-compliant with deferoxamine, was switched to deferasirox 1500 mg/day (20mg/kg/day). Nine days after starting deferasirox she experienced a low grade fever, extensive erythematous maculopapular rash and facial edema. Deferasirox was discontinued. Two days later the rash had progressed; prednisone was started at 50 mg/day and the rash resolved within 1 week. While still tapering prednisone (20 mg/day), deferasirox was re-started at 500 mg/day. The rash recurred within 2 days and deferasirox was discontinued. One year later the desensitization protocol was given and well tolerated without the development of skin rash; she is currently receiving deferasirox 1500 mg/day without difficulty. Case 2: A 21 year-old female with b thalassaemia major, non-compliant with deferoxamine, was switched to deferasirox 1500mg/day (20mg/kg/day). Ten days after starting deferasirox she developed diffuse erythema multiforme. Deferasirox was stopped and prednisone started at 1mg/kg/day with marked improvement. Five days later, still on prednisone in full doses, she was re-challenged with deferasirox 500 mg/day. The rash recurred and deferasirox was discontinued. One year later, the desensitization protocol was given and well tolerated without the development of skin rash. She is currently receiving deferasirox 1500mg/day without difficulty. Case 3: A 23 year-old female with congenital sideroblastic anemia receiving deferoxamine was switched to deferasirox 1500mg/day (20mg/kg/day) for ease of administration. Eight days after starting deferasirox she developed a maculopapular rash confined to the palms of the hands and soles of the feet, but associated with severe pruritis. Deferasirox was stopped and the patient declined prednisone. She resumed deferoxamine and was offered the deferasirox desensitization protocol. Desensitization was given successfully but required a three day extension of treatment with solution 1 (2ml) because of recurrent rash, which resolved over the following two days with the temporary addition of benadryl. She is currently receiving deferasirox 150mg/day on weekly dose escalation without difficulty. CONCLUSION: Deferasirox is often the chelation agent preferred by patients given its ease of administration. Given its documented reduction in total body iron, with promising effects on the removal of myocardial iron, the use of this agent is increasing. However, skin rash is a side effect that may limit the use of deferasirox in some patients. To our knowledge, this is the first report of a protocol that may successfully desensitize patients with hypersensitivity reactions to deferasirox, allowing them to tolerate this agent in therapeutic doses. Disclosures: Leitch: Novartis Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract 2835 Background: Diffuse large B cell lymphoma (DLBCL) is associated with the human immunodeficiency virus (HIV). The optimal treatment for DLBCL in persons with HIV is uncertain. Anthracycline-based chemotherapy plus rituximab is frequently administered because this therapy has an established survival benefit in non-HIV DLBCL. However, there is controversy regarding the risks and benefits of rituximab in the setting of HIV, and practice remains varied. Due to concerns about tolerance and drug interactions, controversy also exists regarding whether highly active antiretroviral therapy (HAART) should be administered concurrent with chemotherapy. Methods: We completed a retrospective cohort study of all patients with HIV-DLBCL treated with curative-intent, at St. Paul's Hospital in British Columbia, Canada, and at St. Michael's and Sunnybrook Hospitals in Ontario, Canada. Univariate and multivariate analyses were completed to identify factors associated with improved overall survival (OS). Due to differences in provincial funding, we were able to compare patients treated with and without rituximab during the same time period. Results: Seventy-four patients were identified; 21 were treated between 1992 and 2000 (prior to the introduction of rituximab); 53 were treated between 2001 and 2009. Mean age was 45 years, 93% were male, 80% had stage 3–4 disease, 53% had an IPI (International Prognostic Index) > 2, 63% had a CD4 count < 200 and 18% had a CD4 count < 50. Median follow-up was 8.8 months (range 0.7 to 79.1). One-year OS was 53% and 32 of 35 deaths occurred in the first year. Seven deaths were due to infectious complications of chemotherapy, only one of these patients received rituximab, six had CD4 counts greater than 100, and four were receiving HAART. Because none of the patients prior to 2001 received rituximab, and because the pre-2001 cohort was very different from the post-2001 cohort with respect to CD4 counts, HAART usage and primary chemotherapy, comparative survival analyses were restricted to the post-2001 cohort (N=53). In univariate analyses, the only factor associated with improved OS in this cohort was concurrent administration of HAART (p=0.002). A Cox proportional hazards model incorporating use of rituximab, age, IPI > 2, CD4 count < 200, and concurrent HAART was constructed. As illustrated in table 1, IPI > 2, CD4 count < 200, and concurrent HAART were significantly and independently associated with overall survival. Conclusions: In this retrospective analysis, rituximab did not appear to be associated with a high toxic death rate in patients with HIV-DLBCL. However, rituximab was also not associated with significantly improved OS. Concurrent administration of HAART, higher CD4 count and lower IPI were independently associated with improved OS in patients with HIV-DLBCL. It is possible that this study was under-powered to detect a benefit of rituximab, however, we also hypothesize that previous studies reporting a benefit of rituximab in this population may have been biased by the use of historical controls. Disclosures: Leitch: Roche Canada: Honoraria.

Abstract 3897 Background: Multicentric Castleman disease (MCD) is a monotypic but non-clonal lymphoproliferation with increased incidence in HIV infection. It is characterized by human herpes virus 8 (HHV-8) infection of the lymphocytes. Signs and symptoms (sx) are largely mediated by HHV-8 induced production of IL-6. Although life expectancy in MCD appears to have improved in the era of highly active antiretroviral therapy (HAART), it remains poor, and the optimal treatment approach in patients (pts) not responding to HAART is undefined due to few large series in which to evaluate management. Contributing to poor outcome is a concomitant increased incidence of other HHV-8 related disorders such as Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL), particularly primary effusion lymphoma and plasmablastic lymphoma (PBL). We report the clinical presentation, treatment and outcome of 8 pts with HIV associated MCD diagnosed and treated at our center since 2005. Methods: Pts with HIV-associated MCD were identified from the clinical database of the hematology practice. Charts were reviewed and the following data was extracted: baseline characteristics such as prior opportunistic infections or neoplasms, HAART received and response (CD4 count, HIV viral load [VL]), clinical and laboratory features (including HHV-8 in tissues and plasma HHV-8 VL), MCD course as well as treatment and outcome. Results: Median age at onset of MCD sx was 43 (range 31–63) years (y) and all pts were male. HIV risk was men who have sex with men (MSM) in all and 1 pt had a history of KS. Seven pts were receiving HAART at MCD presentation and the median CD4 count was 385 (140-950) cells/mL and HIV VL 318 ( Conclusions: MCD can be challenging to diagnose due to its waxing and waning nature and frequently poor accessibility of tissue for biopsy. Simultaneous diagnoses such as KS, NHL, HLH and HSP further compound these difficulties. Anti-HHV-8 therapy is a potentially promising treatment for MCD and possibly other HHV-8 mediated conditions, with a long term remission achieved in OUR first pt treated with VGCV. The diagnosis and management of MCD requires a multi-disciplinary approach. To our knowledge, this is one of the largest single institution experiences with HIV-associated MCD reported. Disclosures: No relevant conflicts of interest to declare.

Abstract 2522 Background: The association between HIV and immune thrombocytopenic purpura (ITP) is well documented. Although HIV-associated ITP responds both to highly active anti-retroviral therapy (HAART) and treatments used in classic ITP, the clinical features of HIV-associated ITP were documented prior to the widespread use of HAART, and there are currently no widely accepted guidelines for the management of HIV-associated ITP. Here we describe the clinical features, treatment, and outcomes of patients diagnosed with severe HIV-associated ITP in the HAART era. Methods: We searched the BC Centre for Excellence in HIV/AIDS (CFE) database to identify patients with ≥ 1 platelet count Results: Of 8922 patients in the CFE database since 1996, 31 (0.3%) with a diagnosis of ITP and a platelet count 20 × 109/L was 13.5 (1-1379) days. Median platelet response within 30 days was 58 (5-322) × 109/L (n=26) but only 3 patients (10%) achieved a platelet count in the normal range. At a median follow-up of 48 (0.2-138) months, 27 patients (87%) required secondary ITP treatment for a recurrent platelet count Conclusions: Most patients with severe HIV-associated ITP diagnosed in the HAART era achieved a safe platelet count with primary ITP treatment and there were few treatment complications. However, nearly all required retreatment for severe ITP, including 8 of 13 patients receiving HAART with initial ITP therapy. Inferior platelet response was associated with a history of IDU, comorbidities, and hepatitis B or C coinfection, and 3 of 4 deaths occurred in patients with a history of IDU, therefore new approaches to the treatment of severe ITP in this patient population are needed. This is to our knowledge the largest series of HIV-associated ITP reported in the era of HAART. Disclosures: No relevant conflicts of interest to declare.

Abstract 4768 Background Primary effusion lymphoma (PEL) is a non-Hodgkin lymphoma (NHL) which comprises 4% of all AIDS-related lymphomas. PEL has a predilection for body cavities, causing pleural and pericardial effusions and ascites, but may present as masses. EBV is present in PEL cells in 80% of cases, but HHV-8 infection in PEL cells is required for the diagnosis (dx). Historically, treatment encompassed approaches including intracavitary antiretroviral medications (ARV) or chemotherapeutic agents, single or multi-agent systemic chemotherapy, and systemic ARVs, but median survival in case series using these approaches was only 6 months (mo). Treatment with multi-agent chemotherapy and highly active ARV therapy (HAART) yields good outcome in other HIV-NHL with survival approaching that of the HIV-negative population, but gives unknown survival rates in PEL. Recent consideration has been given to targeted therapy directed against HHV-8 infection with antiviral agents, with encouraging outcomes reported in the literature, particularly the HHV-8 associated syndromes Kaposi Sarcoma (KS) and Multicentric Castleman's Disease. We report on 5 patients (pts) diagnosed with PEL and treated at St. Paul's Hospital, 2 of whom are receiving valganciclovir (VGCV) therapy directed against HHV-8 infection of PEL cells. Methods We conducted a retrospective review of pts with a tissue dx of PEL since 2004. PEL data was collected from the clinical charts and HIV-related data from the BC Centre for Excellence in HIV/AIDS (CFE) database. A literature search was performed to capture prior studies of anti-HHV-8 medications used to treat PEL. Results The median age at PEL diagnosis was 60 (range 48-68) years (y); gender was: male, n=4; and female, n=1. 2 pts had a history of KS. The median CD4 count at PEL dx was 230 (50-560) cells/ml, 1 pt had a CD4 count of 50 cells/ml and all others were ≥210 cells/ml; median HIV viral load (VL; reported in 4) was 81 (35-176,600) copies/ml. The median time from HIV dx to PEL dx was 6 (0-21) y and from initiation of HAART to PEL dx 1 (0-11) y. Clinical PEL presentation was: pleural effusions, n=4; pericardial effusion, n=2; ascites, n=1; associated mass, n=1; mass without effusions, n=1. PEL treatment was: CHOP + HAART, n=2; CHOP + HAART + VGCV, n=1; HAART + VGCF, n=1; supportive care, n=1. 2 pts receiving CHOP and HAART are both in complete remission (CR) at 8 and 57 months (mo) from PEL dx. 2 pts diagnosed since December 2008 are receiving VGCV and HAART, and 1 of these pts is receiving CHOP with good tolerance (the other pt declined cytotoxic chemotherapy). Of 3 pts receiving CHOP, there was 1 episode of febrile neutropenia (FN) in 1 pt and 5 episodes of FN and 3 clinical infections in a second pt. The same pt had profound anemia and thrombocytopenia requiring transfusion support; this pt did not receive VGCV. 1 pt receiving VGCV with HAART and CHOP required G-CSF support but did not develop FN or clinical infection. 1 pt presented with a poor performance status, received supportive care only and died within one mo of PEL dx; all others are alive at 4, 8, 14 and 57 months from PEL dx. A literature review identified 2 reports of pts with PEL receiving systemic cidofovir (CDFV) directed against HHV-8. One pt with a CD4 count of 72 cells/ml and an HIV-VL of 75,000 copies/ml received unspecified systemic chemotherapy, HAART and intravenous (IV) CDFV followed by VGCV and is in CR at 68 mo from PEL dx. A second pt with a CD4 of 498 cells/ml (HIV-VL not reported) received HAART, IV cidofovir and interferon and is in CR at 28 mo. Conclusions PEL treatment has focused on optimization of HIV control with HAART and lymphoma control with chemotherapy, however, antiviral medications as targeted therapy directed against HHV-8 infection of PEL cells may be used without undue toxicity and possibly with success. PEL generally involves latent HHV-8 infection, which is theoretically not susceptible to antiviral medications, but there are reports in the literature of encouraging results achieved by combining agents to induce lytic infection (including chemotherapeutic agents) with anti-herpes virus therapy. Our review indicates good tolerance of VGCV with HAART ± CHOP chemotherapy, and that with newer treatment approaches, pts may live longer than the 6 mo median survival previously reported. To our knowledge, our pts receiving VGCV are the third and fourth pts reported receiving anti-HHV-8 therapy as treatment for PEL. Disclosures: Off Label Use This presentation discusses the use of valganciclovir in the treatment of HHV-8 associated primary effusion lymphoma..

Hodgkin lymphoma (HL) occurs in HIV-infected individuals more frequently than in the HIV-negative population and the incidence is rising. Patients (pts) with non-Hodgkin’s lymphoma in HIV appear to have improved outcomes if they receive HAART with chemotherapy (CT). ABVD is standard CT for HL and is frequently administered with HAART in pts with HIV-HL. However, some components of the ABVD regimen may interact with antiretroviral (ARV) medications to alter metabolism and increase toxicity. In particular, vinblastine (VBL) is metabolized by CYP3A4 and protease inhibitors, particularly ritonavir (RTV), appear to inhibit this cytochrome potentially leading to higher VBL exposure. Little definitive information is available regarding how interactions might affect clinical outcome. We conducted a retrospective review of 36 pts with HIV-related HL to identify the frequency of neurotoxicity (NT), hematologic toxicity (HT), and lung toxicity (LT), to identify risk factors for severe (grade III–IV) toxicity, and to determine its clinical significance. Clinical data were collected from the CFE database and by chart review from 3 centers. The median age at HL diagnosis (dx) was 41 (range 29–66) years and 34 (94%) were male. HL was advanced stage in 28 (78%). Hasenclever score could be calculated in 23 pts and was 0–4 and ≥5 in 15 and 8 pts respectively. ECOG PS was 0–1 in 13 and ≥2 in 8 (n=21). HIV risk factor was: sexual, n=21 and other, n=5 (n=26). Median CD4 count at HL dx was 210 (2–660) cells/ul (n=31). Median HIV viral load (VL) was undetectable (500,000) copies/ml (n=25). Hepatitis B and C coinfection was present in 8 and 7 pts respectively (n=29). Prior AIDS was present in 23, all opportunistic infections. Twenty-four pts received HAART with CT. Primary HL CT was: ABVD, n=29 (81%); MOPP/ABV, n=4 (11%); palliative, n=3 (8%). G-CSF was used in 22 pts. All pts received prophylaxis for PCP and 3 for HSV/VZV. HAART included 17 Arts in numerous combinations. Infectious complications were: bacterial infection, n=6; febrile neutropenia, n=4; HSV, n=3; PCP, n=1. HT occurred in 21 (75%) of 28 assessable pts and was grade 3–4 in 18 (64%; 18 and 15 were on HAART, respectively). NT occurred in 14 (50%) pts and was grade 3–4 in 6 (21%; 13 and 5 on HAART respectively, n=28). Of 6 cases of severe NT, 3 were autonomic neuropathy with pseudobowel obstruction that in 1 pt resulted in perforation. Bleomycin LT occurred in 3 pts (n=26). CT dose reduction (DR) of ≥25% in ≥1 agent was required in 9 pts (n=26). Factors associated with grade 3–4 HT were: receiving RTV, p=0.04, HR 2.9 (95% CI 1.1–7.4); and receiving lopinovir (LPV), p=0.02, HR 7.0 (2.3–21.3) and for any HT were: RTV, p=0.004, HR 3.1 (1.3–7.3); emtricitabine, p=0.01, HR 4.8 (1.4–11.6); and LPV, p=0.04, HR 4.4 (1.6–12.1). Factors for grade 3–4 NT were: LPV, p=0.05, HR 10.8 (2.0–59.5) and for any NT was: RTV, p=0.01, HR 4.0 (1.3–12.1). Fourteen pts received RTV and of 8 receiving LPV, 7 received LPV with RTV (p=0.007). At a median follow-up of 15.3 (0.1–154.8) months (mo) 25 pts (69%) are alive. The median overall survival (OS) for all pts was 44.5 (2–154.8) mo and there was no difference in OS by baseline features or the occurrence of HT or NT. However, CT dose reduction was associated with inferior OS (p=0.04, HR 3.9 [1.0–15.7]); although only 1 of 9 deaths was from HL progression; others were: infectious, n=6; and unrelated, n=2. In conclusion, pts with HIV-HL appear to experience a significantly increased incidence of NT compared to rates reported in non-HIV HL pts. In contrast, rates of HT and LT appear to be similar to those in non-HIV HL. The use of RTV or LPV during CT appeared to be associated with an increased risk of NT, suggesting a clinically significant interaction between these ARV agents and CT, particularly VBL. Prospective studies to devise a rational dosing strategy using measurements of ARV and/or CT levels are warranted.

The prognostic significance of CD38 expression and the cut off value has not been fully investigated. As CD38 is readily available test in patients with chronic lymphocytic leukemia (CLL), we investigated its role in prediction of disease progression when a cut off value of 20% is used. Progression free survival (PFS) was defined as the time from diagnosis to first treatment or last follow up. An electronic database search of pts with CLL who presented at St Paul’s Hospital between 1969 and 2007 was performed. Among 465 pts with CLL, 161 pts (35%) had their CD38 expression measured by flow cytometry. CD38 expression and its association with other prognostic factors such as age, Rai stage, lymphocyte count at diagnosis, gender and other immunophenotypic makers were analyzed. Out of 161 pts, positive CD38 expression (>20%) was found in 36 patients (22%). Comparing the baseline characteristics of the CLL pts with CD38+ and negative disease, we found CD38 positivity more common in male pts than in female pts (p=0.03). Also patients with CD38 positive disease tend to present with more advanced stage disease (p=0.056). Progression free survival at 2, 5 and 10y for the CD38+ CLL pts was 89%, 61% and 41% respectively compared with 95%, 81% and 62% for the CD38 negative group (p=0.03). Univariate analysis revealed the following factors as significant or marginally significant for disease progression: CD38+ (p=0.03), male gender (p=0.07), Rai stage (p Table: Characteristics of patients with CLL based on CD38 ≥20% and Parameter CD38 ≥20% (%) CD38 Fig: Progression free survival for patients with CLL based on CD38 expression, cut off level 20%. Fig:. Progression free survival for patients with CLL based on CD38 expression, cut off level 20%.

There is limited access to advanced molecular and immunophenotypic techniques such as immunoglobulin heavy chain variable mutational status and ZAP-70 expression analysis in many parts of the world. To facilitate the development of a clinical model based on readily available clinical and well-standardized pathological data, we analyzed the well known prognostic factors in chronic lymphocytic leukemia (CLL) and proposed a scoring system. We searched the CLL database and among 465 patients (pts) we included 128 pts where the staging, blood counts, immunophenotypic and follow up data are complete. The baseline characteristics of this group and the significance of the proposed factors on the progression-free survival on univariate analysis are summarized in the table. Progression–free survival (PFS) was defined as the time from diagnosis to the time where treatment for CLL is indicated and if no treatment id indicated, the time of last follow up. In this 5 point scoring system we added one point for the presence of each one of the following factors: male gender, Rai stage 1 or more, lymphocyte count of 20 ×109/l or higher, lymphocyte doubling time less than 12 m, CD 38 expression of 20% or more. We further lumped these groups into 3 groups: no risk factors, one risk factor and tow or more risk factors. Thirty eight patients (30%) were found to have no risk factors and their 5 and 10 year PFS was 100% and 100% respectively. Forty nine pts (38%) have at least one risk factor and their 5 and 10 y PFS was 92% and 81% respectively. Forty pts (31%) have two or more risk factors and their 5 and 10 y PFS was 48% and 20% respectively. Those differences in PFS were significant (p Table: Risk factors for disease progression Parameter N (%) 5-y PFS 10-y PFS p value (UVA)* *Univariate analysis Sex: Male 71 (56) 67% 43% 0.01 Female 56 (44) 91% 73% Rai stage: 0 103 (80) 87% 77% Fig: Progression free survival based on the number of risk factors for disease progression (p

Patients (pts) with PMF and iron overload (IOL) may receive iron chelation therapy (ICT), although there are no data demonstrating that this improves clinical outcome. Red blood cell (RBC) transfusion dependent (TD) pts with thalassemia receiving ICT have improved survival and decreased end-organ toxicities and RBC-TD pts with myelodysplastic syndrome (MDS) receiving ICT have improved survival. We performed a review of 41 pts seen from January 1987 to April 2007 with a bone marrow biopsy confirmed diagnosis (Dx) of PMF. Clinical data were collected from the practice database, the Provincial Home Hemosiderosis Program of British Columbia database, and by chart review. Pts receiving ICT were treated with desferrioxamine (DFO) 0.5–3g by subcutaneous infusion over 12 hours, 35 days per week or with deferasirox (DFX) 20mg/kg/day orally, dose adjusted to response and pt tolerance. 29 were male and 12 female. Median age at PMF Dx was 64 (43–86) years (y) and 24 pts were >60y. White blood cell (WBC) count at Dx was 30x109/L in 8, hemoglobin (Hgb) 1x109/L in 7. Karyotype analysis was: normal, n=16; del(6)(q25), n=1; tri(14), str12p, n=1; complex, n=1. Lille, Strasser and Mayo prognostic scores were: low risk, n=15, 8, 11; intermediate, n=15, 19, 9; high, n=5, 11, 5 respectively. Primary PMF treatment was: supportive care, n=23; hydroxyurea, n=10; immunomodulatory, n=4; splenectomy, n=2. Clinical evidence of IOL was documented in 21 pts; number of RBC units (NRBCU) received, n=18; ferritin >2000ug/l, n=6 (and ferritin >1000ug/l, n=1); CHF, n=5; liver disease, n=3; endocrine, n=3. 16 pts were RBC transfusion–independent (TI) and 25 were TD; of these 10 received ICT. Median duration of ICT was 18.3 (0.1–117) months (mo) and reasons for initiating ICT were: NRBCU received, n=9; elevated ferritin, n=6; clinical evidence of IOL, n=3. Five pts received DFO, 4 DFX, and 1 DFO followed by DFX. In ICT pts, initial/Pre-ICT ferritin levels were significantly higher than in TD-NO ICT pts at a median of 2318 (range 263–8400) and 527 (120–934) mg/L respectively (p=0.05) and decreased significantly in TD-ICT pts at most recent follow-up to 1571 (1005–3211) mg/L (p=0.01). Causes of death were: TI patients, no deaths; TD-NO ICT patients, 11 deaths (73%): probably PMF-related, n=9; progression to PMF-blast phase (BP), n=3; sepsis, n=3; cardiac, n=2; bleeding, n=1, unknown, n=2 ; TD-ICT patients, 2 deaths (20%); PMF-BP, n=1; bleeding, n=1. Kaplan- Meier analysis showed a median overall survival (OS) for all pts of 126.5 (14.4–293.2) mo. In a univariate analysis of TD pts, factors significant for OS (and 5y OS) were: WBC count at Dx (4.0–30x109/L, 69%; 30x109/L, 0%; p=0.002); monocyte count at Dx (1.0x109/L, 0%; p=0.0001); Mayo prognostic score (low, 67%; intermediate, 50%; high, 0%; p=0.05); NRBCU transfused (50U, 12%; p=0.02) and receiving ICT (ICT, 89%; NO-ICT, 34%; p=0.003). In Cox regression analysis of TD pts, factors significant for OS were: NRBCU (p=0.001) and ICT (p=0.0001). For TI, TD-NO ICT and TD-ICT pts respectively the median OS was not reached (NR) at 200 mo, 58 mo and NR at 293 mo respectively (p=0.01 for TD-NO ICT vs TI and NS for TD-ICT vs. TI). The hazard ratio (HR) for pts receiving >20 RBCU was increased at 7.6 (95% CI 1.2–49.3) and the HR for pts receiving ICT was improved at 0.15 (0.03–0.77). In conclusion, 61% of PMF pts developed RBC-TD and had inferior OS, however TD pts receiving ICT had superior OS compared to TD pts not receiving ICT and the OS of TD-ICT pts was comparable to the OS of TI patients, suggesting a benefit to ICT. These are to our knowledge the first data documenting improved clinical outcome in pts with PMF receiving ICT. Prospective studies of IOL and the impact of ICT in pts with PMF are warranted.

Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL). There is little information in the literature about its risk and outcome. In this study we assessed the incidence, presenting characteristics and outcomes of patients (pts) with CLL who developed RT. An electronic database search of pts with CLL who presented at St Paul’s Hospital between 1969 and 2007 was performed. Among 465 pts with CLL, 24 pts (5%) developed RT. Presenting features included B-symptoms (17%), lymph node enlargement (58%), progressive cytopenia (29%), hypercalcemia (4%), and spleno/hematomegaly (13%). The median age at diagnosis of CLL and RT were 64 y (range 33–80 y) and 67 y (range 48–81 y) respectively. The median time to transformation from CLL diagnosis was 61 months (range 1–257 m). Twenty one patients (88%) had been previously treated for CLL. Seventeen patients (71%) had received >1 prior therapy. The median lymphocyte count at diagnosis was 12 ×109/L (range 4–120 ×109/L). Six patients (25%) are still alive with a median follow up of 38 m (range: 3–66 m). The only predictive factor for better survival post-transformation on univariate analysis was age of less than 60 y at CLL diagnosis (p=0.01). Other factors such as CLL Rai stage, lymphocyte count at diagnosis were not predictive for survival. This group of patients was compared with randomly selected group of patients with CLL but did not have RT. The baseline characteristics of the groups are presented in the table. No significant differences were found between the two groups in terms of gender, age at diagnosis, Rai stage or median lymphocyte count at diagnosis. The 5 and 10 year OS for the RT group were 76% and 39% compared to 93% and 84% for the CLL group (p= 0.002), respectively. In summary, RT significantly shortens the survival of CLL patients. There were no obvious predictive factors for RT in CLL pts at diagnosis. Table: Baseline characteristics of Richter and CLL groups. | Parameter | Richter group (%) | CLL group (%) | P value | |:--------------------------------------------:| ------------------- | --------------------- | ------- | | Number | 24 | 37 | | | Sex: M/F (ratio) | 16/8 (2:1) | 22/15 (1.5:1) | 0.052 | | Age at Diagnosis: Median (range) | 64 (33–80) | 60 (37–85) | 0.6 | | Rai stage at diagnosis: 0, 1+2, 3+4 | 7, 16,1 (29, 67, 4) | 23, 14, 0 (62, 38, 0) | 0.3 | | Median lymphocyte count at diagnosis (range) | 12 ×109/1 (4–120) | 8 × 109/1 (5–394) | 0.056 | ![Fig: ][1] Fig: OS of pts with RT compared with CLL pts and no RT [1]: pending:yes

Primary myelofibrosis (PMF) is a myeloproliferative disorder characterized by progressive bone marrow failure, extramedullary hematopoiesis and risk of progression to blast phase (BP). Many PMF patients (pts) require red blood cell (RBC) transfusions, risking iron overload (IOL)-related organ dysfunction. Pts with myelodysplastic syndrome and RBC transfusion dependence (TD) have worse overall survival (OS), which may be improved by iron chelation therapy (ICT). To assess the effect of TD and ICT on survival in PMF, we reviewed 30 pts seen from 1985 to 2007 with a marrow biopsy confirmed diagnosis. 21 pts were male and 9 female and median age at Dx was 66.5 (range 43–84) years (y). ECOG Performance Status; 0, n=13; 1, n=9; 2, n=7; 3, n=1. WBC count was 30x109/L at diagnosis in 5 pts, and hemoglobin (Hb) 50, n=11. Initial PMF treatment was: supportive care, n=21; low-dose chemotherapy, n=4; immunomodulatory, n=3; splenectomy, n=2. Clinical evidence of IOL, n=14 total: CHF, n=4; liver disease, n=3; endocrine, n=3; ferritin ≥1000 ug/L at Dx, n=6. Baseline features that differed between transfusion-independent (TI) and TD and between non-ICT-TD and ICT pts: total RBCU transfused (p=0.0001 and p=0.03) and evidence of IOL (p=0.003 and p=0.06), respectively. 5 pts received ICT for a median of 75.7 (range 2.9–117) months (mo); 4 received desferrioxamine (DFO) 0.5–3g by subcutaneous infusion 12 h/d, 5 d/wk and 2 received deferasirox (1 switched from DFO). At a median follow-up (FU) of 58.8 (0.1–243.7) mo, 2 non-ICT pts and 1 ICT pt progressed to PMF-BP; 2 received chemotherapy and all 3 died of progressive BP within weeks. Median OS for all pts, TI, TD and ICT pts was: 102.1 (14.4–243.7) mo; not reached at 204.9 mo; 60.8 (14.4–243.7) mo and 83.6 (60.8–202.9) mo and 5y OS was 67%; 100%; 55% and 66% respectively (p=0.014 for TD vs. TI). Factors significant for OS were: RBC-TD (p=0.014, hazard ratio [HR] 43.6, confidence intervals [CI] 41–46.2); increasing RBC transfusion requirement (TR; 2 fold change in RBCU/4wk; p=0.018, HR 5.0 [4.3–5.7]); Hb

Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis and risk of progression to acute myeloid leukemia (AML). Many MDS patients (pts) require red blood cell (RBC) transfusions, risking iron overload (IOL)-related organ dysfunction. We previously showed in a multivariate analysis of 178 pts, improved survival in 18 pts with low and int-1 IPSS risk MDS and IOL receiving iron chelation therapy (ICT), and now examine the effect of ICT on AML-free survival (LFS). The effect of ICT on cytopenias and RBC transfusion requirements (TR); was also examined. To control for possible bias favoring ICT pts, a subgroup analysis was performed. Each of 18 ICT pts had a non-ICT control pt (CP) selected and these groups are matched for gender; neutrophil count (NC), platelet count (PLTC) and hemoglobin (Hb) at diagnosis (Dx); MDS subtype; no of cytopenias, karyotype; IPSS score; ECOG Performance Status; no of serious infections; initial ferritin level (FL); total RBC units (U) received; primary MDS treatment (Rx); and duration of follow-up (FU; all p=NS). Median age in ICT pts was 64 (range 32–70) years (y) vs. 78 (39–81)y for CP (p=0.04). Features of the 178 pts are previously reported. In a univariate analysis (n=178), factors significant for LFS were: MDS subtype; IPSS risk; increased FL; total RBCU transfused; ≥1 serious infection; and receipt of ICT (all p

Background: We previously reported that 20 patients with newly diagnosed, stage III/IV mantle cell lymphoma (MCL) treated prospectively with an in vivo rituximab purge, autologous stem-cell transplantation (ASCT) and rituximab maintenance experienced superior progression free survival (PFS) compared to 40 matched, historical controls treated with conventional chemotherapy. We now report extended follow-up from this trial. Methods: Eligible patients were treated with 4–6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) followed by high dose therapy (cyclophosphamide, carmustine and etoposide) and ASCT. Rituximab (375 mg/m2) was given once 5 days prior to stem cell collection (as an in vivo purge), and as two, 4-week maintenance courses 8 and 24 weeks after ASCT. Historical control patients matched for age, stage and gender were randomly selected from a lymphoma database maintained by the British Columbia Cancer Agency. Two control-patients were selected for every trial patient. All control patients were treated with either an anthracycline based-regimen, or a regimen containing fludarabine and cyclophosphamide. Results: Median follow-up is 5.3 years for the experimental cohort and 10.1 years for the control cohort. In the ASCT cohort, 8 patients have relapsed and 4 patients have died, 2 of progressive disease, 1 of a presumed cardiac event 7 months post-ASCT, and one of hepatitis B reactivation 11 months post-ASCT. Five-year OS and 5-year PFS were superior in MCL patients treated with ASCT+ rituximab compared to matched, historical MCL patients treated with conventional chemotherapy (5y OS 80% vs. 38%, P=0.0017; 5y PFS 72% vs. 19%, P=0.0001). One patient developed myelodysplastic syndrome 5.5 years after ASCT, and one patient was diagnosed with breast cancer 4.8 years after ASCT. Conclusions: With more than 5 years of follow-up MCL patients treated with ASCT plus rituximab continue to experience significantly improved OS and PFS compared to matched, historical controls. Overall Survival Overall Survival

The treatment of ARL is complicated by the numerous immuno-chemotherapy, antiretroviral, and prophylactic options available to lymphoma specialists. The optimal management in the era of combination antiretroviral therapy (cART) is unclear. We administered a survey instrument to determine physician preferences and perceptions in the management of ARL and to assess the variability in treatment in Canada. The survey was developed with items grouped into key domains of ARL management (physician demographics, attitudes, and treatment preferences) and piloted for content validity and clarity. The final questionnaire was administered to lymphoma physicians with valid contact information in the provinces of Ontario (ON; n=155) and British Columbia (BC; n=48). The Dillman Tailored Design Method was followed for multi-modality (internet and standard mail) survey administration. Of 196 physicians, 131 either responded by completing the questionnaire (n=117; 60% response rate) or declining to participate (n=14; 7%). Most responders were male (63%), white (70%), practicing in an academic setting (63%), and belonged to a median age group range of 41–50 years. The majority (98%) had a positive attitude towards the treatment of ARL, as measured by a previously validated 2-item attitude scale. However, barriers to adequate care were still identified; 84% of physicians agreed that uncontrolled human immunodeficiency virus infection represented a major barrier to ARL care and 54% agreed that a patient’s concurrent intravenous drug abuse impaired care. Most physicians recommended the concomitant use of cART in the care of their patients with ARL (n=72 of 109 responses; 66%). Similarly, a majority of respondents recommended CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine, and prednisone; n=92 of 108 responses; 85%) to form the backbone of chemotherapy. The addition of the rituximab was preferred by 41% physicians but not by 40% others, with remaining respondents unsure of the agent’s role. In logistic regression analysis, use of rituximab was predicted only by location of practice (province), after adjusting for other potential predictors including physician age, race, gender, practice environment (academic vs. community), years of experience, ARL patient volume, and modality of survey response. Physicians from BC were much more likely to administer rituximab than ON practitioners (OR 44.5; 95% CI: 7.76–255.0, p

Aberrant expression of the cell surface marker CD30 in systemic B-cell HIV-related NHL other than anaplastic large cell lymphoma (ALCL) has been reported. CD30 is a member of the tumor necrosis factor (TNF) family of receptors, and activation of CD30 mediates cell cycle regulation in preclinical models. The outcome of AIDS-related lymphoma (ARL) patients (pts) has improved dramatically in recent years with good control of HIV infection and the ability to intensify chemotherapy appropriate to the lymphoma. To determine whether CD30+ systemic ARL might have different clinical outcome and require a tailored approach to therapy, we performed a retrospective clinical-pathological correlation in pts seen at St. Paul’s Hospital in Vancouver, Canada (SPH) and focused on 39 B-cell lymphoma (BCL) pts since 1992. Clinical and HIV-related data were abstracted by chart review and from the CFE data-base. Stored biopsy material diagnostic of BCL was sectioned and stained for CD30 expression by immunohistochemistry. Median age was 41 (range 20–64) years and 37 pts were male. 16 pts had diffuse large B-cell lymphoma (DLBCL), 17 other B-cell NHL excluding ALCL, and 6 Hodgkin’s Lymphoma (HL); 29 were advanced stage. HIV risk was sexual in 31 and injection drug use (IDU) in 8. Median CD4 at diagnosis was 140 (10–770) cells/ul and 20 pts received HAART. Lymphoma therapy was administered according to era and histology: CHOP-like ± Rituximab (R) n=28; ABVD-like n= 6; CODOX-M/IVAC-R n=1; HAART alone n=1; resection n=1; declined therapy n= 2. 8 pts received added R and 4 added radiation therapy. 20 were CD30+ and 19 CD30−; the only baseline characteristic that differed significantly according to CD30 status was histology p

Patients (pts) with MDS and iron overload often receive iron chelation therapy (ICT), although there are no data demonstrating that this improves clinical outcome. Pts with thalassemia receiving ICT do have improved survival and a decrease in number of end-organ toxicities. We performed a retrospective review of 178 pts seen at St.Paul’s Hospital in Vancouver, Canada, from January 1981 to April 2006, with a bone marrow diagnosis (Dx) of MDS. Clinical data were collected from the practice database, the Iron Chelation Program of British Columbia database, and by chart review. Pts receiving ICT were treated with desferroxamine 0.5–3g by subcutaneous infusion over 12 hours, 5 days per week. 105 were male and 73 female. MDS Dx were: RA, n=36; RARS, n=42; RAEB, n=28; RAEB-t or AML, n=16, CMMoL, n=25; other, n=31. Age at Dx was a median of 69 (18–94) years. Median absolute neutrophil count (ANC) was 1.6 (33–155) G/l, hemoglobin (Hgb) 96.5 (33–155) G/l, and platelet count 115 (7–644) G/l. Cytogenetic analysis was available in 128 pts; low risk (as defined by the IPSS), n=85; intermediate, n=22; high, n=21. Calculation of IPSS score was feasible in 133 pts; low risk, n=44; int-1, n=55; int-2, n=17; high, n=17. An elevated ferritin level, defined as a serum ferritin of ≥ 2000 ug/ml, was found in 28 pts. Clinical evidence of iron overload was present in 22 pts; CHF with no other contributing factor n=5; liver disease n=18; endocrine dysfunction, n=4; other, n=4; biopsy or imaging evidence was available in 6 pts. Of 18 pts receiving ICT, median duration of ICT was 15 (0–37) months (mo) and reasons for initiating ICT were: elevated ferritin, n=13; clinical and biochemical evidence of iron overload, n=3; number of transfusions received, n=2. In ICT pts, median ferritin level pre-ICT was 4215 (1500–8400) and post-ICT was 2659 (567–5228). In non-ICT pts with elevated ferritin, median ferritin after Dx was 1647 (265–5009) ug/L and at recent follow up was 3188 (763–12723) ug/L. There was a trend toward higher initial ferritin level in ICT pts (p

EBV infection of B-lymphocytes is known to promote cell proliferation and survival. In contrast to NHL in HIV-negative patients (pts), in whom ≤5% are EBV-positive (EBV+), up to 50% are EBV+ in systemic HIV-related NHL. Highly active antiretroviral therapy (HAART) has improved the outcome of AIDS-related lymphoma (ARL) pts and allows intensification of lymphoma therapy. To determine whether EBV+ systemic ARL might behave more aggressively and require intensification of therapy, we performed a retrospective clinical-pathological correlation in pts seen at St. Paul’s Hospital in Vancouver, Canada, and focused on 39 B-cell lymphoma (BCL) since 1992. Clinical and HIV-related data were abstracted by chart review and from the CFE data-base. Stored biopsy material diagnostic of BCL was sectioned and stained for EBV by EBER. Median age was 40 (range 20–64) years and 37 pts were male. 16 pts had diffuse large B-cell lymphoma (DLBCL), 17 other B-cell NHL and 6 Hodgkin’s Lymphoma (HL); 29 were advanced stage. HIV risk was sexual in 25 and injection drug use (IDU) in 14. Median CD4 count at diagnosis was 140 (10–770) cells/ul and 23 pts received HAART. Lymphoma therapy was administered according to era and histology: CHOP-like ± Rituximab (R) n=28; ABVD-like n=6; CODOX-M/IVAC-R n=1; HAART alone n=1; resection n=1; declined therapy n=2. 9 pts received added R and 3 added radiation therapy. 11 received therapy directed against other herpes viruses (HVT) at some point in ARL treatment. 25 were EBV+ and 14 EBV−; no baseline HIV or lymphoma related characteristics differed significantly according to EBV status nor did receipt of HVT. In a Kaplan-Meier analysis, EBV expression was significant for overall survival (OS); median survival (MS) for pts with EBV+ ARL was 38 (2.5–74.3) months (mo) vs. 6.1 (0–18.5) mo for EBV− (p

Prognostic factors to predict an aggressive clinical course in chronic lymphocytic leukemia (CLL) such as CD38, ZAP-70 and IgH mutation status have been well described, however, readily available presenting features predictive of long-term stability are less well defined. We performed a retrospective analysis of 335 consecutive patients with CLL seen at St. Paul’s Hospital from January 1969 to July 2005. Patients were identified from the practice data-base and clinical and pathological data abstracted by chart review. Long-term stability was defined as no requirement for treatment for at least 6 years (n=66, group A). Characteristics of group A were compared to all other pts (group B, n=269), and, to avoid follow-up bias, to pts followed for ≥6 y who required treatment (group C, n=62). 65 pts in group A were B-cell in phenotype and 1 was T-cell; group B 268 pts B-cell, 1 T-cell; group C all 62 B-cell. Median age at diagnosis for groups A, B and C were 59.5 (range 33–80) y; 68 (30–94) y; and 60 (30–82) y, respectively (p Characteristic OS @ 120 mo (%) Lymphocyte count at Dx (X109/L) Group A (stable ≥ 72 mo, n=66) Group B (all others, n=269) Group C (not stable, ≥72 f/u mo, n=62) All pts 93 64 64 ≤10 100 100 100 >10 91 64 64 ≤20 93 38 38 >20 0 of 2 0 of 5 0 of 5 p (log rank) A vs. B p In conclusion, in this series of 335 patients with CLL, lower lymphocyte count at diagnosis predicted for long-term stability, decreased requirement for treatment and improved OS.

Monoclonal Lymphocytosis of Undetermined Significance (MLUS) is a clonal lymphoproliferation, usually of B-cells. MLUS has the immunophenotype of Chronic Lymphocytic Leukemia (CLL) but an absolute lymphocyte count of 10 X 109/L or less and no lymphadenopathy, organomegaly, cytopenias, or symptoms attributable to the lymphoproliferation. There is little published information as to whether the clinical course of MLUS differs significantly from that of CLL. We performed a retrospective analysis of 335 consecutive patients with clonal lymphocytosis seen at St. Paul’s Hospital diagnosed between January 1969 and July 2005. Patients were identified by a search of the practice database and clinical and pathological data were abstracted by chart review. MLUS was present in 106 patients and CLL in 229. All MLUS were of B-cell phenotype and 227 patients had B-CLL. Median age at diagnosis was 64.5 (range 33–86) y for MLUS and 65 (30–94) y for CLL (p50 X 109/L) occurred in 14% of MLUS and 11% of CLL (p Characteristic OS at 10 years (%) P (log-rank) MLUS CLL Age ≤65 68 81 0.07 >65 59 45 0.59 Gender M 38 68 0.47 F 100 76 0.02 LDT ≤12 mo 47 74 0.10 >12 mo 80 47 0.93 CD38 negative 90 73 0.60 (positive ≥ 30% of cells) 3 of 3 0 of 2 0.32 Transformation events n=1 n=15 0.025 In conclusion, in this series of 335 patients with clonal lymphoproliferation, MLUS pts had significantly better OS than did pts with CLL, a difference which was seen in female MLUS pts in particular. Significantly fewer MLUS pts required treatment over their course than did pts with CLL. In CLL pts, there appeared to be an increased rate of transformation to aggressive non-Hodgkin's lymphoma or PLL.

Acute leukemia, especially acute myeloid leukemia (AML), occurs more frequently in the elderly population. Treatment outcomes for this condition have traditionally been poor and very few patients survive for prolonged periods following diagnosis. We performed a retrospective chart review of all patients sixty years of age and older diagnosed with acute leukemia at St. Paul’s hospital, Vancouver, Canada, from June 1984 to July 2004. One hundred and three patients were diagnosed with acute leukemia [AML- 81; ALL- 15; ALN (acute leukemia not otherwise specified)- 7]. The median age was 72 (range 60–88) years. Fifty-seven (55%) and 46 (45%) patients had de novo and secondary leukemia, respectively. Sixteen patients (28%) had an unfavourable karyotype. Fifty-three patients (51%) received induction chemotherapy (treated) and 50 (49%) were provided with supportive care only (untreated). Treated patients were younger [67 years (60–79)] than untreated patients [76 years (61–88)], (p/= 80 years were treated (n=17). Of the treated patients, 33 (62%) achieved a complete remission (CR), 10 (19%) had resistant disease and 10 (19%) died from complications related to treatment. The median overall survival for the entire group was 103 (1–1229) days, and for treated versus untreated patients was 216 (1–1213) and 38 (2–1229) days, respectively (p=0.0021). The disease free survival in treated patients achieving a CR (n=33) was 262 days (9–722). Less than 5% of patients were alive at 4 years from diagnosis. Univariate variables predictive of prolonged survival included receiving induction chemotherapy (p=0.0027), de novo as opposed to secondary leukemia (p=0.0420), and younger age, with a relative increase in death in older subgroups (60–69, 70–79, 80+), (p=0.0311). Induction chemotherapy was the only independent predictor of prolonged survival in multivariate analysis (p=0.0027). There was no statistically significant difference in the number of treated patients and treatment outcomes between 1984–1993 and 1994–2004. In conclusion, this single-institution series of 103 patients aged sixty years and older with acute leukemia, shows that the prognosis of this disease in older patients is extremely poor. Even though induction chemotherapy seems to prolong survival in patients who are fit to receive treatment, the prognosis remains grim and most patients ultimately die of leukemia, supporting a role for investigational regimens focusing solely on this age group. It is no longer appropriate to follow regimens that have remained largely unsuccessful and unchanged over 20 years.

BCL-2 expression in diffuse large B cell lymphoma (DLBCL) in HIV-negative patients (pts) is associated with inferior outcome, an effect at least partially overcome by the addition of rituximab (R) to multi-agent chemotherapy (MA-CT). The effect of BCL-2 expression on DLBCL outcome in HIV-positive pts is less well defined. We performed a retrospective clinical-pathological correlation in 141 pts with systemic HIV-associated lymphoma seen at St. Paul’s Hospital between 1982 and 2004; this analysis includes 36 DLBCL since 1992. Clinical DLBCL data were obtained by chart review; HIV-associated data from the data-base of the BC Centre For Excellence in HIV/AIDS. Stored biopsy material diagnostic of DLBCL was sectioned and stained for BCL-2 expression. Median age at DLBCL diagnosis (dx) was 42 (range 20–64)y, DLBCL stage advanced 27; ECOG PS >1 n=11; median LDH ratio 1.4 (0.5–8.6); IPI >2 n=11; CD4 at DLBCL dx >100 n=21; prior AIDS dx n=18; hepatitis B and/or C n=9; on highly active anti-retroviral therapy (HAART) at DLBCL dx n=11; BCL-2+ n=11. HAART with DLBCL treatment (tx) n=17; received CHOP-R n=9, CHOP or ACOP n=18; G-CSF n=10; herpes virus tx n=10; PCP prophylaxis n=35. Significant factors for inferior overall survival (OS) included prior AIDS, median OS (MS) 3.2 vs. 7.4 mo with no AIDS; no HAART use, MS 2.6 vs. 5.2 mo with HAART; BCL-2+, MS 3.2 vs. 5.2 mo for BCL-2 negative; and receiving MA-CT without R, MS 3.8 vs. 7.6 mo for MA-CT + R (p