Older age has been shown to adversely impact overall survival (OS) in chronic lymphocytic leukemia (CLL) however, prior population-based studies did not analyze the impact of cytogenetic abnormalities or were prior to the availability of ibrutinib. Objectives: i) We sought to compare outcomes of patients based on their age at treatment to examine if older age has an impact on OS in patients who were treated during the period when fludarabine-rituximab was the standard upfront therapy and when ibrutinib was first introduced and ii) compare outcomes based on whether the patient received primary treatment at an academic or community-based centre. Methods: The BC Provincial CLL Database, a population-based databasewas used to include patients who have received treatment in British Columbia (BC), Canada between 2004 and 2016. Results: A total of 1122 patients were included (<70 years at treatment, n = 589) with median age at diagnosis 66 years. Younger patients had higher Rai stage (55% vs. 44% stage I-II, p < 0.001), higher lymphocyte count at diagnosis (13 ? 109/L vs. 10 ? 109/L, p = 0.004), greater proportion with B-symptoms at diagnosis (15% vs 10%, p = 0.004), shorter time from diagnosis to treatment (13.9 months vs. 21.4 months, p = 0.001), higher proportion treated at an academic centre (79% vs. 69%, p < 0.001) and more were treated with fludarabinerituximab or FCR (69% vs. 42%, p < 0.001) compared to older patients. Older patients had both a significantly (p < 0.001) shorter OS from treatment start (4.7 years) and disease specific survival (8.1 years) than younger patients (median OS and DSS not reached). Of interest, there was no difference in OS between patients treated at an academic centre or community centre (p = 0.087). First-line treatment with chemoimmunotherapy improved OS (HR 0.465, 95% CI: 0.381?.567).

We performed a retrospective study comparing treatment patterns and overall survival (OS) in chronic lymphocytic leukemia (CLL) patients with the advent of ibrutinib to provide current real-world data. METHODS:Using a provincial population-based database, we analyzed CLL patients who received upfront treatment in British Columbia before ibrutinib availability (1984-2014), during ibrutinib access for: relapse only (2014-2015) and for upfront treatment of patients (with 17p deletion or unfit for chemotherapy) (2015-2016). Analysis included up to third-line treatment. RESULTS:Of 1729 patients meeting inclusion criteria (median age, 66 years; 1466, period 1; 140, period 2; 123, period 3), FR was the most common first-line therapy (35.8 %, 54.3 % and 40.7 %, periods 1-3, respectively) and 18.7 % received ibrutinib upfront in period 3. The most common therapies in relapse were chemoimmunotherapy (36.1 % and 55.6 %, periods 1 and 2, second-line; 29.2 %, period 1, third-line) and ibrutinib (69.8 %, period 3, second-line; 46.4 % and 70.3 %, periods 2 and 3, third-line). OS improved for patients treated in periods 2-3 over period 1 (median OS not reached vs. 11.9 years, p < 0.001; no difference in OS for periods 2-3, p = 0.385). CONCLUSION:Ibrutinib has replaced chemoimmunotherapy as the preferred therapy in relapse. Overall survival has improved over time with access to ibrutinib.

This study evaluates outcomes in chronic lymphocytic leukemia (CLL) based on first-line therapy in a large consecutive population-based cohort of 669 patients with fluorescence in-situ hybridization (FISH) data in British Columbia, Canada during the period when chemoimmunotherapy was standard first-line treatment. When analyzed as a time-dependent variable, patients who required treatment (n=336) had a 4.7 times higher hazard of death than patients who did not (95% confidence interval 2.8–7.9, P<0.001). The majority of patients received fludarabine-rituximab (FR) in front-line. On multivariate Cox regression analysis, fludarabine-based first-line therapy predicted longer time-to-next-treatment (TTNT) (HR 0.53, 95% confidence interval 0.33–0.87, P=0.012) but no difference in overall survival (OS) compared to alkylator-based therapy. Deletion 17p was an independent predictor of worse TTNT and OS. The most common second-line treatments were cyclophosphamide-vincristine-prednisone-rituximab and FR. There was no difference in OS between patients retreated in second-line with the same first-line regimen (n=33) versus different regimen (n=113). In conclusion, front-line treatment with fludarabine leads to a longer time until need for next treatment than alkylator-based therapy; however, fludarabine or alkylator therapy produces no difference in OS. This study provides a historical baseline for the comparison of novel agents with standard treatments in CLL on a population-level.

Chemoimmunotherapy with rituximab improves survival in clinical trials in upfront chronic lymphocytic leukemia (CLL) treatment. This study compared clinical outcomes with and without rituximab added to first-line chemotherapy in a provincial cohort of CLL patients. Between 1973 and 2014, 1345 patients received CLL treatment: 48% with rituximab, 52% chemotherapy alone. Median overall survival (OS) and treatment-free survival (TFS) were significantly longer with rituximab: OS 8.9 vs. 6.2 years, p<.0001; TFS 3.6 vs. 2.1 years, p<.0001. Addition of rituximab to chemotherapy was a strong independent predictor of mortality with a 32% mortality reduction after controlling for co-variates (age, sex, stage, and treatment with purine analogs). This large population-based study complements clinical trial and registry data demonstrating the benefit of adding rituximab to first-line CLL therapy and adds further evidence of the efficacy of rituximab-based chemoimmunotherapy in a real-world setting.

This study evaluates prognostic markers as predictors of clonal evolution (CE) and assesses the impact of CE on overall survival (OS) in a population-based cohort of 159 consecutive eligible patients with chronic lymphocytic leukemia (CLL) obtained from the British Columbia Provincial CLL Database. CE was detected by interphase fluorescence in situ hybridization (FISH) in 34/ 159 patients (21%) with 65% of CE patients acquiring deletion 17p or 11q. CD38 positive status (>= 30%) on flow cytometry predicted 2.7 times increased risk of high-risk CE (acquisition of deletion 17p or 11q) on multivariate analysis. Prior CLL therapy was not a significant predictor of CE. CE was associated with 4.1 times greater risk of death when analyzed as a time-dependent variable for OS after adjusting for age, lymphocyte count, and FISH timing. High-risk CE was associated with worse OS while acquisition of low/intermediate-risk abnormalities (trisomy 12, deletion 13q, and IGH translocation) had no difference in OS. Our study demonstrates the negative impact of CE detected by FISH on OS in this population-based cohort. These data provide support for repeating FISH testing during CLL follow-up as patients with high-risk CE have reduced survival and may require closer observation.

Background: Clinical trials report that chemoimmunotherapy with rituximab (R) improves overall survival (OS) and progression-free survival in the treatment (tx) of symptomatic CLL patients (pts). R has been available for first-line CLL tx in BC, population 4.5 million, since 2004. We compared clinical outcomes with and without addition of R to chemotherapy in a large unselected provincial cohort of pts treated for CLL, to determine the "real world" effectiveness of addition of R to standard chemotherapy.

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.

Detection of recurrent chromosome abnormalities by fluorescence in situ hybridization (FISH) is an essential component of care in chronic lymphocytic leukemia (CLL) patients. In the province of British Columbia (BC), Canada, population 4.6 million, CLL patients receive uniform evaluation and therapy with FISH testing performed in three jurisdictions. The aims of this study were to (i) validate CLL-FISH testing among the BC cytogenetic laboratories to ensure standardization of results and (ii) characterize population-level CLL-FISH abnormalities by pooling provincial data. From 2004 to 2011, 585 consecutive patients underwent pretreatment CLL-FISH testing at laboratory A (50.1%), laboratory B (32.3%), or laboratory C (17.6%). For validation purposes, 26 CLL-FISH abnormalities were tested by each laboratory's protocol, with 91% result concordance. Discordant results involved percent abnormalities at or near cutoff values; therefore, a 10% universal cutoff was established when pooling results. Applying the universal cutoff to the provincial cohort, CLL-FISH abnormalities were detected in 74.9%: 54.9% 13q-, 18.8% +12, 8.5% 11q-, and 7.7% 17p-. In this large population-based cohort of patients referred for CLL-FISH testing, frequencies of abnormalities detected by FISH analysis were highly consistent with those reported in single-institution and clinical trial populations. Provinces or districts that work together to care for CLL patients can effectively pool data with appropriate laboratory validation to ensure standardization of results.

The incidence of chronic lymphocytic leukemia (CLL) in the Asian population is up to 10 times lower than that in Caucasians. Studies on CLL in Asian residents in North America may help to determine the relative genetic and environmental causes of such a difference. Computerized records of CLL incidence from the combined British Columbia (BC) databases (n = 2736) and the Hong Kong Cancer Registry (HKCR, n = 572) were traced. Ethnic Chinese cases of CLL in BC were identified (n = 35). The world age standardized rates (WASRs) of CLL (per 100 000) were calculated in BC (1.71), HK (0.28) and BC Chinese (0.4), respectively. Using standard incidence ratios (SIRs), the observed BC Chinese case number was comparable to the figure projected from HK rates (SIR 1.3, p = 0.1) but significantly lower than the figure following BC rates (SIR 0.22, p < 0.0001). The difference was maintained over both genders, in all age groups and through the years. Our data over three decades suggest that genetic factors outplay environmental factors to give lower CLL rates in Chinese.

Abstract Abstract 1401 Introduction: CLL has been considered a genetically stable disease; however, recent evidence suggests that clonal evolution (CE) occurs at a higher rate than previously known. The clinical significance of CE in terms of CLL progression, requirement for and response to therapy (tx), overall (OS) and treatment-free survival (TFS) is not clear. The relationship between CE and tx and to the pathophysiology of CLL is also currently unknown. There is a need for improved understanding of CE in CLL and its possible impact on prognosis, tx, and outcomes. We performed a population-based analysis of all patients (pts) referred for CLL fluorescence in situ hybridization (FISH) testing in BC, Canada who had 32 FISH studies done to determine the incidence of CE and its association with clinical outcomes. Methods: FISH testing has been standard of care for CLL pts in BC since 2004 and includes minimally evaluation of 4 prognostically significant recurrent cytogenetic (CG) abnormalities (abn): deletion 13q (13q-), deletion 11q (11q-), trisomy 12 (+12) and 17p- as well as IGH abn in a pt subset. Complete clinical and pathological data has been systematically retrospectively collected on all pts who have had CLL FISH testing performed. We included all pts who had 32 sequential CLL FISH tests 33 months apart from 2004-Dec 2011. Primary endpoints were (a) incidence of CE and (b) overall survival. Results: Of 861 pts screened, 134 met inclusion criteria. 21 pts (16%) had CE with median (med) age 57 yrs (range 45–80) at dx and 63 yrs (49–83) at time CE detected; 16 (77%) were male; Rai stage was low in 7 pts (33%), int in 11 (52%) and high in 3 (14%). At med follow-up of 7 yrs (1–37), 19/21 (91%) of CE pts and 99/113 (88%) non-CE pts received tx. Tx included nucleoside analog (NA) in 3 (14%) vs 23 (20%) pts, NA + rituximab (R) in 8 (38%) vs 53 (47%) pts, chlorambucil in 5 (24%) vs 14 (12%) pts and cyclophosphamide based in 3 (14%) vs 8 (7%) pts in the CE and non-CE groups respectively. 9 (43%) CE vs 36 (32%) non-CE pts underwent stem cell transplant (HSCT). 2 untx pts developed CE. CG abns detected on initial FISH test, classified by Dohner hierarchy were: 13q- (32%), +12 (22%), 17p- (12%), 11q- (11%), none of the 4 abns (23%). A total of 28 abns defining CE were detected in the 21pts and the most common were: 11q- (10 pts, 48%), 13q (10 pts, 47%). Predictors of CE on univariate analysis included lymphocyte count at dx (OR 1.01 per increase in lymphs by 1 ×109/L, 95% CI 1.00–1.02, p=0.048) and presence of 13q- at 1st FISH testing (OR 0.4, 95% CI 0.14–0.98, p=0.047); however these were not predictive of CE on multivariate analysis (MVA) after controlling for covariates (p=0.13 and p=0.19 respectively). No other baseline characteristics were predictive for CE including gender (p=0.31), age (p=0.38), WBC at dx (p=0.07), and CD38 positivity (p=0.56). OS was markedly reduced in pts who developed CE compared to those who did not: HR 5.9, median OS 8.2 yrs vs not reached, p=<0.001 (Fig 1). On MVA, CE retained its negative effect with HR 6.3 (95% CI 2.2–17.6), p<0.001, after adjusting for sex, age, Rai stage and baseline CG abn. Conclusion: CE is more common than previously recognized and carries a poor prognosis. In this study pts with CE fared worse than those with 17p-. OS of pts with CE in this cohort is in keeping with the med OS for 11q- and 17p- reported in the literature, indicating that presence of CE signifies a new poor prognostic indicator. These observations should prompt FISH testing in all pts at diagnosis and relevant time points in follow-up, such as with change in clinical behaviour and prior to new tx. Furthermore, as CE was thought to be tx related, the fact that 2 untx pts developed CE is a novel finding and provides further evidence of the clinical importance of CE in CLL. It is unclear whether CE pts should be considered for more aggressive tx, including HSCT. Results of our study provide a better understanding of the relationship of CE and disease progression in CLL, allowing for improved pt management and tx of this clinically heterogeneous and incurable disease. Disclosures: No relevant conflicts of interest to declare.

Retrospective analyses suggest iron overload is associated with inferior survival (OS) in lower risk MDS and iron chelation therapy (ICT) with improvement. However, an analysis of RARS patients found no such association. We analyzed subtypes of lower risk MDS. Median OS for non-RARS without and with ICT was 44 months and not reached (P<0.001), and for RARS 99 and 134.4 months (P=NS); in red blood cell (RBC) transfusion dependent RARS patients not receiving ICT, median OS was 73.8 months (P=0.025). These results suggest a stronger association between ICT and OS in non-RARS MDS than in RARS, with significantly superior OS in transfusion dependent patients receiving ICT.

Abstract Abstract 3897 Background: Important advances in the understanding of CLL pathogenesis include the discovery that NOTCH1 mutations are present in ∼28% of pts harboring +12. There is a need for improved understanding of the clinical outcomes of CLL patients (pts) with +12 on a population-level, as this subgroup is rapidly becoming the focus of biologic studies evaluating pathogenesis of disease and clinical trials investigating novel targeted therapies. In the province of BC, population 4.5 million, CLL pts receive uniform evaluation and therapy based on centrally derived protocols with FISH testing implemented since 2004. We sought to characterize the clinical outcomes of +12 in this large unselected population-based cohort of CLL pts. Methods: Clinical and laboratory data on all pts referred for CLL FISH testing at 1 of 3 BC cytogenetic labs from 2004–2011 were entered into the BC Provincial CLL Database and included in this analysis. Pts without a confirmed diagnostic date were excluded. Baseline features of pts with and without +12 were compared using Fisher's exact test for categorical and Wilcoxon rank sum test for continuous (cnts) variables. Primary and secondary endpoints were OS and TFS (defined as time from diagnosis [dx] to first therapy). Percent of abnormal (%abn) nuclei harboring +12 was evaluated for association with OS/TFS. Cox proportional hazard (PH) models were constructed to determine predictors of OS/TFS for the +12 cohort, including age at dx, sex, Rai stage (0, 1–2, 3–4), WBC at dx, CD38 positivity and concomitant 17p-, 11q- or deletion 13q (13q-). Cox PH models were also constructed to determine effect of +12 on TFS/OS for the entire cohort. Results: As of Dec. 2011, 882 pts had CLL FISH testing in BC of which 164 (19%) had +12 on their 1st FISH test: 8 (5%) with concomitant 17p-; 14 (9%) with 11q-; 142 (86%) without either 17p- or 11q-, of which 43 (30%) had 13q-; 16/124 tested (13%) had an IGH translocation [t(IGH)]. Of the 164 +12 pts, median age at dx was 60 yrs (range 35–93), 70% were male, 10% had Rai stage 3–4. At median follow-up of 4.5 yrs (range 0–19), 95 pts (59%) received treatment, 31 (19%) died. For the +12 cohort, median OS was 14.7 yrs (95% CI 9.8–19.0) and median TFS 3.7 yrs (95% CI 2.7–5.4). Of the 658 non +12 CLL pts (N12CPs), prevalence of recurrent cytogenetic abnormalities (RCA) were: 17p-, 10%; 11q-, 11%; 13q-, 60%; t(IGH) 7%. Significant differences between +12 and N12CPs included more CD38+ pts (66% vs 28%, P<0.001), higher t(IGH) incidence (13% vs 7%, P=0.04) and fewer 17p- (5% vs 10%, P=0.03) or 13q- (26% vs 60%, P<0.001) abn among +12 pts. When pts were grouped by hierarchical FISH abn, +12 pts retained an intermediate OS (median 15.9 yrs) and TFS (median 4.2 yrs) when compared to other RCAs (Fig 1A). Multivariate analysis (MVA) for the whole cohort (n=822) demonstrated no significant effect of +12 on OS (HR 0.72, 95% CI 0.36–1.43, P=.35) or TFS (HR 0.86, 95% CI 0.69–1.36, P=.86) after adjustment for covariates. For the +12 cohort (n=162), univariate analysis demonstrated shorter OS associated with age (P=.001), Rai stage (P=.01) and 17p- (P=.07). A longer OS was associated with presence of 13q- (median OS 11.6 vs 18.7 yrs, P=.04), Fig 1B. Shorter TFS was associated with Rai stage (P Conclusion: We report the largest, population-based cohort of CLL pts with FISH testing and confirm that +12 occurs in 19% of CLL pts and in the absence of 17p- or 11q-, confers an intermediate prognosis. The presence of 13q- had a protective effect on TFS and a trend towards improved OS, thus improving the prognosis of a subset of +12 pts. This finding is consistent with recent observations that NOTCH1 mutations and 13q- are mutually exclusive in +12 pts and may explain the clinical heterogeneity seen in this subgroup. Further research into these distinct subsets of +12 pts is warranted. Disclosures: No relevant conflicts of interest to declare.

Clinical trials report that fludarabine and rituximab (FR) as initial therapy for chronic lymphocytic leukemia (CLL) improves progression-free and overall survival (OS) when compared historically to fludarabine alone. To determine whether similar results are achievable with oral FR in a community-based setting, we conducted a population-based analysis of patients treated for CLL or small lymphocytic lymphoma (SLL) in British Columbia, where FR is standard initial therapy. Ninety-eight patients received FR for CLL/SLL from 2004 to 2009. Two- and 4-year OS was 90% and 73%, respectively (median not reached); 2- and 4-year treatment-free survival (TFS) was 69% and 54% (median 4.0 years). Age ≥ 60 years or ≥ 70 years had no effect on OS or TFS. Toxicity led to treatment discontinuation in 13%. FR with oral fludarabine was safely, conveniently and successfully given to community-based patients, irrespective of age, for first-line therapy for CLL/SLL, achieving OS and TFS similar to those in clinical trials.

Immunoglobulin heavy chain translocations (t(IGH@)) are suggested to portend a poor prognosis in chronic lymphocytic leukemia (CLL). To determine the clinical significance of a t(IGH@) on CLL-specific cytogenetic abnormalities, we analyzed the outcomes of 142 CLL patients referred for fluorescence in situ hybridization (FISH) analysis with our standard FISH panel, which includes testing for a t(IGH@). Whereas patients with unfavorable (deletion 17p, deletion 11q) and intermediate (trisomy 12, normal FISH) cytogenetics with concomitant t(IGH@) had similar median treatment-free survival (TFS) as those without a t(IGH@), patients with deletion 13q (del13q) and a t(IGH@) had significantly worse TFS than those without a t(IGH@): median TFS 4.7 versus 8.0 years, P = 0.03 (hazard ratio 4.21, 95% confidence interval 1.06-16.69 y, P = 0.04 in multivariate analysis after adjusting for age, sex, Rai stage, and white blood cell count). The presence of a t(IGH@) further stratified patients with del13q into two prognostic entities, whereby outcomes of those with coexistent del13q and a t(IGH@) were similar to outcomes of those with high risk cytogenetics. Knowledge of the t(IGH@) status in CLL is therefore of clinical importance, as del13q patients with concomitant t(IGH@) may not retain the previously expected favorable outcome.

Abstract 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 <5 x109/L in all others. Specific MDS treatment (rx) was: supportive care, n=82; erythropoiesis stimulating agents (ESA), n=22; immunosuppressive therapy (IST), n=10; lenalidomide, n=7; and chemotherapy, n=6. 137 patients received RBC transfusions and 38 received ICT: deferasirox (DFX), n=19; deferoxamine (DFO), n=9; DFO followed by DFX, n=9; and DFX followed by DFO, n=1. The median duration of ICT was 10.5 (range 0.5–64) months. Clinical features significantly associated with OS in univariate analyses of all 182 patients included: specific MDS dx; IPSS score; total number of red blood cell (RBC) units transfused over the course of follow-up; receiving ICT; specific MDS rx received; requirement for hospitalization; experiencing at least one episode of infection; and AML transformation (P=0.01 for all); serum ferritin level >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=0.01 for all). In an MVA stratified for RARS, significant were: specific MDS dx (P<0.0001); IPSS score (P=0.005); specific MDS rx (P=0.038) and receiving ICT (P=0.039). At a median follow-up of 28 (0.1–245.9) months, 121 patients were alive (non-RARS, n=83 [64.3%]; RARS, n=38 [71.6%]) and the projected median OS for all patient was 99 months. The projected median OS for non-RARS patients without ICT and with ICT was 44 months and not reached (NR), respectively, and for RARS without and with ICT was 99 and 134.4 months (P<0.0001). The 5 year OS in these four groups was 39.2% and 91.7% (P=0.04); and 72.4% and 76.3%, respectively (P=NS). However, when RARS ICT patients were compared to only RBC transfusion dependent RARS patients not receiving ICT, the median OS was 73.8 vs 134.4 months, respectively, and 5 year OS was 59.9% and 76.3%, respectively (P=0.025). 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.

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 <4 or >30x109/L in 8, hemoglobin (Hgb) <100 G/L in 5, platelet count <100x109/L in 5, monocyte count >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%; <4.0 or >30x109/L, 0%; p=0.002); monocyte count at Dx (<1.0x109/L, 74%; >1.0x109/L, 0%; p=0.0001); Mayo prognostic score (low, 67%; intermediate, 50%; high, 0%; p=0.05); NRBCU transfused (<20U, 30%; 21–50U, 27%; >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.

Abstract Abstract 2363 Poster Board II-340 Background: Clinical trials report that FR as initial therapy in symptomatic CLL produces an overall response rate of 90% and significantly improves progression-free survival (PFS) and overall survival (OS) compared retrospectively to F alone [Byrd Blood 2003, 2005] and that FCR (F, cyclophosphamide and R) improves response rates and PFS compared to FC alone [Hallek ASH 2008]. FR has been the standard initial therapy for CLL/SLL in British Columbia (BC) (population = 4.2 × 106) since 2004. We wished to determine if, in an unselected community based population, the same results could be achieved with FR therapy as those seen in highly selected clinical trial populations. Patients and Methods: The BC Cancer Agency (BCCA) Lymphoid Cancer Database was searched to identify pts who received FR as initial therapy for CLL/SLL as per BCCA guidelines (F 40mg/m2/day orally D1-5 or 25mg/m2/day IV D1-5 [adjusted for renal function] and R 375mg/m2 IV D1, q 28 days for 4-8 cycles). Pts were excluded if they had more than one hematologic malignancy (n=2). OS was calculated from date of FR to date of death or last follow-up. Treatment-free survival (TFS) was calculated from date of FR to date of next treatment or death from toxicity. Factors present at initiation of treatment were analyzed for impact on outcomes. Results: 98 pts were identified who received FR from 2004-2009 as initial therapy for CLL (83%) or SLL (17%). Median age at FR was 62 y (range, 42 – 86 y). 36% had Rai stage 3 or 4 and 13% had ECOG performance status 2-3. Median lymphocyte count was 30 × 109/L (range 0.6-282 × 109/L) and LDH was elevated in 34% (29/86 with available levels). Nearly half of all pts tested were positive for CD38 (34 of 69 pts, 49%) and ZAP 70 expression (10 of 22 pts, 45%). FISH was performed in 35 pts: 13q deletion, 21 (60%); 11q deletion, 5 (14%); 17p deletion, 10 (29%); trisomy 12, 11 (31%). Most pts (65%) were observed prior to FR for a median of 28 months (range, 3 – 172 mos). Common indications for treatment included symptomatic lymphadenopathy (n=36), cytopenias (n=28), fatigue (n=23), and constitutional symptoms (n=19). Pts underwent a median of 6 cycles of FR (range, 1-8). Treatment was discontinued due to toxicity in 13 pts (13%) (cytopenias, 5; febrile neutropenia, 3; infection, 2; pulmonary disease, 1; ITP, 1; AIHA, 1) and due to progression in 4 pts (4%). Hospitalization during therapy was required in 13 pts (13%) (febrile neutropenia, 5; documented infection, 2; elective splenectomy, 2; pulmonary disease, 2; ITP, 1; rituximab administration, 1). At a median follow up of living pts of 2.4 y, 31 pts (32%) have received additional therapy after FR including CVP in 11 pts (+R, 8); chlorambucil, 7 (+ R, 1; +prednisone, 1); FR, 5; cyclophosphamide, 5 (+prednisone, 3; +vincristine, 1); CHOP, 3 (+R, 2). At time of analysis (June 2009), 86 pts were alive; 14 died, 12 from progressive CLL and 2 from toxicity of FR (severe infection, 1; interstitial lung disease, 1). For the entire 98 pts, the 2 and 4 y OS were 90% and 72%, respectively (median not reached); 2 and 4 y TFS were 69% and 54%, respectively (median 4.0 y). Factors at treatment contributing to OS in univariate analysis included elevated LDH (P=0.004), Hb <110 g/L (P=0.03), and the presence of deletion 17p by FISH (P=0.04) or CD38 expression (>15% of CD19+ cells) by immunophenotyping (P=0.04). TFS was significantly worse in those with Hb <110 g/L (P=0.003), Rai stage 3-4 (P=0.008) or lymphocyte count >150 × 109/L (P=0.0013) while cytogenetic abnormalities and immunophenotyping had no effect on TFS. Age ≥ 60 y (n=60) or age ≥ 70 y (n=26) had no effect on either OS or TFS. Conclusions: In this non-selected community based population of pts with CLL/SLL, including many over 60 y (61%) and 70 y (27%) of age, our results show that initial treatment with FR leads to excellent OS and TFS, consistent with clinical trial results: 2 y OS, this study 90%; FR Byrd [Blood 2005] 93%; FCR Hallek [ASH 2008] 91%; 2 y TFS, this study 69%; FR Byrd, 2 y PFS 67%; FCR Hallek 2 y PFS 77%. FR can be safely and successfully given to community based pts, irrespective of age, for first-line therapy for CLL/SLL with OS and TFS similar to that achieved in clinical trial settings. Disclosures: Connors: Roche Canada: Research Funding.

Rituximab is the first monoclonal antibody to be approved as a cancer therapeutic following the publication of the McLaughlin et al., study data in 1998 [1]. Since then rituximab has been increasin...

7085 Background: The discovery of the JAK2 V617F mutation in over 95% of polycythemia vera (PV) patients has led to the development of the new 2008 World Health Organization diagnostic criteria for PV. These specify a requirement for an elevated hemoglobin (Hb, males: >185 g/L, females: >165 g/L) and either evidence of JAK2-mutant cells plus any one of the following minor criteria: a below normal level of serum erythropoietin (Epo), detectable Epo-independent erythroid colony (EEC) formation in vitro, or panmyelosis in the bone marrow, or two of the latter in the absence of detectable JAK2-mutant cells. However, in patients with an elevated Hb and JAK2V617F positivity, there are few data to determine whether any of the 3 minor criteria actually add an independent contribution to the diagnosis of PV. Methods: We performed a retrospective chart review of 77 patients who had an elevated Hb and were positive for the JAK2 V617F mutation and who also had a test for at least one of the 3 minor criteria (serum Epo level: n = 53; EEC formation: n = 66; bone marrow examination: n = 16) to determine the frequency of cases who might lack one or more of these. Results: Although the number of patients with a complete set of data was limited, the results, nevertheless, were sufficient to show that all 3 minor criteria were highly represented and all 77 of the patients analyzed (100%) were positive for at least one of them; i.e., 47 of 53 tested (89%) had a reduced serum Epo level; 65 of 66 tested (98%) had EECs and 15 of 16 tested (94%) had evidence of bone marrow panmyelosis. Conclusions: Neither the Epo level, nor the presence of EECs nor evidence of bone marrow panmyelosis provided additional diagnostic specificity in a population of 77 patients with both JAK2 V617F-positive cells and an elevated Hb. Consideration should be given to limiting serum Epo, EEC, and bone marrow assessments to JAK2 mutant-negative patients. No significant financial relationships to disclose.