ALBERT

Description: Background: Despite a variety of treatment options, indolent non-Hodgkin's lymphoma (iNHL) remains a largely incurable disease with patients experiencing multiple relapses. Both rituximab (RTX) and bendamustine (Benda) are used as single agents for the treatment of relapsed/refractory iNHL. When given in combination to patients with relapsed iNHL, high response rates were observed (Rummel, 2016). Ofatumumab (OFA) is a human, anti-CD20 type-I antibody that binds a distinct epitope from RTX. A phase I/II study showed that OFA has activity in patients with follicular lymphoma (FL) who relapsed after RTX-containing therapy (Hagenbeek, 2008). Based on these experiences, COMPLEMENT A+B evaluated if OFA+Benda would improve progression-free survival (PFS) compared to Benda alone in unresponsive or progressive iNHL after RTX or RTX-containing regimen. Methods: This phase III, open-label, randomized, global, multi-center study enrolled adult patients (≥18 years) with CD20+ small lymphocytic, marginal zone, lymphophasmacytic and Grades 1-3A FL who had either stable disease after or disease progression during or within 6 months of RTX or RTX-containing regimen. Patients were randomized (1:1) to receive either OFA+Benda or Benda. Benda (90 mg/m2 in OFA+Benda arm and 120 mg/m2 in Bendaarm) was given on Days 1 and 2 every 21 days for up to 8 cycles. OFA (1000 mg) was given on Day 1 of Benda cycles and then every 28 days for a total of 12 doses. The primary endpoint was PFS as assessed by an independent review committee (IRC). Key secondary endpoints included PFS in patients with FL, overall response rates (ORR) and overall survival (OS) in all patients and in patients with FL which were tested hierarchically if the prior endpoint was statistically significant. Results: Overall, 346 patients were enrolled (173 in each arm) in 85 centers across 15 countries. Baseline characteristics were similar between the 2 arms. Median (range) age was 62 (21-87) years, majority were males (59%) and 69% had FL. Ann Arbor Stage IVA was common (OFA+Benda: 43%; Benda: 42%). Median duration of follow up was 61.1 months. Median treatment duration was longer in the OFA+Benda arm (OFA+Benda: 260 days; Benda: 135 days). Median (range) number of prior RTX therapy was 1 (1-8). In the OFA+Benda arm, 58% and 65% completed treatment with OFA and Benda, respectively, whereas in the Benda arm, 43% completed treatment. The main reason for premature discontinuation of OFA treatment in OFA+Benda arm was adverse events (AEs), 14%. The main reason for premature treatment discontinuation of Benda was AEs (OFA+Benda: 17%; Benda: 27%). Primary analysis was performed after 217 IRC-assessed PFS events occurred. In the OFA+Benda and Benda arms, 61% and 65% of patients, respectively, had PFS events (Figure 1). Median IRC-assessed PFS was 16.7 months in the OFA+Benda arm and 13.8 months in the Benda arm (hazard ratio [HR]=0.82, 95% confidence interval [CI] [0.62, 1.07]; p=0.1390). Similar results were seen in patients with FL where the median IRC-assessed PFS was similar in FL patients - 16.6 months in the OFA+Benda arm and 12.1 months in the Benda arm (HR=0.76, 95% CI [0.55,1.06]; p=0.1076) (Figure 2). IRC-assessed ORR was similar in both arms (OFA+Benda: 73%; Benda: 75%; difference in ORR [95% C]: -1.2% [-10.4%, 8.1]; p=0.8003). Median OS was 58.2 months and 51.8 months in the OFA+Benda and Benda arms, respectively (HR=0.89, 95% CI [0.63, 1.25]; p=0.4968). Frequencies of deaths (OFA+Benda: 38%; Benda: 41%) and on-treatment deaths (OFA+Benda: 7%; Benda: 9%) were similar in both arms. The main cause of death during the study was disease under study (OFA+Benda: 20%; Benda: 15%). Overall, 73% of patients in the OFA+Benda arm and 80% in the Benda arm experienced a ≥ Grade 3 AE. The most common ≥ Grade 3 AEs were neutropenia, thrombocytopenia, anemia, and leukopenia (Table 1). Conclusions: No significant improvement in PFS was seen with OFA+Benda as compared with Benda alone for patients with RTX-refractory iNHL. The safety profile for OFA was consistent with prior experience. The difference in outcomes compared to those in the GADOLIN trial (Sehn, 2016) could be due to the differences in drug exposure as patients in the GADOLIN study received maintenance anti-CD 20 therapy for up to 2 years; in the patient population as approximately 80% had FL in GADOLIN versus 69% in COMPLEMENT A+B; and in the mechanism of action of type-1 versus type-2 monoclonal antibody. Disclosures Rummel: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: 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, Research Funding; Symbio: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Eisai: Honoraria. Janssens:Sanofi-Genzyme: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. MacDonald:Roche Canada: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Merck: Honoraria. Keating:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davis:Novartis: Employment. Lasher:Novartis: Employment. Lobe:Novartis: Employment. Izquierdo:Novartis: Employment, Equity Ownership. Friedberg:Bayer: Honoraria.

Description: Introduction: Tyrosine kinase inhibitor (TKI) therapy can result in the adverse events of prolonged anemia, thrombocytopenia and/or leukopenia via c-kit blockade in hematopoietic stem cells. Previous studies have reported that even low-grade adverse events could impair a patient's health-related quality of life. One of the benefits of TKI discontinuation is to allow patients to live drug-free, thereby preventing drug-related adverse events including cytopenias. The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported 59.1% and 21.5% molecular relapse-free survival (mRFS) rates after first and second attempts at treatment free remission (TFR) with imatinib (IM) or Dasatinib (DA) discontinuation, respectively. In the present study, we attempted to analyze the impact of TKI discontinuation on changes in hematological parameters, and its impact on TFR success after TKI discontinuation. Methods and materials: Throughout the trial, we have collected the hematoloigc parameters at 22 timepoints in 131 patients. These included Hb level, WBC count with differentials, and platelet count during IM discontinuation (7 times), DA rechallenge (10 times), and DA discontinuation (5 times). Results: With IM discontinuation, most of the hematological parameters showed a significant improvement within 3 months: Hb level rise by +10.47g/L (+8.86%; p=1.67x10-22), WBC count rise by +1.43x109/L (+30.08%; p=2.03x10-16), neutrophil rise by +0.99x109/L (36.76%; p=4.48x10-11), lymphocyte rise by +0.24x109/L (+20.64%; p=6.72x10-9), monocyte rise by +0.13x109/L (+35.9 0%; p=3.33x10-14), platelet count rise by +22.65 x109/L (+12.76%; p=1.03x10-7). Eosinophil counts were not significantly changed (p=0.475). With DA rechallenge, mixed changes were observed in hematologic parameters within 1 month: Hb level significant dropped by 11.57g/L (-8.26%; p=6.38x10-14) and platelet counts also showed a decreasing trend (-9.39x109/L or -4.57%; p=0.07), while significant increases were noted in lymphocyte (+0.41x109/L or +22.22%; p=0.00027), and monocyte counts (+0.14x109/L or +14.29%; p=0.001). No significant changes were noted in WBC counts (+0.32x109/L or +1.64%; p=0.234), neutrophil counts (-0.18x109/L or -10.42%; p=0.285), or eosinophil counts (+0.03 x109/L or 0%; p=0.185). With DA discontinuation, the Hb level rebounded by +7.08g/L within 3 months (+9.45%; p=0.0003). However, there was no significant change in the other parameters 3 months after DA discontinuation, including WBC (p=0.841), neutrophil (p=0.309), lymphocyte (p=0.995), monocyte (p=0.451), eosinophil (p=0.826) and platelet counts (p=0.533). When the changes in hematologic parameters were analyzed in correlation with mRFS, there was no association of those parameter changes with RFS after DA discontinuation. However, associations of mRFS following IM discontinuation were noted as follows: higher mRFS after IM discontinuation was observed in the group with a smaller change in Hb level (≤+1.17%, p=0.004), lymphocyte count (≤+1.06%; p=0.006), and monocyte count (≤+1.43%; 0.005) compared to those with a larger change. In other words, the group showing a rebounded Hb level after IM discontinuation showed a lower mRFS rate compared to those in whom the Hb did not rebound. A lower mRFS was noted in the group with a smaller change in neutrophil count (≤+1.07%) compared to those with a larger change (p=0.008), implying that the group with rebounded neutrophil count showed a higher mRFS compared to those not. Multivariate analysis confirmed: 1) IM treatment duration longer than 8.75 years is associated with a decrease in loss of molecular response by 13% per year (p=0.001, HR 0.871), 2) Hb level rebound above 22gm/L showed 2.8 times higher risk of molecular relapse (p=0.021, HR 2.801), 3) rebound rise of neutrophil count by 1.075% or above reduced the risk of molecular relapse by 52% (p=0.06, HR 0.485). Conclusion: Further research is warranted to explore the functional role of the hematopoietic stem cell fraction following prolonged TKI therapy in CML patients. Hematopoiesis in Ph-negative cell population could contribute to TFR after TKI discontinuation. Figure Disclosures Busque: ExCellThera: Patents & Royalties; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. 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. Delage:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Liew:Novartis: Consultancy, Honoraria. Leber: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.

Description: Introduction: The Canadian trial entitled "Treatment Free Remission Accomplished By Dasatinib" (BMS CA180543, NCT#02268370) is ongoing since Jan 2015, and has completed accrual of 131 patients. The study was designed to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI discontinuation following imatinib (IM) treatment. The preliminary results (ASH 2018) indicate: 1) The 6-month molecular relapse-free survival (mRFS) rate is estimated as 58.0%; 2) DA re-treatment is feasible and safe, with achievement of excellent rates of MMR and MR4; 3) The estimated TFR2 rate after DA discontinuation was 21.5±8.5% at 6 months [7.9-39.5%]). Herein, we report the 4-year follow-up results with updated TFR2 after second TFR attempt following DA discontinuation. Methods and materials: This prospective clinical trial has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. Molecular relapse is defined as an increase in BCR-ABL transcript level above MR4.0 on 2 consecutive occasions, or an increase in BCR-ABL transcript level above MR3.0 on a single occasion. 100mg daily of DA is started if molecular relapse is confirmed and is discontinued 12 months after achieving MR4 following a 2nd TFR attempt. Results: As of Jun 25, 2019, 58 (44.3%) of 131 enrolled patients experienced molecular relapse after IM discontinuation with a mRFS rate of 59.1% [50.1-67.0%] and 56.8% [47.8-64.8%] at 6 and 12 months, respectively. TFR using loss of MMR as an event was 69.8% at 6/12 months. Of the 58 patients who lost response, 53 patients (91.4%) lost response within 6 months after IM discontinuation: 7 (10.1%) lost response within 2 months, 20 (34.5%) within 3 months, 14 (24.1%) within 4 months, 9 (15.5%) within 5 months, and 3 (5.2%) within 5-6 months. Beyond 6 months, 5 patients (15.5%) lost response within 7, 8, 10, 20, 21 months, respectively. Only two patients experienced late relapse occuring 15 months after IM discontinuation. 54 patients started DA, of whom 49 patients (90.7%) achieved MR4.5 on DA. Median time to MMR, MR4 and MR4.5 was 0.94, 1.95, and 2.48, respectively. The incidence of MMR, MR4 and MR4.5 at 3 months was 99.0% (86.3-99.0%), 91.5% (78.4-96.7%), and 76.6% (60.9-86.0%), respectively. 32/49 patients receiving DA attained MR4.5, and discontinued DA for a 2nd TFR attempt (TFR2). 25/32 (78.1%) of these patients lost molecular response at a median of 3.67 months after DA discontinuation. The estimated TFR2 after DA discontinuation was 18.5% at 6 months [6.8-34.7%], TFR2 using loss of MMR as a definition of molecular relapse was 20.4% [7.6-37.4%], while TFR2 using two consecutive losses of MR4 was 25.4% [9.4%-45.2%]. Two patients continued to attain deep molecular response at MR4.2 and undetectable level (equivalent to MR5.5) beyond 18 months after DA discontinuation. At last follow-up of Jun 25, 2019, 30 patients are still being monitored on trial on IM discontinuation (n=20), DA rechallenge (n=4) or DA discontinuation phases (n=6). With a median follow-up duration of 36 months, risk factor analyses were performed using Cox's proportional hazard regression model suggesting a strong correlation of mRFS with total duration of IM treatment prior to IM discontinuation (p

Description: 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.

Description: 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.

Description: Introduction: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported a 59.1% and 21.5% molecular relapse-free survival (RFS) rate after first attempt of treatment free remission (TFR1) with imatinib (IM) discontinuation and after a 2nd attempt of TFR (TFR2) with dasatinib (DA) discontinuation, respectively. Throughout the first and second attempts of TKI discontinuation, the kinetics of BCR-ABL qPCR transcript rise were very similar after TFR1 and TFR2. This prompts us to have a better understanding of the dynamics of BCR-ABL qPCR rise after TKI discontinuation. Methods and materials: This prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. We have analyzed the monthly BCR-ABL1 qPCR value and doubling time (DT) in the first 6 months following IM discontinuation. The qPCR level before IM discontinuation or the qPCR level from the prior month was used as a baseline. DT at each measurement was calculated as x = ln(2)/K, where x is the DT and k is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The distribution of DT for all patients was assessed at each timepoint of DT measurement within the first 6 months. In order to define the best cut-off levels of BCR-ABL1 qPCR and DT showing the best risk stratification power throughout the first 6 months, DT values were collected and analyzed for molecular relapse-free survival (RFS) from the time of DT measurement. Then, a binary recursive partitioning method was applied using RFS which is calculated from the time of each DT measurement. Based on the DT cut-off value, the group was divided into 2 groups. The RFS was compared according to the groups. Results: As of March 25, 2019, out of 131 patients enrolled, 58 patients (44.3%) lost a molecular response. The 6- and 12-months' molecular relapse-free survival (mRFS) rate was estimated as 59.1% (50.1-67.0%) and 56.8 % (47.8-64.8%), respectively. BCR-ABL1 qPCR transcript level after IM discontinuation showed a rapid rise between the first 2-4 months, followed by a gradual rise after 4 months. The proportion of the patients showing DT less than 12.71 days but above 0 was 3.8% at 1 mo, 25.2% at 2 mo, 15.3% at 3 mo, 12.2% at 4 mo, 2.3% at 5 mo and 2.3% at 6 mo, respectively. DT values were collected and analyzed for molecular RFS from the time of DT measurement. Binary recursive partitioning method was applied and provided 12.71 days as the best DT cutoff value to stratify the patients according to the RFS from the time of each DT measurement. In other words, the patients having DT less than 12.71 days but above 0 at any time within the first 6 months had a higher risk of failing the TFR attempt, while those with DT equal to or over 12.71 days at any time has a lower risk of losing TFR after IM discontinuation. The best result was reported in the group with stable BCR-ABL qPCR transcript level. A rapid incline of BCR-ABL qPCR transcript level was observed 2-4 months after IM discontinuation. According to the DT measured at 2 months, the group with DT less than 12.71 days but above 0 showed the lowest mRFS rate of 5.0% (0.9-14.8%) at 12 months (HR 5.74), compared to the group with DT equal to/over 12.71 days (12 months' mRFS 47.4% [23.2-68.3%]) or the group with DT equal to/less than 0 days (12 months' mRFS 87.5% [77.3-93.3%]; p

Description: 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.

Description: Introduction: Hypomethylating agents (HMAs) such as decitabine (DEC) or azacitidine (AZA) are FDA approved therapies for patients with different myeloid malignancies as single agent or in combination with venetoclax. Both DEC and AZA require IV infusion for 1 hour or subcutaneous (SC) injections daily for 5-7 days of every 28-day treatment cycle. They both have limited oral bioavailability due to rapid degradation by cytidine deaminase (CDA) in the gut and liver. An orally bioavailable HMA option could reduce clinic visit frequency and reduce infusions/injections related adverse events and burden. ASTX727 is an oral tablet comprised of a fixed-dose combination (FDC) of CDA inhibitor cedazuridine (C) at 100 mg with DEC at 35 mg. In a phase 2 study, C-DEC (ASTX727) demonstrated pharmacokinetic (PK) AUC exposure similar to IV-DEC at 20mg/m2 with comparable clinical activity and safety (Garcia-Manero, et al, 15th Int'l MDS Symposium, 2019). We describe here the results of a phase 3 study designed to demonstrate exposure bioequivalence of oral C-DEC and IV-DEC and generate clinical data using C-DEC in a larger population (ASCERTAIN study). Methods: The study used a randomized cross over design where patients were randomized 1:1 to either Sequence A: C-DEC (100 mg/35 mg respectively) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B receiving IV-DEC in Cycle 1 followed by C-DEC on Cycle 2 to compare PK (primary endpoint AUC equivalence over 5 days of dosing) and pharmacodynamic (PD) of DNA demethylation using LINE-1 assay. All patients received C-DEC in all subsequent cycles from Cycle 3 onwards until treatment discontinuation to study clinical efficacy and safety of C-DEC. Patients were eligible as per the FDA-approved label (MDS IPSS Intermediate [Int]-1,-2 or high risk[HR] and CMML patients). Clinical responses were assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: 138 patients were randomized, of whom 133 were treated with median age of 71.0 years (range 44-88), median weight was 83.1 kg (range 45-158), and median BSA was 1.99 m2 (range 1.4-2.9 m2). The IPSS status of the patients were Int-1 in 44%, Int-2 in 20%, and HR in 16%, and 12% of pts had CMML. Patients in the two arms were well balanced regarding cytogenetic risk, baseline hemoglobin, neutrophils, platelets, or red blood cell or platelet transfusion dependence. For the primary end point, the decitabine AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 856 from the C-DEC and 865 from IV-DEC resulting in an oral/IV AUC ratio of 98.9% (90% CI of 92.7-105.6%). All sensitivity and secondary exposure analyses confirmed the primary results. Comparison of hypomethylating activity as measured by LINE-1 demethylation showed difference between oral C-DEC and IV-DEC demethylation of

Description: Introduction: Venous thromboembolism (VTE) encompasses a spectrum of disorders involving thrombosis in the venous circulation, namely deep vein thrombosis (DVT) and pulmonary embolism (PE). The incidence of thrombosis is significantly elevated in patients with malignancy due to a hypercoagulable state. In addition to the elevated risk of thrombus formation in patients with malignancy, certain tumours have a predilection for intravascular extension, termed tumour thrombus. The presence of tumour thrombus considerably worsens prognosis, alters staging, and can influence the treatment options for these patients. While tumour thrombus can have have a significant impact on patients, the clinical course and optimal management of tumour thrombus remains unknown. We aim to describe the natural history of tumour thrombus and compare outcomes in those treated with or without anticoagulation at our centre. Methods: We performed a retrospective, observational review of patients over 16 years of age with tumour thrombus at a single-centre between January 2008 and December 2017. Patients with documented tumour thrombus on computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US) were included in this study. Patients already on anticoagulation were excluded. Data were collected through medical record review including baseline characteristics, treatment history, complications and clinical outcomes. Overall survival and VTE recurrence rates between those treated with or without anticoagulation were demonstrated using Kaplan-Meier survival curves and Log-rank test. Cox-proportional hazards models were used to estimate the hazard ratio for tumor thrombosis with and without adjustment for patient characteristics including comorbidities, treatment, acuity, and location. Results: A total of 153 patients were identified to meet inclusion criteria over the study period. The majority of patients were male (65.4%) with an mean age of 65.7. The most common malignancies associated with tumour thrombus were renal cell carcinoma (34.6%) and hepatocellular carcinoma (28.8%), with 125 patients (82.5%) having stage III or IV malignancies. The most common locations of tumour thrombus were the portal vein (37.5%), renal vein (32.9%) and inferior vena cava (26.3%). Forty-one patients (26.8%) were treated with anticoagulation. Of the entire study population, 18 patients (11.8%) developed VTE within a 6 month study period after being diagnosed with tumour thrombus. Of those that developed VTE following a diagnosis of tumour thrombus, 11 were on anticoagulation (61%) and 7 were not (39%). Five patients receiving anticoagulation experienced major bleeding. Mortality was 42.5% at 6 months with no significant difference in survival between those treated with or without anticoagulation (Figure 1; p = 0.42). Proportion hazards models were not completed at the abstract submission deadline; full study results will be presented at the ASH meeting. Conclusion: In our study, we show that there is no significant difference in survival between patients with tumour thrombus treated with or without anticoagulation. While there is no clear evidence that anticoagulation improves outcomes across all patients with tumour thrombus, further studies are needed to identify subgroups of patients who may benefit from anticoagulation given their increased risk of VTE. Figure 1 Disclosures Keating: Sanofi: Membership on an entity's Board of Directors or advisory committees; 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.

Description: 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