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PURPOSE: The role of frailty in affecting survival in myelodysplastic syndromes (MDS) is increasingly recognized. Despite this, a paucity of data exists on the association between frailty and other clinically meaningful outcomes including health care resource utilization and costs of care. METHODS: We linked the Ontario subset of the prospective Canadian MDS registry (including baseline patient/disease characteristics) to population-based health system administrative databases. Baseline frailty was calculated from the 15-item MDS-specific frailty scale (FS-15). Primary outcomes were public health care utilization and 30-day standardized costs of care (2019 Canadian dollars) determined for each phase of disease (initial, continuation, and terminal phases). Negative binomial regression was used to assess the association between frailty and health care costs with Poisson regression to explore predictors of hospitalization. RESULTS: Among 461 patients with complete FS-15 scores, 374 (81.1%) had a hospitalization with a mean length of stay of 10.6 days. Controlling for age, comorbidities, Revised International Prognostic Scoring System, and transfusion dependence, the FS-15 was independently associated with hospitalization during the initial ( P = .02) and continuation ( P = .01) phases but not the terminal disease phase ( P = .09). The mean 30-day standardized cost per patient was $8,499 (median, $6,295; interquartile range, $2,798-$11,996), largely driven by cancer clinic visits and hospitalization. On multivariable analysis, the FS-15 was independently associated with costs of care during the initial disease phase ( P = .02). CONCLUSION: We demonstrate an association between frailty and clinically meaningful outcomes including hospitalization and costs of care in patients with MDS. Our results suggest that baseline frailty may help to inform patients and physicians of expected outcomes.

Many patients with lower-risk myelodysplastic syndromes (LR MDS) require long-term red blood cell (RBC) transfusions to manage anemia. The consequences of RBC transfusions in LR MDS with ring sideroblasts (LR MDS-RS) are not well known. We estimated the association between cumulative RBC dose density and clinical and patient-reported outcomes using data from the MDS-CAN registry for patients enrolled between January 2008 and December 2018. Outcomes included overall survival, hospitalization, and health-related quality of life (HRQoL). A total of 145 enrolled patients with LR MDS and RS ≥5% had a median follow-up time of 27.1 months; 45 had no transfusions during follow-up, 51 had1 transfusion per month, and 49 had ≥1 transfusion per month. The cumulative density of RBC transfusions was associated with significantly greater mortality, hospitalization, and inferior HRQoL, suggesting that exposure to RBC transfusion may constitute a significant treatment burden in patients with LR MDS-RS.

Background: Observational studies suggest an anti-neoplastic effect associated with statins, metformin, dipeptidyl peptidase-4 inhibitors (DPP4i), while sulfonylureas may have a neutral or detrimental effect. The aim of this study was to determine the impact of these medications in patients with myelodysplastic syndromes (MDS). Methods: A prospective Canadian national registry containing disease and patient-related characteristics enrolled patients with MDS between January 1, 2006 and December 31, 2019. The Ontario subset of the registry was linked to population-based health system administrative databases. The primary outcome was the impact of statin/oral hypoglycemic medication exposure on overall survival (OS). Cumulative medication exposure (in months) was evaluated from 1-year prior to registry enrollment to date of death or end of follow-up (March 31, 2020) as a time-varying covariate. Cox regression analysis controlling for comorbid disease burden (Aggregated Diagnosis Groups; ADG) and sociodemographic factors (age, sex, rurality, income quintile) examined the relationship between medication exposure and OS. Our secondary outcome was leukemia-free survival (LFS), in which cause-specific hazard model was used to evaluate the association between medication exposure and LFS, taking death as the competing event. Results: In total, 533 patients aged >66 years were included (395 lower-risk IPSS, 130 higher-risk IPSS). The median age was 76.0 years (IQR 72.0-81.0), 65.1% were male and 9% had secondary MDS. The mean follow-up was 2.6 years (SD+ 2.4). Starting one year prior to registry enrollment and until the end of follow-up, 49.3% used a statin, 18.9% used metformin, 9.0% used a sulfonylurea and 6.4% used a DPP4i. On univariate analysis, we identified an improved OS in the lower-risk IPSS group using DPP4i (HR 0.98, 95% CI 0.95-1.00, p=0.05), while there was no significant difference in the higher-risk IPSS group for users of DPP4i (HR 1.03, 95% CI 0.99-1.07, p=0.21). In both lower and higher-risk IPSS groups, there was no difference in mortality for statins (HR 1.00, CI 1.00-1.01, p=0.93), metformin (HR 1.00, CI 0.99-1.01, p=0.81) and sulfonylureas (HR 1.00, CI 0.99-1.02, p=0.43). Increased age (p There was no association between exposure to the studied medications and LFS in the lower-risk group: metformin (HR 0.99, 95% CI 0.96-1.02, p=0.32), sulfonylureas (HR 0.99, 95% CI 0.94-1.04, p=0.57) and statins (HR 0.99, 95% CI 0.98-1.01, p=0.41). The impact of DPP4i exposure on LFS could not be assessed in lower risk disease due to infrequent events. There was also no association in the higher-risk IPSS group: DPP4i (HR 1.06, 95% CI 1.00-1.12, p=0.05), metformin (HR 1.02, CI 0.98-1.05, p=0.34), sulfonylureas (HR 1.04, 1.00-1.08, p=0.07) and statins (HR 1.02, 1.00-1.04, p=0.12). On multivariable analysis in the lower-risk IPSS group, no associations were identified between the use of medications of interest and all-cause mortality: DPP4i (HR 0.98, 95% CI 0.95-1.00, p=0.06), metformin (HR 1.00, 95% CI 0.99-1.01, p=0.99), sulfonylurea (HR 1.00, 95% CI 0.99-1.02, p=0.65) and statins (HR 1.00, 95% CI 0.99-1.00, p=0.56). In those with known cause of death, the main cause of death amongst DPP4i users was infection (35.7%) followed by acute myeloid leukemia (AML) (21.4%) and cardiac disease (14.3%), while the main cause of death in patients not on DPP4i was progressive MDS (23.2%) followed by AML (22.5%) and infections (22.1%). Conclusions: DPP4i may confer a survival benefit in lower-risk but not higher-risk MDS that cannot be explained by a reduction in cardiovascular deaths. Metformin, sulfonylureas and statins showed no impact on OS and LFS in lower and higher-risk groups. Improved bone marrow function through exosome inhibition and increased granulocyte-macrophage colony stimulating activity is the suggested mechanism for the potential survival benefit with DPP4i in lower-risk IPSS patients. This represents the first study evaluating the impact of oral hypoglycemic mediations and statins in a large cohort of patients with MDS. Further prospective studies are required to further evaluate the effects of DPP4i in MDS. Disclosures Leber: AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Khalaf: Pfizer: Honoraria; Novartis: Honoraria; Paladin: Honoraria. Sabloff: TaiHo: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Yee: Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Research Funding; Janssen: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding. Buckstein: Celgene: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; TAIHO: Research Funding; Otsuka: Research Funding.

The optimal hemoglobin (HgB) threshold for red blood cell transfusions in adult patients with myelodysplastic syndromes (MDS) has not been defined. We conducted a randomized multi-center study of two transfusion algorithms (liberal, to maintain Hgb 110-120 g/L, versus restrictive, 85-105 g/L) and combined our findings from RBC-ENHANCE with those of REDDS a previously published study of similar design. Primary objectives were measures of compliance to transfusion thresholds and the achievement of a 15 g/L difference in pre-transfusion Hgb. Secondary outcomes included measures of QOL, iron studies and safety. 66 patients were randomized between February 2015-2020, 33 to each arm in 15 international participating sites. The compliance was 58% and 81% in the restrictive and liberal arms respectively and the mean pre-transfusion Hgb thresholds for restrictive and liberal arms were 85.9 (SD 9) and 98.8 g/L (SD 9). Patients in the liberal arms experienced a mean of 3.4 (SD 2.6) more transfusion visits and received a mean of 5.3 (SD 5.5) extra units of blood during the 12-week study. Selected QOL scores were superior pre-transfusion and more patients achieved clinically important differences in the liberal arm. Further data are needed to establish the feasibility of liberal transfusion policies in MDS outpatients. Trial Registration: REDDS: ISRCTN26088319 RBC-ENHANCE: NCT 02099669

Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment-free remission (TFR) success after TKI discontinuation, the optimal cut-off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse-free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut-off period of time. The shortest cut-off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut-off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut-off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%).

Cytoplasmic and membrane-bound BCL-2 family proteins regulate apoptosis, a form of programmed cell death, via dozens of binary protein interactions confounding measurement of the effects of inhibitors in live cells. In cancer, apoptosis is frequently dysregulated, and cell survival depends on antiapoptotic proteins binding to and inhibiting proapoptotic BH3 proteins. The clinical success of BH3 mimetic inhibitors of antiapoptotic proteins has spawned major efforts by the pharmaceutical industry to develop molecules with different specificities and higher affinities. Here, quantitative fast fluorescence lifetime imaging microscopy enabled comparison of BH3 mimetic drugs in trials and preclinical development by measuring drug effects on binding affinities of interacting protein pairs in live cells. Both selectivity and efficacy were assessed for 15 inhibitors of four antiapoptotic proteins for each of six BH3 protein ligands. While many drugs target the designed interaction, most also have unexpected selectivity and poor efficacy in cells.

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038., Open Access funding enabled and organized by Projekt DEAL. This study was funded by Pfizer.

Ruxolitinib improves splenomegaly and other disease-related symptoms in patients with myelofibrosis, but over time, many patients lose this benefit. It is difficult to determine whether this is due to resistance or intolerance to the drug; thus, we have used the more inclusive term of ruxolitinib failure. The survival of patients with myelofibrosis after ruxolitinib failure is poor but varies significantly by the pattern of the failure, underlining the need for a clinically appropriate classification. In this review, we propose diagnostic guidance for early recognition of the pattern of ruxolitinib failure and we recommend treatment options. The most frequent patterns of ruxolitinib failure are loss or failure to obtain a significant reduction in splenomegaly or symptom response, and the development or persistence of clinically significant cytopenias. Ruxolitinib dose modification and other ancillary therapies are sometimes helpful, and splenectomy is a palliative option in selected cases. Stem-cell transplantation is the only curative option for these patterns of failure, but its restricted applicability due to toxicity highlights the importance of ongoing clinical trials in this area. Recent approval of fedratinib by the US Food and Drug Administration provides an alternative option for patients with suboptimal or loss of spleen response. The transformation of myelofibrosis to accelerated or blast phase is an infrequent form of failure with an extremely poor prognosis, whereby patients who are ineligible for transplantation have limited treatment options.

The doubling time (DT) of the BCR-ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re-growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT 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 optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high-risk group (DT12·75 days but0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse-free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate-risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low-risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P 0·001). Monthly assessment of DT helps identify high-risk patients for treatment-free remission failure with an imminent risk of molecular recurrence, and to define low-risk patients who can be spared the frequent monitoring of monthly molecular tests.

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.

Ruxolitinib was recently approved for the treatment of patients with polycythemia vera who are resistant/intolerant to hydroxyurea based on data from the RESPONSE studies. This phase 3b, Expanded Treatment Protocol study (NCT02292446) of ruxolitinib for hydroxyurea-resistant/intolerant patients with polycythemia vera (

Summary: Unleashing blocked apoptosis has emerged as an important tool in treating cancer as shown by the recent success of the BCL2 inhibitor venetoclax. However, MCL1 represents another important target as it is the predominant survival signal in many types of cancers and functions as a resistance mechanism to BCL2 inhibition. Caenepeel and colleagues and Ramsey and colleagues have developed two novel, potent, and selective MCL1 inhibitors that are effective against many hematologic malignancies, and Nangia and colleagues describe how one of these inhibitors can be successfully combined with BCL-xL and MEK inhibition to treat KRAS-mutated lung cancer. See related article by Ramsey et al., p. 1566. See related article by Caenepeel et al., p. 1582. See related article by Nangia et al., p. 1598.

In 2008 the first evidence-based Canadian consensus guideline addressing the diagnosis, monitoring and management of transfusional iron overload in patients with myelodysplastic syndromes (MDS) was published. The Canadian Consortium on MDS, comprised of hematologists from across Canada with a clinical and academic interest in MDS, reconvened to update these guidelines. A literature search was updated in 2017; topics reviewed include mechanisms of iron overload induced cellular damage, evidence for clinical endpoints impacted by iron overload including organ dysfunction, infections, marrow failure, overall survival, acute myeloid leukemia progression, and endpoints around hematopoietic stem-cell transplant. Evidence for an impact of iron reduction on the same endpoints is discussed, guidelines are updated, and areas identified where evidence is suboptimal. The guidelines address common questions around the diagnosis, workup and management of iron overload in clinical practice, and take the approach of who, when, why and how to treat iron overload in MDS. Practical recommendations for treatment and monitoring are made. Evidence levels and grading of recommendations are provided for all clinical endpoints examined.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by intravascular hemolysis, thrombophilia, and marrow failure. Its phenotype is due to absent or reduced expression of GPI-linked complement regulators and subsequent sensitivity of hematopoietic cells to complement-mediated damage and lysis. Introduction of the terminal complement inhibitor eculizumab drastically improved outcomes in PNH patients; however, despite this improvement, there remain several challenges faced by PNH patients and physicians who care for them. One of the most important is increasing awareness of the heterogeneity with which patients can present, which can lead to significant delays in recognition. Data from the Canadian PNH Registry are presented to demonstrate the variety of presenting symptoms. In Canada, geography precludes consolidation of care to just a few centers, so management is distributed across academic hospitals, linked together as the Canadian PNH Network. The Network over the last several years has developed educational programs and clinical checklists and has worked to standardize access to diagnostics across the country. Herein, we address some of the common diagnostic and therapeutic challenges faced by PNH physicians and give our recommendations. Gaps in knowledge are also addressed, and where appropriate, consensus opinion is provided.

Glasdegib, in combination with low-dose cytarabine (LDAC), is the first smoothened inhibitor approved for treatment of acute myeloid leukemia. Glasdegib plus LDAC is indicated for patients in whom therapy options are limited, e.g. older patients and those ineligible for intensive chemotherapy due to preexisting comorbidities. This review summarizes the recommendations of a panel of hemato-oncologists regarding the selection of patients best suited for treatment with glasdegib plus LDAC and the management during therapy with this combination. The panel considered the impact of concomitant medications and comorbidities during treatment with glasdegib plus LDAC, and discussed common adverse events (AEs) associated with glasdegib plus LDAC. Management strategies for AEs discussed by the panel included dose modifications, supportive care therapies, and prophylactic treatments. Finally, the panel highlighted the importance of patient communication and education regarding the possible AEs that may occur during treatment.

The incorporation of patient-reported outcomes with traditional disease risk classification was found to strengthen survival prediction in patients with myelodysplastic syndromes (MDS). In the present Canadian MDS registry analysis, we validate a recently reported prognostic model, the Fatigue-International Prognostic Scoring System among higher-risk patients [FA-IPSS(h)], which incorporates patients' reported fatigue, assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30), with a threshold of ≥45 points, in higher IPSS score, stratifying them into distinct subgroups with different survival outcomes. We further validated this concept, using the Revised IPSS >3·5 as cut-off for the definition of higher-risk MDS, and patients' reported fatigue according to Edmonton Symptom Self-Assessment Scale (ESAS) Global Fatigue Scale (GFS), a single-item fatigue rating scale, which is easier to deploy. This emphasises the power of self-reported fatigue at refining overall survival predictions in higher-risk MDS and further bolsters the importance of considering patient-related outcomes in global assessments.

Pathology synopses consist of semi-structured or unstructured text summarizing visual information by observing human tissue. Experts write and interpret these synopses with high domain-specific knowledge to extract tissue semantics and formulate a diagnosis in the context of ancillary testing and clinical information. The limited number of specialists available to interpret pathology synopses restricts the utility of the inherent information. Deep learning offers a tool for information extraction and automatic feature generation from complex datasets. Using an active learning approach, we developed a set of semantic labels for bone marrow aspirate pathology synopses. We then trained a transformer-based deep-learning model to map these synopses to one or more semantic labels, and extracted learned embeddings (i.e., meaningful attributes) from the model’s hidden layer. Here we demonstrate that with a small amount of training data, a transformer-based natural language model can extract embeddings from pathology synopses that capture diagnostically relevant information. On average, these embeddings can be used to generate semantic labels mapping patients to probable diagnostic groups with a micro-average F1 score of 0.779 Â ± 0.025. We provide a generalizable deep learning model and approach to unlock the semantic information inherent in pathology synopses toward improved diagnostics, biodiscovery and AI-assisted computational pathology. Pathology synopses are short texts describing microscopic features of human tissue. Medical experts use their knowledge to understand these synopses and formulate a diagnosis in the context of other clinical information. However, this takes time and there are a limited number of specialists available to interpret pathology synopses. A type of artificial intelligence (AI) called deep learning provides a possible means of extracting information from unstructured or semi-structured data such as pathology synopses. Here we use deep learning to extract diagnostically relevant textual information from pathology synopses. We show our approach can then map this textual information to one or more diagnostic keywords. We provide a generally applicable and scalable method to unlock the knowledge in pathology synopses as a step toward exploiting computer-aided pathology in the clinic. Mu et al. utilize a deep learning natural language processing model as part of an active learning approach to extract diagnostically relevant semantic information from bone marrow pathology synopses. Their findings demonstrate the potential for artificial intelligence in assisting clinicians in assessing, cataloging and triaging medical text datasets such as pathology synopses.

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038., Open Access funding enabled and organized by Projekt DEAL. This study was funded by Pfizer.

Measurable (minimal) residual disease (MRD) is an established, key prognostic factor in adult B-cell acute lymphoblastic leukemia (B-ALL), and testing for MRD is known to be an important tool to help guide treatment decisions. The clinical value of MRD testing depends on the accuracy and reliability of results. Currently, there are no Canadian provincial or national guidelines for MRD testing in adult B-ALL, and consistent with the absence of such guidelines, there is no uniform Ontario MRD testing consensus. Moreover, there is great variability in Ontario in MRD testing with respect to where, when, and by which technique, MRD testing is performed, as well as in how the results are interpreted. To address these deficiencies, an expert multidisciplinary working group was convened to define consensus recommendations for improving the provision of such testing. The expert panel recommends that MRD testing should be implemented in a centralized manner to ensure expertise and accuracy in testing for this low volume indication, thereby to provide accurate, reliable results to clinicians and patients. All adult patients with B-ALL should receive MRD testing after induction chemotherapy. Philadelphia chromosome (Ph)-positive patients should have ongoing monitoring of MRD during treatment and thereafter, while samples from Ph-negative B-ALL patients should be tested at least once later during treatment, ideally at 12 to 16 weeks after treatment initiation. In Ph-negative adult B-ALL patients, standardized, ideally centralized, protocols must be used for MRD testing, including both flow cytometry and immunoglobulin (Ig) heavy chain and T-cell receptor (TCR) gene rearrangement analysis. For Ph-positive B-ALL patients, MRD testing using a standardized protocol for reverse transcription real-time quantitative PCR (RT-qPCR) for the BCR-ABL1 gene fusion transcript is recommended, with Ig/TCR gene rearrangement analysis done in parallel likely providing additional clinical information.

Background The phase 2 BRIGHT AML 1003 trial evaluated efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized patients to receive glasdegib + LDAC (n = 78) or LDAC alone (n = 38). The rate of complete remission (CR) was 19.2% in the glasdegib + LDAC arm versus 2.6% in the LDAC arm (P = 0.015). Methods This post hoc analysis determines whether the clinical benefits of glasdegib are restricted to patients who achieve CR, or if they extend to those who do not achieve CR. Results In patients who did not achieve CR, the addition of glasdegib to LDAC improved overall survival (OS) versus LDAC alone (hazard ratio = 0.63 [95% confidence interval, 0.41–0.98]; P = 0.0182; median OS, 5.0 vs 4.1 months). Additionally, more patients receiving glasdegib + LDAC achieved durable recovery of absolute neutrophil count (≥ 1000/μl, 45.6% vs 35.5%), hemoglobin (≥ 9 g/dl, 54.4% vs 38.7%), and platelets (≥ 100,000/μl, 29.8% vs 9.7%). Transfusion independence was achieved by 15.0% and 2.9% of patients receiving glasdegib + LDAC and LDAC alone, respectively. Conclusions Collectively, these data suggest that there are clinical benefits with glasdegib in the absence of CR. Trial registration ClinicalTrials.gov NCT01546038 (March 7, 2012)

Identifying precise targets of individual cancers remains challenging. Chronic lymphocytic leukemia (CLL) represents the most common adult hematologic malignancy, and trisomy 12 (tri12) represents a quarter of CLL patients. We report that tri12 human pluripotent stem cells (hPSCs) allow for the identification of gene networks and targets specific to tri12, which are controlled by comparative normal PSCs. Identified targets are upregulated in tri12 leukemic cells from a cohort of 159 patients with monoclonal B cell lymphocytosis and CLL. tri12 signaling patterns significantly influence progression-free survival. Actionable targets are identified using high-content drug testing and functionally validated in an additional 44 CLL patient samples. Using xenograft models, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor is potent and selective against human tri12 CLL versus healthy patient-derived xenografts. Our study uses hPSCs to uncover targets from genetic aberrations and apply them to cancer. These findings provide immediate translational potential as biomarkers and targets for therapeutic intervention.

e20011 Background: Neutropenia is a common hematologic Grade (Gr) 3+ adverse event (AE) recorded in patients with chronic lymphocytic leukemia (CLL) receiving venetoclax (VEN). In this analysis, we evaluated fixed duration VEN monotherapy given to patients with relapsed or refractory (R/R) CLL with and without pre-existing Gr3+ neutropenia. Methods: This post-hoc analysis pooled data from patients in the ongoing Phase 3b trials VENICE-I and VENICE-II with R/R CLL who had received ≥1 dose of VEN monotherapy (ramp-up to 400 mg QD). Gr4 hematologic AEs and Gr3+ neutropenia ( < 1000 cells/mm3) with infection or fever were managed using dose interruption/reduction. Granulocyte colony stimulating factor (G-CSF) was used in Gr3+ neutropenia. Results: At data cutoff (June 30, 2019), 44/468 (9%) patients had Gr3+ neutropenia at baseline (BL; Gr3+ neutropenia group), 80% of whom received G-CSF during the study vs 38% of those with < Gr3 neutropenia at BL ( < Gr3 neutropenia group). Median on-study duration for VEN was 20.2 months (range: 0.1–36.1). Median number of prior CLL therapies was 2 for both groups (range: 1–10). Serious infections were experienced by 10/44 (23%) and 69/424 (16%) of patients in the Gr3+ and < Gr3 neutropenia groups, respectively. The most common AEs leading to discontinuation overall were second primary malignancies (13/468; 3%). 5/468 (1%) patients in the total population discontinued due to neutropenia/febrile neutropenia. One case of Gr5 infection with concomitant Gr3 neutropenia was reported in the < Gr3 neutropenia group post-VEN discontinuation. See Table. Conclusions: In this large post-hoc analysis, discontinuation due to neutropenia was rare (1%) in the overall population and accounted for 3/11 AE discontinuations in the Gr3+ neutropenia group; 10 patients had a serious infection. Patients with pre-existing neutropenia can be managed on VEN, though concurrent use of G-CSF is likely to be required. Additional data to follow. Clinical trial information: NCT02756611; NCT02980731 . [Table: see text]

BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P

Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD.We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56.A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]).Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.).

We completed a phase 1 dose-escalation trial to evaluate the safety of a dopamine receptor D2 (DRD2) antagonist thioridazine (TDZ), in combination with cytarabine. Thirteen patients 55 years and older with relapsed or refractory acute myeloid leukemia (AML) were enrolled. Oral TDZ was administered at 3 dose levels: 25 mg (n = 6), 50 mg (n = 4), or 100 mg (n = 3) every 6 hours for 21 days. Intermediate-dose cytarabine was administered on days 6 to 10. Dose-limiting toxicities (DLTs) included grade 3 QTc interval prolongation in 1 patient at 25 mg TDZ and neurological events in 2 patients at 100 mg TDZ (gait disturbance, depressed consciousness, and dizziness). At the 50-mg TDZ dose, the sum of circulating DRD2 antagonist levels approached a concentration of 10 μM, a level noted to be selectively active against human AML in vitro. Eleven of 13 patients completed a 5-day lead-in with TDZ, of which 6 received TDZ with hydroxyurea and 5 received TDZ alone. During this period, 8 patients demonstrated a 19% to 55% reduction in blast levels, whereas 3 patients displayed progressive disease. The extent of blast reduction during this 5-day interval was associated with the expression of the putative TDZ target receptor DRD2 on leukemic cells. These preliminary results suggest that DRD2 represents a potential therapeutic target for AML disease. Future studies are required to corroborate these observations, including the use of modified DRD2 antagonists with improved tolerability in AML patients. This trial was registered at www.clinicaltrials.gov as #NCT02096289.

Key Clinical Message Cyclic thrombocytopenia is often misdiagnosed as immune thrombocytopenia due to similar clinical features, a fact of significance because cyclic thrombocytopenia generally responds poorly to treatments used successfully in immune thrombocytopenia. A precise diagnosis must establish the statistical significance of periodicity of the platelet counts using statistical methods (eg, Lomb‐Scargle periodogram).

Abstract text: Background/Introduction: Chronic Myelomonocytic Leukemia (CMML) is an uncommon MDS/MPN overlap syndrome that has historically been included under the umbrella of myelodysplastic syndromes (MDS) for clinical trial and treatment. As a result, DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine have been the established standard of care for the treatment of CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver so treatment has required intravenous infusion or subcutaneous injections daily for 5-7 days every month (m) adding significant burden to older cancer patients due to daily time commitment and travel to treatment centers. In the context of pandemic SARS-CoV-2, parenteral therapy also increases contact with medical settings with increased infection risk. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination of decitabine and the CDA inhibitor cedazuridine that produced equivalent exposure (99%; 90% CI 93% to 106%) to IV decitabine 20 mg/m 2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019), and Median overall survival (mOS) for the entire study population in the ASCERTAIN study was approximately 32 months (Savona, 2021). Here, we present outcome data for this study for the enrolled subpopulation of patients with CMML. Methods: We used a randomized cross over design in which patients were randomized in the first 2 cycles 1:1 to either Sequence A: (decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m 2 in Cycle 2), or Sequence B: (IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2). We conducted an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days (unless delays were needed). All patients received oral decitabine/cedazuridine in Cycles 3 and above until disease progression or unacceptable toxicity. Patients were eligible per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: Of the 133 patients enrolled and treated in ASCERTAIN, 16 (12%) had a diagnosis of CMML with demographics and as follows: median age 71.5 years, 69% Male/31% Female, median weight 87kg (range 65-124), 25% ECOG 0, 75% ECOG 1. Population disease characteristics were: 19% poor or intermediate risk cytogenetics, with median baseline hemoglobin 90 g/L, neutrophils 1.27 X 10 9/L, platelets 84 x 10 9/L, bone marrow blasts 5%, with 38% RBC transfusion dependent. Patients received a median of 7 cycles of therapy (range 3-24). Treatment-emergent adverse events of CTCAE Grade 3 or higher in > 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [69%], thrombocytopenia [63%], anemia [56%], leukopenia [19%]), febrile neutropenia (31%), fatigue (13%). Two patients (12.5%) had Complete Responses (CR), 8 (50%) had marrow CR ([mCR], including 3 (19%) with hematologic improvement (HI); Overall Response rate (ORR) [CR + PR+ mCR + HI] was 75%. Of six patients with baseline RBC transfusion dependence 3 (50%) became transfusion independent. Leukemia-free survival was 28.2 months and after a median follow up of more than 33 months, median overall survival had not been reached. Two patients (13%) went on to Hematopoietic Stem Cell Transplant (HCT). Conclusions: In the overall study, oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m 2 with a resultant clinical activity safety and efficacy profile in CMML patients consistent with the published literature (e.g Zeidan, et al 2017) and the Phase 2 experience. The use of oral decitabine/cedazuridine is a reasonable approach in CMML patients. References: Garcia-Manero, et al ASH 2019 Savona, et al, Int. MDS Symposium, 2021 Zeidan, et al, Cancer 2017: 3754-3762. Figure 1 Figure 1. Disclosures Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. McCloskey: Pfizer: Consultancy; Takeda: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy; COTA: Other: Equity Ownership; BMS: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Griffiths: Boston Biomedical: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Genentech: Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; Takeda Oncology: Consultancy, Honoraria; Novartis: Honoraria; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding. Yee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Geron: Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria; Janssen: Research Funding; Onconova: Research Funding; Genentech: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; MedImmune: Research Funding; Jazz: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees. Zeidan: BeyondSpring: Consultancy; Janssen: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; AstraZeneca: Consultancy; Pfizer: Other: Travel support, Research Funding; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Ionis: Consultancy; Daiichi Sankyo: Consultancy; Epizyme: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Geron: Other: Clinical Trial Committees; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; Astellas: Consultancy; Astex: Research Funding; Jazz: Consultancy; Jasper: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patel: Agios: Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria. Sabloff: Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding; AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DeZern: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Janssen: Research Funding; AbbVie: Consultancy; Actinium: Consultancy; Agios: Consultancy; Amgen: Consultancy; Astex: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Blueprint Medicines: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Mesoblast: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees.

Background: AML is a complex disease that encompasses a huge variation of cytogenetic and mutational backgrounds, which is often complicated by age related functional deficits (Klepin et al. 2013). Given the expanding availability of reduced-intensity treatment options, patient fitness and frailty measures have become increasingly instrumental in the decision between a wide range of treatment options. Furthermore, studies have also demonstrated potential benefits in older patients who receive intensive induction chemotherapy (Julisson 2011), creating a need for additional assessments to identify suitable induction candidates. Some frailty-associated assessments including timed-up-and-go test (TUGT) and the short physical performance battery have been linked to outcomes but are not yet in broad clinical use (Kleplin et al. 2013, Khalaf et al. 2020). To minimize the burden of implementing new patient assessments, we evaluated the utility of commonly available clinical measures of frailty-associated factors including sit-to-stand test and iADL status in predicting patient outcomes. Methods: We performed a retrospective cohort study of elderly patients newly diagnosed with AML at Juravinski Cancer Center between Jan 2019 and Dec 2020. We examined a total of 44 patients aged 65+. The primary outcome was overall survival (OS). Significant risk factors were identified using the Cox proportional hazards model. Results: 43 patients had sufficient data and were included in the analysis. The median age was 70 years (range 65-89), 53% were female and 47% were male. At the time of review, 21 patients were deceased (48.8%). The median survival time was 345 days. 26 patients received full induction treatment (7+3, FLAG-IDA, or Vyxeos), and 18 received conservative treatment (LDAC, azacytidine, or supportive care). The clinical wellness of the patients at diagnosis time was assessed by baseline clinical and laboratory findings. (Table 1) The Cox regression model was used to examine these variables in predicting overall survival (Figure 1). As expected, the ELN risk group was significantly correlated with OS (HR 2.94 95%CI [1.41-6.11]), along with laboratory measures of disease burden including blood blast count (HR 1.02 [1.00-1.03]), WBC, (HR 1.02 [1.01-1.03]) and ANC (HR 1.05 [1.02-1.08]). We then assessed the influence of patient fitness factors on OS. The HCT-CI score was used as an aggregate comorbidities measure. While typically used for post-SCT prognosis, we found that HCT-CI assessed at diagnosis time was a significant predictor of OS (HR 1.22[1.04-1.45]). When added to a multivariate Cox model including ELN and age, the HCT-CI independently predicted OS (p = 0.003) and improved prediction efficiency by the Akaike information criteria (115 vs 122). This corroborates earlier findings by Sorror et al. 2017, who showed incorporation of biochemical and AML-specific variables to HCT-CI yields improved prognostic value. Within the HCT-CI, the AST and cardiac disease scores were the most associated with OS (HR 1.03[1.00-1.05] and 2.27[1.09-4.76]). While clinical and laboratory assessments were readily available, functional assessments of frailty were scarce. Previously reported frailty measures such as KPS score or TUGT were not assessed at the study center. OT/PT routinely administer sit-to-stand or standing balance tests as a part of fall risk assessment. However, this data was only available for 18 patients (41.8%). Independent sit-to-stand was not detected as a significant OS predictor (HR 0.63[0.14-2.83]), possibly related to the very limited sample size. BMI was marginally predictive (HR 1.07[0.99 - 1.08]), but unlike HCT-CI it was not an independent predictor when combined with ELN. Patient age did not significantly predict OS. Conclusion: This single center retrospective study was aimed at examining the role of existing clinical or functional measures of fitness and frailty in predicting overall survival. HCT-CI and ELN were found to be the most predictive factors amongst the variables examined, suggesting that a morbidity index such as HCT-CI could provide prognostic utility. However, functional assessments of frailty were not readily completed, limiting the ability to evaluate their usefulness. A future larger prospective study focused on optimizing and incorporating routine functional assessments of frailty is needed to address this topic. Figure 1 Figure 1. Disclosures Leber: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Khalaf: Novartis: Honoraria; Paladin: Honoraria; Pfizer: Honoraria.

Background/Introduction: Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%; 90% CI 93% to 106%) to standard IV DEC 20 mg/m 2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study. Methods: We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m 2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety. Results: Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 10 9/L (range 0.11-7.1), platelets (plt) 86 x 10 9/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in >10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR; CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant. Conclusions: Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m 2 IV DEC; in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population. References: Garcia-Manero, et al, ASH 2019 Savona, et al, Int. MDS Symp. 2021 Garcia-Manero, et al, Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients with Lower-Risk Myelodysplastic Syndromes. J.Clin.Onc. 2021 39:13, 1426-1436 Figure 1 Figure 1. Disclosures McCloskey: Pfizer: Consultancy; Jazz: Consultancy, Speakers Bureau; COTA: Other: Equity Ownership; Incyte: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Novartis: Consultancy; BMS: Honoraria, Speakers Bureau; Amgen: Speakers Bureau. Griffiths: Alexion Pharmaceuticals: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Genentech: Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Boston Biomedical: Consultancy. Yee: Paladin: Membership on an entity's Board of Directors or advisory committees; TaiHo: 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; Genentech: Research Funding; Geron: Research Funding; Janssen: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan: Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Ionis: Consultancy; Astellas: Consultancy; Epizyme: Consultancy; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Jasper: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; BeyondSpring: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Janssen: Consultancy; Acceleron: Consultancy, Research Funding; AstraZeneca: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Gilead: Consultancy, Other: Clinical Trial Committees; Agios: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; BioCryst: Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Aprea: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Astex: Research Funding. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees. Sabloff: Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Odenike: AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy; Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Jazz: Research Funding; Astellas Health: Honoraria; Immunogen: Research Funding; Astra Zeneca: Honoraria; Aptitude Health: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Novartis: Consultancy; Mesoblast: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Daiichi Sankyo: Consultancy; Otsuka: Consultancy; Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; Astex: Consultancy; Amgen: Consultancy; Agios: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Janssen: Research Funding; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding.