ALBERT

Description: Introduction The primary goal for treatment of higher-risk MDS patients (pts) is to improve overall survival (OS) and delay acute myeloid leukemia (AML) evolution. The IWG 2006 response criteria are used in clinical trials and in clinical practice for assessing efficacy of MDS therapies. These criteria were originally proposed by an international group of experts based on available data and consensus. In an ad hoc landmark analysis of the AZA-001 study using the 2006 IWG criteria, pts who achieved hematological improvement (HI), complete response (CR), marrow CR (mCR), or partial response (PR) demonstrated improved OS. The aim of this study is to validate the IWG 2006 response criteria among a large cohort of higher-risk MDS pts. Methods Pts with higher-risk MDS (intermediate-2 (Int-2) or High Risk by International Prognostic Scoring System (IPSS)) who had received treatment and for whom details of response and outcome were available were included from the MDS CRC database. Pts were also classified per IPSS-R. The best response to treatment was categorized per the published IWG 2006 response criteria as CR, PR, mCR, HI, stable disease (SD) or progressive disease (PD). The primary endpoint was OS. Results We identified 646 treated higher-risk MDS pts. Table-1 summarizes baseline characteristics. The first line treatment was hypomethylating agent-based therapy (HMA) in 470 pts (74%). The median duration of follow up was 23.2 months (mo) (95% CI: (19.9, 26.5). Median OS from diagnosis was significantly longer for pts with int-2 IPSS risk disease IPSS (26.2 mo (21.5, 29.7)) compared to those who were High Risk (18.8 mo (15.9, 23.6); (p = 0.026). Median OS from diagnosis also differed by IPSS-R category (p 〈 0.001): for pts with Low risk (n = 6) it was not reached; Intermediate risk it was 41.7 mo (31.8, NR); High Risk it was 28.4 mo (24.1, 33.2); and for pts with Very High it was 16.5 mo (15.3, 19.1). The best IWG 2006 response rate for first line therapy among evaluable pts (n=597) was CR in 93 pts (16%), mCR in 10 (2%), PR in 57(10%), HI in 60 (10%), SD in 233 (39%), and PD in 144 (24%). The median OS based on IWG 2006 best response for first line therapy was 41 mo for CR, 12 mo for mCR, 26 mo for PR, 13 mo for HI, 14 mo for SD and 7 mo for PD. (p

Description: Introduction Somatic mutations in SF3B1 ,a gene encoding a core component of RNA splicing machinery, have been identified in patients (pts) with myelodysplastic syndrome (MDS). The SF3B1 mutation (MT) is more commonly detected in pts with ring sideroblasts (RS) morphology and is associated with favorable outcome. The pattern of response among SF3B1 mutated MDS pts to available treatment options, including erythropoiesis stimulating agents (ESA), hypomethylating agents (HMA) and lenalidomide is not known. The distinct underlying disease biology among such pts may alter response to treatment. Methods Pts treated at MDS CRC institutions with MT vs wild-type SF3B1 (WT) controls were matched 1:2. Matching criteria were age at diagnosis, year of diagnosis and International Prognostic Scoring System (IPSS) category at diagnosis. IPSS category was split into two groups (Low or Int-1 vs. Int-2 or High). Matching was performed using the R package by calculating a propensity score, which was then used to determine the two most similar WT SF3B1 patients for each SF3B1-mutated pt, without replacement. Additionally, to be included in the population, pts also had to have been treated with one of the following: ESAs, HMA, or lenalidomide. Response to treatment was evaluated by international Working Group criteria (IWG 2006) and classified as response if hematological improvement or better was achieved (HI+). Survival was calculated from date of treatment until date of death or last known follow-up, unless otherwise noted. Results: We identified 48 Pts with MT and 96 matched controls. Table 1 summarizes baseline characteristics comparing MT vs WT SF3B1 cohorts. SF3B1 MT was detected more often in association with RS, as expected. The majority of pts had lower-risk disease by IPSS and revised IPSS (IPSS-R). Pts with MT had higher platelets than controls. The most common concomitant somatic mutations observed were TET2 (30%), DNMT3A (21%), and ASXL1 (7%). Median follow-up time from diagnosis was 35 months (mo). Median overall survival (OS) from diagnosis was significantly longer for patients with SF3B1 MT (108.5 mo (68.8, NA)) than wild-type controls (28.3 mo (22.3, 36.4); p 〈 0.001). Patients with an SF3B1 MT had a decreased hazard of death (hazard ratio [HR]: 0.49 (95% confidence limits [95% CL]: 0.29, 0.84); p = 0.009) ESA was the first line therapy for 43 pts (88%) with MT and 55 WT Pts (56%). For ESA treated pts, 14 out 40 MT Pts responded (35%) compared to 9/56 among WT Pts (16%), p 0.032. Among those treated with HMA therapy, 5 out 21 (24%) MT pts responded compared to 11/46 (24%) WT Pts (p 0.99). Finally, for Pts treated with lenalidomide 4/16 (25%) and 4/21 (19%) responded among SF3B1 MT and WT Pts respectively, p 0.7. Conclusions SF3B1 somatic mutation in MDS is commonly associated with RS, lower risk disease, and better OS. Pts with SF3B1 mutation had higher response to ESA compared WT SF3B1. No difference in response to HMA or lenalidomide was observed compared to WT patients. Response rates to lenalidomide and HMA were low in both MT patients and controls. Biologically rational therapies are needed that target this molecular disease subset. Table 1. Baseline characteristics SF3B1 MT (n=48) SF3B1 WT (n=96) P value Age median 65 67 0.6 Gender male 29 (60%) 64(67%) 0.5 Race White 44/45 (98%) 83/90 (92%) 0.34 WHO classification RA RARS RCMD RARS-T Del5 q RAEB-I RAEB-II MDS-U MDS/MPN CMML 3 24 8 4 1 3 3 2 0 0 6 9 17 2 6 10 9 3 11 9 IPSS Low Int-1 Int-2 High 29 (60%) 16 (33%) 3 (6%) 0 21 (22%) 69 (72%) 4 (4%) 2 (2%) 〈 0.001 IPSS-R Very low Low Intermediate High Very High 15 (31%) 26 (54%) 5 (10%) 2 (4%) 0 11 (11%) 37 (39%) 26 (27%) 18 (19%) 4 (4%)

Description: Background: The majority of MDS patients (pts) have anemia and are treated initially with ESAs. Particularly for lower-risk MDS pts (International Prognostic Scoring System (IPSS) Low and Int-1), once ESAs are no longer effective, treatment options are limited to drugs commonly used for higher-risk MDS, such as hypomethylating agents, or off-label use of immunomodulatory drugs. As a result, most pts receive only transfusion support post-ESA, representing a pt group with an unmet medical need frequently targeted for drug development, for whom long-term outcome is unknown. Methods: We studied pts diagnosed with lower-risk MDS from 1997-2014 at MDS CRC institutions and treated with ESAs (epoetin alpha (epo) or darbepoetin (darb)). The best response to treatment was categorized per International Working Group 2006 response criteria (hematological improvement (HI), complete response (CR), or partial response (PR)). The primary endpoint was overall survival (OS) at the time of ESA failure, defined as cessation of treatment due to relapse or refractoriness; a secondary endpoint was time to AML transformation or death, from time of response (for responders) or failure (for nonresponders) determination. Descriptive statistics were used for baseline characteristics. The Kaplan Meier method was used to estimate OS and a log rank analysis was used to compare response categories. Cox regression analysis was performed for multivariable analysis. Results: Of 206 patients included in analyses, median age was 71.6 years (range: 25.3-88.1), 36% were female, 5% were African-American, and 11% had t-MDS. WHO categories included RA (14%), RARS (16%), RCMD (42%), MDS-u (6%), del (5q) (4%), RAEB-1 (9%), RAEB-2 (2%), RARS-T (2%), MDS/MPN-u (3%), and CMML-1 (2%), with pts classified as IPSS Low (39%), Int-1 (61%), or IPSS-R Very Low (16%), Low (55%), Intermediate (26%), and High (4%). IPSS cytogenetic risk groups were Good (72%), Intermediate (22%), and Poor (6%). Baseline median hemoglobin was 9.4 g/dl (range: 5.5-14.2), serum epo level was 97.2 (range: 14.2-3899.0), and 11% were transfusion-dependent. Treatment included darb (59%) and epo (41%) at median doses of 300 mcg (range: 100-500) and 40,000 units (range: 5,000-80,000), respectively. Pts remained on therapy for a median of 30.4 weeks (range: 0.0-447.7) and had a median follow-up of 28.4 months (95% confidence interval (CI): 24.5, 45.4). First treatments following ESA failure included azacitidine (41.7%), decitabine (10.2%), lenalidomide (16.6%), experimental drugs (3.1%), other growth factors (13.6%), ATG and/or other immunosuppressants (8%), chemotherapy (0.1%) , transplant (0.1%) and others (6.6%). The overall response rate (ORR) to ESAs was 18.8%, with 0% achieving CR; 0.1% PR; and 18.7% HI. Responses for epo were 17.3% and for darb were 19.8% (p=.67 for difference). For both ESAs, 81.2% of patients had disease refractory to treatment: 69.4% with stable disease and 12% with progressive disease with no significant differences between epo and darb by responder status. Median response duration for epo and darb were 21.9 weeks (range: 3.0 - 447.7) and 39.1 weeks (range: 0.0 - 350.7) respectively (p=0.045). Median survival from the date of diagnosis was 28.4 months (95% CI: 24.5, 45.4), and from ESA failure was 23.9 months (95% CI: 19.9, 33.0): 21.6 months (95% CI: 15.6, 39.2) for epo and 28.8 months (95% CI: 21.2, 39.7) for darb (p=0.99) (Figure). Median time to AML transformation or death was 17.4 Months (95% CI: 14.1, 22.9): 25.4 months for responders and 16.8 months for non-responders (p=.069). For patients who received ESAs for a minimum of 4 months (39% of pts for epo and 61% for darb), ORR was 16.5%, and median survival from ESA failure was 23.0 months (95% CI: 14.7, 33.0): 22.3 months (95% CI: 13.1, NA) for epo and 24.7 months (95% CI: 14.3, 39.7) for darb (p=0.87). Conclusion: In this large, but uncontrolled cohort, response rates were similar for lower-risk MDS patients treated with epo and darb, though duration was longer for darb. There was a trend for improved outcomes in patients who responded to ESAs. Lower-risk MDS patients treated with ESAs have an OS of less than 2 years from the time of failure, and can thus be considered a high-risk MDS group for whom subsequent therapies are not standardized, representing an unmet medical need. Figure 1. Figure 1. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Komrokji:Incyte: Consultancy, Honoraria, Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Speakers Bureau.

Description: Introduction: Somatic mutations are common in MDS and mutation profiling is becoming increasingly standard as part of the initial diagnostic evaluation. The value of serial monitoring of mutation profiles in MDS patients at multiple disease course time points is unknown. We evaluated the impact of serial mutation monitoring in a cohort of MDS patients. Methods: MDS patients from participating institutions of the MDS CRC with molecular genetic data by next-generation sequencing available from at least two distinct time points were included in analyses. Mutations present at the first time point were compared to those present at subsequent time points and correlated with age, International Prognostic Scoring System (IPSS) score, and overall survival, measured from diagnosis. Cox proportional hazards model of time from diagnosis to death or loss of follow up with time varying number of mutated genes, gained genes and lost genes adjusted for sex, age at diagnosis, and IPSS category at/near diagnosis was applied. Results: Of 737 MDS patients with molecular genetic data available from 1994 to 2016, 94 had information on the 18 genes presented in Table 1 from at least two distinct time points. Patients had a median of 2 (range 2-9) myeloid mutation panel assessments, with a median interval of 3.3 months (range 0.1-39) between studies. Mutation testing was repeated at the investigator's discretion either at time of suspected disease progression or change of therapy. Clinical characteristics of the patients are summarized in Table 2. Almost half (46%) had an initial mutation profile performed within 1 month of diagnosis, 23 patients (24%) within 1-12 months, and 28 patients (30%) more than 12 months after diagnosis. At the time of initial evaluation, patients had a median of 1.5 mutations (range 0-4), with the most common being TP53 (28%), RUNX1 (20%) TET2 (18%), DNMT3A (17%), and ASXL1 (17%). Independent of age or IPSS score at baseline, the number of mutations initially present in a gene set consisting of ASXL1, EZH2, ETV6, RUNX1, TP53 was associated with poor overall survival (HR 2.19, p=0.003, 95% CI, 1.30-3.69). Overall, 32 patients (34%) acquired at least one additional mutation at subsequent testing, including ASXL1 (10%), RUNX1 (7%), TP53 (5%), SETBP1 (5%), and DNMT3A (4%). The acquisition of additional mutations in any gene in subsequent testing was associated with worse overall survival (HR 1.93, p=0.0002, Cl, 1.36-2.75), irrespective of age, IPSS score, and the number of mutations initially identified among the core group of five prognostically significant mutations. Of note, treatment was similar for patients who were found to have acquired additional mutations compared to those who did not: hypomethylation agents (93% vs 80%, p=0.11), lenalidomide (10% vs 11%, p=0.94), and chemotherapy (38% vs 49%, p=0.33). Patients who acquired at least one additional mutation beyond those identified at diagnosis had a higher rate of acute myeloid leukemia transformation (62% vs 37%, p=0.02). Additional acquired mutations were more likely to be observed in serial testing after AML transformation, compared to patients without AML transformation (36% vs 17%, p=0.01). In this model, acquisition of a mutation in DNMT3A, IDH1, IDH2, SETBP1, or TET2 was associated with poor overall survival (HR 3.88, p=0.006, CI, 1.46-10.3). Gain of mutations in CBL, MPL, NPM1, or PHF6 was also associated with poor survival (HR 8.15, p=0.0008, CI, 2.38-27.86). Loss of mutation in serial testing was observed in 33% of patients was and did not correlate with overall survival (HR 0.66, p=0.25, CI, 0.32-1.36). A small subset of patients who underwent allogeneic stem cell transplantation were found to lose their diagnostic mutation(s) at the time of transplant. Conclusions: The acquisition of new mutations in MDS patients undergoing serial monitoring is associated with poor overall survival independent of age, sex, and IPSS, in some part related to the indication for testing. Serial mutation profiling identified a small number of patients who acquired "actionable" mutations for which clinical trials were potentially available, but did not substantively alter treatment choices. Further investigation of the relationships between disease biology, treatment effects, and acquisition/loss of mutations should be conducted in the context of clinical trials. The role of serial mutation profiling in MDS warrants further investigation. Disclosures Lee: Boehringer Ingelheim: Consultancy; Baxalta: Consultancy; Amgen: Consultancy; Alexion Pharmaceuticals: Consultancy; Pfizer Inc: Consultancy. Steensma:Genoptix: Consultancy; Janssen: Consultancy; Millenium/Takeda: Consultancy; Ariad: Equity Ownership; Celgene: Consultancy; Amgen: Consultancy. Ritchie:Arian: Speakers Bureau; Novartis: Honoraria; Incyte: Speakers Bureau; Pfizer: Honoraria; Celgene: Speakers Bureau. Desai:Boehringer Ingelheim: Consultancy. Komrokji:Boehringer-Ingelheim: Research Funding; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy.