Citations

Abstract Background: One of the main complications in CLL is Richter syndrome (RS). RS derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B-cell lymphoma (DLBCL) type. RS occurs in 2.2% to 8% of patients with CLL and the prognostic is poor with a median survival from 5 to 8 months. Detection of RS by imaging has resulted in conflicting and non-significant results. Aim: The objective of this study was to validate recent findings correlating FDG/PET imaging and histological features in CLL and to demonstrate that a tumoral maximum standardized uptake value > 10 measured on 18F-FDG-PET is a new valid marker to discriminate RS. Results: From June 2006 through December 2012, 240 patients from the Division of hematology of Centre Hospitalier Lyon Sud and Créteil and from the Mayo Clinic Rochester have been analyzed with a mean age of 62 years (21-91). Clinical, histological (confirm by biopsy) and biological parameters have been identified with 10% of the patients as having RS, 34% stable CLL disease; 42% of rapid CLL progression (histological features of progression defined as increased large cell number, large confluent proliferation centers or high proliferation rate assessed by Ki-67 but not meeting criteria for diffuse large B-cell lymphoma/RS) and 14% with others diseases (e.g. infection and or cancers). For patients with stable CLL disease, the median tumoral SUV max was 2 (range: 0-2.4). Among patients with a rapid progression of CLL, 90% had a tumoral SUV max <10 but greater than the liver median SUV max (4.5 range: 1-11). In contrast, 90% of patients with RS had a median tumoral SUV max >10 (12.9; range: 5-27). A statistically significant difference between SUV max of CLL patients with stable disease and RS was observed (2.2 vs. 12.9; p< 0.0001) and similarly for SUV max of CLL patients with rapid disease progression and RS (4.5 vs 12.9; p< 0.0001). Regardless of the RS prevalence (2.2% to 8%), statistical tests identified a threshold of tumor SUV max > 10 as the more discriminating cut off. Using this threshold, the sensitivity and specificity of PET to identify RS in our cohort are 91% and 95% respectively. Assuming an RS prevalence of 2.2%, positive predictive value (PPV) and negative predictive value (NPV) using the >10 threshold were 28.7% and 99.8%; for an 8% prevalence of RS, the PPV and NPV are 60.8 and 99.2% respectively.The proportion of correctly classified patients with RS is more accurate using a threshold of tumoral SUV max > 10 than 5 (2.2% RS prevalence: 94.8% versus 71.8%; 8% RS prevalence: 94.6% versus 73.5%). Finally analysis of the area under the curve (AUC) reveals a value of 0.95 (95% confidence interval: 0.89- 0.99). Recently, Falchi et al, reported on 332 patients with CLL classified as 95 RS, 117 rapid progression and 120 stable disease and demonstrated a strong correlation between histological features and PET imaging. A SUV max ≥10 strongly correlated with a shorter overall survival. Similarly, in our study we have shown excellent sensitivity and negative predictive value estimated at 100%, revealing the ability of 18F-FDG-PET-CT to rule out the diagnosis of RS if the tumor SUV max is less than 10. Conclusion: 18F-FDG-PET-CT is a valuable tool in the diagnostic evaluation of RS for patients with CLL. It is not only useful to identify RS syndrome and guide the site of biopsy but also to identify CLL patients who will experience more rapid disease progression. An SUV max > 10 is the optimal threshold to distinguish RS in CLL. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Guadecitabine (SGI-110) is a novel next-generation HMA administered as a small volume subcutaneous (SC) injection which results in extended decitabine exposure. Phase 2 studies have been conducted in TN-AML patients who were not candidates for intensive chemotherapy using two different doses and schedules of guadecitabine. We report here a comparative efficacy and safety analysis of the 5-day and 10-day regimens. Methods: TN-AML patients who were not candidates for intensive chemotherapy based on age (≥ 65 y), poor performance status (PS 2), comorbidities, or poor risk cytogenetics were enrolled in 2 separate treatment cohorts in the Phase 2 study. In the first cohort, patients were randomized (1:1) to either 60 mg/m2/d or 90 mg/m2/d on Days 1-5 (5-day regimen). In the second cohort, patients were treated with 60 mg/m2/d on Days 1-5 and Days 8-12 (10-day regimen) for up to 4 cycles, followed by 60 mg/m2/d Days 1-5 in subsequent cycles. Cycles were scheduled every 28 days for both regimes with dose reductions/delays allowed based on response and tolerability. Patients remained on treatment as long as they continued to benefit with no unacceptable toxicity. The primary endpoint was the composite Complete Response (CRc): Complete Response (CR) + CR with incomplete platelet recovery (CRp) + CR with incomplete neutrophil recovery (CRi) using modified International Working Group (IWG) criteria (Cheson et al, 2003). Secondary endpoints included overall survival (OS), and safety. Results: There was no difference in efficacy or safety between 60 and 90 mg/m2/d on the 5-day regimen (Yee et al, European Hematology Association meeting 2014, S647), so data are reported here for the two doses combined on the 5-day cohort. There were 51 patients treated in the 5-day regimen cohort and 52 treated with the 10-day regimen. There was no statistically significant difference in patient characteristics between the 2 regimens; median age 77.9 vs. 77.3 years ; male 59% vs. 65%; PS 2 or higher 35% vs. 40%; median BM blasts 40.0% vs. 49.5%; poor risk cytogenetics 46% vs. 43% for the 5-day and 10-day cohorts, respectively. Follow up of the 10-day cohort patients was shorter as it started after completion of enrolment of the 5-day cohort. The median follow up was 25.7 and 12.4 months and median number of cycles was 5 (range 1-26) and 3 (range 1-13) for the 5-day and 10-day cohorts, respectively. There was no significant difference in the primary efficacy endpoint, CRc, between the 2 regimens (p=0.43). CRc was achieved in 29/51 patients (57%) on the 5-day regimen (19 CR, 3 CRp, and 7 CRi) and in 25/52 patients (48%) on the 10-day regimen (16 CR, 5 CRp, and 4 CRi). Median OS was 10.5 and 8.7 months for the 5-day and 10-day cohorts, respectively (p=0.89). The 30, 60, and 90-day all-cause mortality rates were not statistically significant between the two cohorts: 5.9%, 15.7%, and 21.6% on the 5-day regimen and 1.9%, 17.3%, and 28.8% on the 10-day regimen. The most common Grade ≥3 AEs regardless of relationship to guadecitabine were: febrile neutropenia 59% vs. 60%, thrombocytopenia 47% vs. 38%, neutropenia 39% vs. 33%, anemia 27% vs. 19%, pneumonia 24% vs. 27%; and sepsis 12% vs. 19%, for the 5-day and 10-day cohorts respectively, none of which was statistically significant. Fifteen patients remain on treatment (5 from the 5-day cohort and 10 from the 10-day cohort). Conclusions: Guadecitabine is clinically active with a good safety profile in TN-AML patients not candidates for intensive chemotherapy. Unlike in relapsed/refractory AML, where the 10-day regimen of guadecitabine showed a trend toward improved efficacy (Roboz et al, Annals of Oncology 25 Supplement 4, 2014), there was no significant difference in either efficacy or safety between the 5-day and 10-day regimens in newly diagnosed AML patients. Guadecitabine 60 mg/m2/d SC Days 1-5 is currently being investigated in an 800-patient multicenter randomized phase 3 study in TN-AML patients unfit to receive intensive chemotherapy (ASTRAL-1 Phase 3 clinical trial: ClinicalTrials.gov reference NCT02348489). Disclosures Kropf: Teva Pharmaceuticals: Consultancy. O'Connell:Celgene: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Griffiths:Astex: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Savona:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Rosenblat:Astex Pharmaceuticals, Inc.: Research Funding. Berdeja:Celgene: Research Funding; Onyx: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Array: Research Funding; Curis: Research Funding; Acetylon: Research Funding; MEI: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Takeda: Research Funding. Wilson:Astex Pharmaceuticals, Inc.: Employment. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Janssen: Consultancy; Astex Pharmaceuticals, Inc.: Consultancy.

Abstract Background: SGI-110 is a second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume SC injection that yields longer half-life and more extended DAC exposure than DAC IV infusion. A phase 1 clinical trial of SGI-110 demonstrated a differentiated pharmacokinetic profile from DAC IV, potent hypomethylation, and clinical responses in previously treated patients with MDS and AML (Kantarjian et al. 2012). Phase 1 established 60 mg/m2 QDx5 as the biologically effective dose (BED), and 90 mg/m2QDx5 as the Maximum tolerated dose (MTD) in MDS patients given in 28-day cycles. Phase 2 is conducted to evaluate dose response between the BED and MTD in MDS patients. Methods: Int, or HR MDS, and CMML patients who were either treatment-naïve or previously treated were randomized to either 60 mg/m2 or 90 mg/m2QDx5 every 28 days. Efficacy was evaluated by the clinical responses of CR, PR, marrow CR (mCR), and Hematological Improvement (HI) based on the International Working Group Criteria 2006 as well as transfusion-independence. Adverse events (AEs) as graded by the CTCAE v4 criteria and pharmacodynamic biological activity as measured by Long Interspersed Nucleotide Element LINE-1 (an index of global DNA methylation) were also assessed. Patients are being followed for overall survival. Results: The study completed target enrolment with 102 patients: 53 who were refractory or have relapsed on prior treatment, and 49 previously untreated. Fifty three patients were randomized to 60 mg/m2 and 49 patients to 90 mg/m2 QDx5 with a median follow up of 8.2 months (range 1-21). Most baseline patient characteristics were well balanced between the 2 treatment arms with no significant differences in median age (71.7 vs. 72.5 y); male gender (70 vs. 61%); ECOG PS 2 (15 vs. 12%); HR MDS (28 vs. 37%); transfusion-dependence (57 vs. 55%), median baseline Hb (9.25 vs. 9.3 g/dL); platelets count (42.5 vs. 45 x109/L), and neutrophils count (1.19 vs. 1.16 x109/L) for the 60 and 90 mg/m2 QDx5 respectively. However, there were 15 CMML patients (28%) randomized to 60 mg/m2 vs. only 7 CMML patients (14%) randomized to 90 mg/m2(p=0.097). All but 2 patients in the previously treated group received one or more HMA. At the time of the data cutoff, 38 of 102 patients (37%) were still on treatment. Median number of treatment cycles was 4 for previously treated patients, and 5 for the treatment naïve group (range 1-22 cycles). CR+mCR were observed in 10/53 (19%), and 11/49 (22%) in the 60 and 90 mg/m2 arms respectively (p=0.8). CR was observed in 7/49 treatment naïve patients (14%) while CR+mCR were observed in 11/53 previously treated patients (21%) with no significant differences between 60 and 90 mg/m2 arms. Transfusion independence for at least 8 weeks was reported in 32% and 24% for platelets and RBCs respectively with no difference between the 2 treatment arms. Treatment naïve patients benefited from higher rate of transfusion-independence (58% and 46% for platelets and RBCs respectively). Potent demethylation was achieved in both treatment arms with a mean LINE-1 DNA demethylation of 27.3 and 30.5% for 60 and 90 mg/m2 respectively (p=0.12). Overall incidence of Grade ≥3 AEs regardless of relationship to treatment was reported in 81 vs. 88% for 60 and 90 mg/m2 treatment arms respectively (p=0.42).There was a slightly higher but non-significant difference in Grade ≥3 thrombocytopenia (51 vs 38%) and pneumonia (20 vs. 13%) for the 90 mg/m2 arm compared to 60 mg/m2. Early 8-week any-cause mortality occurred in 3/102 patients treated (3%), 2 at 60 and 1 at 90 mg/m2. Follow up for survival is still ongoing. Conclusions: SC SGI-110 is a well-tolerated novel HMA with biological and clinical activity in the treatment of Int and HR MDS, and CMML patients with particularly promising activity in patients previously treated with azacitidine or decitabine. Clinical responses, transfusion independence, DNA demethylation as assessed by LINE-1, and Safety did not significantly differ between the 2 treatment doses. Disclosures Tibes: Astex Pharmaceuticals, Inc.: Research Funding. Rosenblat:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Issa:Astex Pharmaceuticals, Inc.: Consultancy, Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Roboz:Astex Pharmaceuticals, Inc.: Consultancy.

Abstract Introduction: CMML is a heterogeneous malignancy characterized by peripheral monocytosis and a propensity for AML transformation. Given the low incidence of CMML and its broad range complexity, a large disease-specific data set is necessary to discern independent co-variates predictive of disease behavior. Several prognostic models derived from smaller data sets have been developed to stratify CMML patients into distinct groups that are predictive for OS. However, the validity of these models in a large international data set has never been investigated. Here, we present the largest International CMML data base established to date and report key baseline characteristics predictive for disease outcome. We externally validate and perform a detailed statistical comparison between the International Prognostic Scoring System (IPSS), Revised (R)-IPSS, Global MD Anderson Scoring System (MDASC), MD Anderson Prognostic Score (MDAPS), Dusseldorf Score (DS), Mayo, and Spanish Scoring Systems (CPSS). Methods: Data were abstracted by each contributing institution and deposited for central data review at the Moffitt Cancer Center. Manual review of cases was performed to ensure data quality prior to analysis. Only WHO defined CMML was included. The primary objective of this study was to establish an international CMML data set and validate the above models calculated at the time of presentation to each center. All prognostic models were calculated as previously described. The Kaplan–Meier (KM) method was used to estimate median OS and the log rank test was used to compare KM survival estimates with SPSS version 21.0. Random Forest Survival (RSF) and ROC analysis was done with R. Results: Between July 1981 and June 2014, 1832 CMML patients were captured in the International CMML database. Median age at diagnosis was 70 (16-93) years with a male (67%) predominance. By the WHO classification, the majority of patients had CMML-1 (79.9% vs. 20.1%) and most patients were evenly subcategorized as MPN-CMML (49.8%) versus MDS-CMML (50.2%) by FAB criteria. Splenomegaly was demonstrable in 25%. Most patients had favorable cytogenetics by both IPSS (70%) and CPSS (67.6%) classification schemas. Mean BM blast % was 5.6 and mean monocyte count was 4.85x103/dL. Median OS of the entire data set was 31.6 months. All tested prognostic models were valid and able to predict OS (p<0.0001). To compare relative model performance, 1013 complete cases with sufficient data to calculate all risk models were compared using time dependent receiver operator characteristic (ROC) curves and their area under the curves (AUC). ROC curves were calculated for OS at 36 months. The R-IPSS model had the highest AUC (0.694) while the DS model had the lowest (0.635). The difference in AUC between the R-IPSS and DS models was statistically significant (p = 0.003) whereas there was no significant difference from other models tested. To determine which models were most vulnerable to reclassification from low-risk to higher risk, we calculated a vulnerability score defined by the number of models able to up-stage low-risk disease in more than 15% of cases. Using this metric, the Mayo and MDASC scores were least vulnerable to up-staging by other models. Lastly, we used an orthogonal method for determination of variable importance (RSF for OS at 36 months). RSF is an ensemble method of classification and regression tree methodology. Ranking of variables by their weighted importance determined by this procedure identified the top five variables were hemoglobin, circulating blasts, platelet count, number of cytopenias, and karyotype. A new risk model was developed using the results of the RSF with an AUC of 0.720, which was comparable but not significantly different than other modern scoring systems. Conclusions: This represents the largest international CMML-specific data set derived from eight unique centers of excellence. All modern prognostic models were valid and performed comparably. Despite novel strategies for variable importance discovery, an improved model could not be constructed. This data suggest that the power of clinical variables has reached an asymptote and highlights the need for incorporation of molecular and other novel biological features. This data set is currently being populated with molecular data and is being leveraged to test published CMML molecular prognostic models which will be disclosed at the time of presentation. Disclosures Garcia-Manero: Epizyme, Inc: Research Funding. Fenaux:Celgene, Janssenm, Novartis: Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: The majority of pts with MF present with a mutation in exon 14 of the JAK2 gene (JAK2V617F). Studies have suggested that in pts with MF and this mutation, a lower AB is associated with a myelodepletive phenotype and shortened survival (Tefferi, Leukemia 2008; Guglielmelli Blood 2009; reviewed in Vannucchi, Ther Adv Hematol 2011). For example, in a Cox proportional hazard model for factors predictive of overall survival (OS) in pts with primary MF, a JAK2V617F AB of <25% was associated with a shortened OS (p=0.002; Guglielmelli, Blood 2009). In the phase III trials of ruxolitinib (RUX) therapy in JAK inhibitor-naïve MF, RUX-treated pts had a median decrease in AB of 16% (maximal) in COMFORT-I followed up to 216 weeks and 7% in COMFORT-II at 48 weeks. The median AB at the start of therapy was not reported for COMFORT-I and in COMFORT-II was 84.5% (Cervantes, Blood 2013; Deininger, Blood2015). Methods: In this communication, we report on clinical correlates of quantitative baseline JAK2 mutational status and the effect of treatment on JAK2V617Fmutational burden in the PERSIST-1 trial. This trial enrolled JAK inhibitor-naïve pts with primary or secondary MF without restrictions on baseline platelet counts, randomized 2:1 between PAC and BAT (excluding JAK2 inhibitors) arms. Stratifications included Dynamic International Prognostic Scoring System (DIPSS) risk category, and baseline platelet counts (<50,000/μL, 50,000-100,000/μL, >100,000/μL). Following the 24-week primary analysis, crossover was allowed by physician/pt choice and 90/107 BAT-treated pts (84%) crossed over to receive PAC. Baseline characteristics have been previously reported (Mesa, ASCO 2016) and included 203/327 (62%) pts with Primary MF, 42 (13%) with post-essential thrombocythemia MF and 81 (25%) with post-polycythemia vera MF. 320 of 327 pts had informative PCR testing for JAK2V617F. We report the baseline characteristics of pts with high (≥50%) AB of JAK2V617F, low (<50%) AB of JAK2V617Fand those without a detectable mutation at baseline (<0.1%), as well as the effect of PAC and BAT on AB and correlation with outcome measures. Results: 131 (40.9%) had AB >50% (high AB), 115 (35.9%) had an AB ≥0.1% and ≤50% (low AB), and 74 (23.1%) had AB <0.1% (wild-type JAK2). Median AB values were 80.3% for the high AB group and 30.3% for the low AB group. Baseline characteristics that were significantly different between high and low AB pts are shown in the Table. No differences were noted in the DIPSS risk category or baseline percentage of blasts between pts with low or high AB. There were a higher percentage of pts with a lower AB in the PAC arm (64% vs. 48%; p=0.01). PAC therapy resulted in a median decrement in AB at Week 24 of −15.8% vs −7.9% for pts in the BAT arm (Figure). The median greatest reduction from baseline in AB in PAC-treated pts was −31.6%. Decrease in AB was strongly correlated with spleen volume reduction (p=0.003) and trended towards correlation with improvement in total symptom score (p=0.07) in PAC-treated, but not in BAT-treated pts. Overall survival was shorter in PAC-treated pts with a minimal AB reduction vs pts with greater decreases in AB. Conclusions: In the PERSIST-1 trial, pts with a JAK2V617FAB of <50% had substantially different disease and demographic characteristics when compared with those pts with a >50% AB despite similar distribution of DIPSS scores. In this trial, reduction in AB associated with PAC, but not BAT correlated with clinical benefit. Disclosures Vannucchi: Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau. Mead:Baxalta: Consultancy, Honoraria. Perkins:Novartis Oncology: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Travel, Accommodations, Expenses. Mayer:CTI BioPharma Corp.: Other: Travel, Accommodations, Expenses, Research Funding. Schouten:Sanofi: Consultancy; Novartis: Consultancy. Farber:Alexion: Equity Ownership; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Seattle Genetics: Speakers Bureau; Pharmacyclics: Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Consultancy, Research Funding. Nangalia:Novartis: Consultancy, Other: Travel, Accommodations, Expenses. Dean:CTI BioPharma Corp.: Employment, Equity Ownership. Zhou:CTI BioPharma Corp.: Employment, Equity Ownership. Singer:CTI BioPharma Corp.: Employment, Equity Ownership, Other: Leadership . Mesa:Novartis: Consultancy, Honoraria; Incyte: Research Funding; Gilead: Research Funding; CTI BioPharma: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Promedior: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria; Shire: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau.

Abstract Background: The current standard of care for eligible newly diagnosed multiple myeloma (MM) patients is induction therapy with novel agents followed by high dose chemotherapy and autologous stem cell transplant (ASCT). The International Myeloma Working Group proposed the Revised International Staging System (R-ISS) based on the presence of adverse chromosomal abnormalities (CA) detected by FISH (t(4;14), t(14;16) or del17p), in combination with ISS and LDH at diagnosis. However, there are a limited number of studies that have validated this risk model in the transplant and novel agents setting. Aims: To determine whether R-ISS is an appropriate risk-model for estimating overall survival (OS) and progression free survival (PFS) for transplant-eligible MM patients. Patients and Methods: We retrospectively studied a cohort of 519 MM patients who received novel drugs in the induction and subsequently underwent ASCT at Mayo Clinic Arizona from 2005 to 2014. In all, 95 patients met the inclusion criteria: comprising complete data at diagnosis (ISS, serum LDH level, and CA by FISH). The primary endpoint was OS from SCT and the secondary end point was PFS from ASCT. R-ISS groups were defined as described by Palumbo et al. J Clin Oncol. 2015; 33(26):2863-2869. Results: There were 50 (52.6%) men and 45 (47.4%) women who underwent ASCT in this period, with a median age at the time of transplant of 66-years-old (range, 36-78). There were 27 patients (28.4%) with high-risk CA: 12 patients (12.6%) with del17p; 11 patients (11.6%) with t(4;14); and 6 (6%) with t(14;16). In addition, 8 patients (8.5%) had high LDH levels and 9 patients (9.5%) presented with renal impairment at diagnosis. The patients were staged at diagnosis according to the three R-ISS groups: 44 patients (46.3%) had stage I, 26 (27.4%) had stage II, and 25 (26.3%) had stage III. CyBorD was the preferred induction regimen which was received by 42 patients (44%). There were 14 patients (15%) who received at least 2 lines of induction. All patients were in at least partial response (PR) at the moment of transplant: 32 in complete response (CR), 32 in very good partial response (VGPR) and the remaining 31 in PR. The response achieved at day +100 after ASCT improved, with 54 patients (57%) in CR, and only 18 patients (19%) in PR. After a median follow-up of 61 months (range, 14-135), median OS from SCT was 108 months (95% CI: 85 - 132 months) and the median PFS was 45.4 months (95% CI: 31.1 - 53.8 months) in the whole series.MM patients with R-ISS III had a significantly shorter median OS compared to patients with R-ISS II or R-ISS I (32.1 months vs. 94.7 months vs. not reached, respectively, P<0.0001) (Figure). No statistically significant differences in baseline characteristics were identified among these groups to explain the differences in OS observed. PFS among these groups was not statistically significant, only showing a trend towards shorter PFS in R-ISS III compared with either R-ISS I or II: median 22.1 months vs. 35.7 months, respectively, (P=0.2). Renal impairment at diagnosis, IgA subtype, ≥ 2 lines of induction treatment, and less than CR achieved at day +100 after ASCT were also associated with significantly inferior OS. Multivariate analysis selected R-ISS as an independent predictor for OS (HR: 2.3, 95% CI: 1.1-4.8; P=0.03), as well as ≥ 2 lines before ASCT. CR at day +100 after ASCT was the most important independent factor for predicting PFS (HR: 0.4; 95% CI: 0.2-0.6; P<0.001). Conclusion: R-ISS assessed at diagnosis was an independent predictor for OS after ASCT in our series, with median OS for the different R-ISS groups comparable to those reported by Palumbo et al. in their subgroup of younger patients. Thus, this study lends further support for the R-ISS as a reliable prognostic tool for estimating OS in transplant-eligible MM patients. In addition, new treatment approaches are needed for the high-risk patients (R-ISS III) with a median OS of 2.5 years. Figure Figure. Disclosures Reeder: Millennium: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Mikhael:Abbvie: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding. Stewart:celgene: Consultancy. Fonseca:Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Bayer: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; AMGEN: Consultancy; Millennium, a Takeda Company: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Novartis: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; BMS: Consultancy; Millennium, a Takeda Company: Consultancy; BMS: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms.

Abstract Introduction: Patients with RR-AML, particularly older adults, have dismal outcomes and limited therapy options. Given low response rates and high toxicity with salvage intensive chemotherapy, and frequent ineligibility for allogeneic stem cell transplantation (alloSCT), many patients are treated with HMAs. Robust data regarding use of HMAs in AML predominates in the frontline setting, while their use in RR-AML has limited supportive data. Here wesought to analyze theoutcomes and their predictors in patients with RR-AML treated with HMAs. Methods:We collected data, spanning a period from 2006 to 2016, from 7 centers in the United States and 4 centers in Europe regarding patients treated with HMAs for RR-AML. Responses were defined by International Working Group criteria. Kaplan-Meier methods estimated overall survival (OS) from initiation of HMAs to death or end of follow-up. Multivariable logistic regression models estimated odds for response, and multivariable Cox Proportional Hazard (CPH) models estimated hazards ratios (HR) for OS. Covariates considered included HMA received, age at diagnosis (in years), AML classification at diagnosis (AML with myelodysplasia-related changes [AML-MRC], therapy-related [t]-AML), disease status (relapsed vs. refractory), number of therapy lines prior to HMA (1 vs. 2 vs. >=3), duration of first complete remission (CR1), white blood cell count, peripheral blood blast percentage, bone marrow (BM) cellularity (<=20% vs. > 20%), BM blast percentage (<=20% vs. >20%), cytogenetic risk group, and the presence of complex or chromosome 7 abnormalities. Results: Of 514 patients, 217 patients (42.2%) had refractory and 297 (58%) had relapsed AML. By end of study, 415 patients (88.5%) had died. Median follow-up for living patients was 11.6 months.Median age at diagnosis was 64 years (range [R], 16-92). AML-MRC was diagnosed in 29.0% while 8.2% had t-AML. Median number of prior therapies was 2 (R, 1-7), with 48.3% receiving 1 prior line, 30.2% receiving 2 prior lines, and 21.5% receiving >=3 prior lines. Prior alloSCT was performed in 21.2%. Only 1.9% had good risk (core binding factor) karyotype, while 56.2% had intermediate risk karyotype, and 41.9% had poor risk karyotype. Azacitidine was used in 45.8% and decitabine in 54.2%; median number of azacitidine cycles was 4 (Interquartile range [IQR], 2-6) compared to 2 for decitabine (IQR, 1-4, p <0.001). Best response to HMAs was CR in 11.7% (95%CI, 9%-14%), CRi in 6.4% (95%CI, 4.3%-8.8%), hematologic improvement (HI) in 8% (95%CI, 5.7%-10.5%), stable disease (SD) in 9.8% (95%CI, 7.2%-12.5%), while 64.1% (95%CI, 57.7%-66.2%) had progressive disease (PD). Median OS from HMA initiation for all patients was 6.9 months (IQR, 3.0-13.3). There was a significant difference in OS based on best response achieved [Figure 1]. Unadjusted OS showed an insignificant trend for worsening with increasing number of prior lines of therapy [Figure 2A]. In unadjusted analyses, there was no difference in OS based on HMA received in all patients [Figure 2B] or the subset who received only 1 prior line of therapy (median OS: Azacitidine vs. decitabine 8.4 vs 7.3 months, p=0.88). Following HMA therapy, the median number of subsequent therapies was 0 (R, 0-6), and only 12.8% underwent alloSCT. In multivariate CPH models, HMA used was not significantly associated with OS (HR=0.80, 95%CI, 0.42-1.51, p=0.49), while increasing age, and presence of complex cytogenetics and chromosome 7 abnormalities were significantly associated with risk of death [Table 1]. In multivariable logistic regression models, HMA used was not associated with achieving CR+CRi (Odds ratio=0.56, p=0.32). Conclusions: In this largest reported cohort of patients with RR-AML treated with HMAs, we found that HMAs are often used as alast line of therapy, with a minority of patients receiving subsequent treatment. Nonetheless, the minority of patients who achieve CR (11.7%) with HMA therapy had a median OS of 25.6 months. Therefore, use of HMAs for management of RR-AML is a reasonable intervention in the absence of clinical trial options. There appears to be no difference in OS or probability of achieving CR+CRi based on HMA used. Ongoing analyses in this dataset include further evaluations of predictors, including genetic mutations, and the development of prediction tools for clinical outcomes with HMA therapy. Figure 1. Figure 1. Disclosures Podoltsev: Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Arian: Speakers Bureau; Pfizer: Honoraria; Celgene: Speakers Bureau. 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. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. 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. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gore:celgene: Consultancy, Honoraria. Zeidan:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis, thrombocytosis, and/or leukocytosis and a broad range of disease-related symptoms. In high-risk patients, the most common first-line treatment is hydroxyurea (HU). The open-label RESPONSE trial demonstrated that ruxolitinib (RUX), a JAK1/JAK2 inhibitor, provided superior efficacy compared with best available therapy in patients with PV who were resistant to or intolerant of HU according to modified European LeukemiaNet (ELN) criteria. This study (RELIEF) was conducted in patients receiving a stable dose of HU and who were generally well controlled but reporting disease-associated symptoms, comparing the change in PV-related symptom burden in patients continuing their HU therapy with those switching to RUX treatment. Methods: RELIEF was a randomized, multicenter, double-blind, double-dummy, phase 3b study of patients with PV aged ≥18 years on a stable dose of HU monotherapy and reporting PV-related symptoms. Patients were required to be receiving HU for ≥12 weeks prior to enrollment and on the same dose level for the last 4 weeks, and have a score ≥8 on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) cytokine total symptom score (TSS-C). The TSS-C comprised symptoms of itching, tiredness, muscle ache, night sweats, and sweats while awake; each symptom was rated on a scale of 0=absent to 10=worst imaginable, with a maximum TSS-C score of 50. Patients also had to meet one of the following: ≤1 phlebotomy in the previous 6 months or no palpable splenomegaly. Those eligible were randomized 1:1 to receive RUX 10 mg BID and HU-placebo, or HU at the same dose/schedule and RUX-placebo. Dose adjustments were permitted for safety and efficacy. After Week 16, patients could receive open-label RUX until Week 48. The primary endpoint was the proportion of patients with a ≥50% reduction in TSS-C at Week 16; secondary endpoints included proportion of patients with a ≥50% reduction in individual TSS-C symptoms and safety. Results: Overall, 54 and 56 patients were randomized to RUX and HU, respectively; 87.0% and 89.3% remained on treatment through Week 16. At baseline, the median age (range) was 64 (36-87) in the RUX group and 66 (19-85) in the HU group; 44% and 61% were men. The majority of patients in the RUX and HU groups did not have baseline platelet counts or WBC above ELN thresholds: platelets >400 and ≤600 x 109/L (RUX 31.5%, HU 28.6%), >600 x 109/L (3.7%, 8.9%); WBC >10 and ≤15 x 109/L (16.7%, 16.1%), >15 x 109/L (11.1%, 14.3%). In the RUX and HU groups, the mean TSS-C at screening (22.4, 23.1) was higher than that at baseline (16.7, 18.0); the ratio of screening to baseline TSS-C was 1.7 and 1.6. The proportion of patients achieving a ≥50% reduction from baseline in TSS-C at Week 16 (primary endpoint) was 43.4% in the RUX group and 29.6% in the HU group (P=0.139; OR, 1.82; 95% CI, 0.82-4.04). The proportions of patients in the RUX vs HU groups achieving a ≥50% reduction in scores for itching and tiredness at Week 16 were 40.0% vs 26.4% and 54.2% vs 32.0%, respectively. Median percentage changes in individual TSS-C symptoms are shown in Table 1. Additional analyses found no correlation between individual changes in HU dose from baseline to Weeks 13-16 and percentage change in TSS-C in the HU arm (r2=0.030). Even patients maintaining the same HU dose from prior to study entry through Week 16 reported symptom improvement: 12/35 (34.3%) with no dose change, 4/12 (33.3%) with a dose increase, and 0/9 (0%) with a dose decrease had a ≥50% reduction in TSS-C. The most common nonhematologic adverse events in the RUX arm on randomized treatment were fatigue (20.4% RUX vs 10.7% HU), headache (16.7% vs 5.4%), and dizziness (13.0% vs 8.9%). The most common adverse events on HU were diarrhea (9.3% RUX vs 19.6% HU) and constipation (7.4% vs 12.5%); most events were grade 1 or 2. Grade 3 or 4 anemia or thrombocytopenia (lab values) were not reported in the RUX group; two patients in the RUX group had grade 3 or 4 neutropenia. Conclusion: In generally well controlled PV patients receiving a stable dose of HU, there was a positive trend in symptom improvement for patients switched to RUX therapy versus those continuing on HU therapy, although this was not statistically significant. The 34% response rate among patients who continued to receive a stable HU dose suggests a placebo effect that led to an underpowered study. Further analyses are required to better interpret these findings. Disclosures Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yacoub:Alexion Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees. Koschmieder:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne:Novartis Pharmaceuticals: Honoraria. Verstovsek:Incyte Corporation: Research Funding. Hunter:Incyte Corporation: Employment, Equity Ownership. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Morozov:Novartis Pharmaceuticals: Employment, Equity Ownership.

Abstract Background: Follicular lymphoma (FL) is an indolent lymphoma generally considered incurable with current standard therapies. Recent advances have resulted in prolongation of overall survival (OS) for patients with FL such that death from competing causes may now limit the mortality impact of FL in some patient groups. Identification of patients for whom FL related mortality is expected to be minimal, or conversely those at high risk of disease related mortality, is highly clinically relevant. We recently reported (Maurer et al, JCO 2014;32:1066-73) that event-free survival (EFS) at 24 months from diagnosis is a robust endpoint for disease related outcome in patients with diffuse large B cell lymphoma (DLBCL). Here we use the same approach to assess if landmark timepoints of EFS can stratify subsequent OS in FL. Methods: All newly diagnosed grade 1-3a FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2011 were eligible. Patients with grade 3b FL, transformation, or presence of DLBCL at diagnosis were excluded. EFS was defined as time from diagnosis to progression, relapse, re-treatment, or death due to any cause. EFS12 was defined based on EFS status 12 months after date of diagnosis; we also assessed EFS at 24 months. OS was defined as time from a specific timepoint (diagnosis, event, or EFS12) until death due to any cause. OS was compared to age and sex matched survival in the general US population using an expected survival approach and standardized mortality ratios (SMR) and 95% confidence intervals (CI). Outcomes were examined in all patients as well as selected subsets defined by initial treatment. Replication was performed using a Lyon, France hospital registry of newly diagnosed grade 1-3a FL patients enrolled from 2002-2010 with survival compared to French population data. Results: 936 patients with grade 1-3a FL were eligible from the MER. The median age at diagnosis was 60 years (range 19-91) and 53% were male. 86% had grade 1-2 disease and 14% grade 3a disease. 23% had high-risk disease (FLIPI score ≥3). 347 (37%) were initially treated with alkylator or anthracyline based immunochemotherapy (IC), 113 (12%) rituximab monotherapy (RM), and 318 (34%) were initially observed; the remaining patients received radiation for limited stage disease (8%), chemotherapy without rituximab (4%), or other therapy (5%). At a median follow-up of 59 months (range 1-131), 403 patients (43%) had an event and 120 patients (13%) had died; 155 patients (17%) failed to achieve EFS12. From diagnosis, patients with FL had inferior OS compared to the general population (SMR=1.24, 95% CI: 1.03-1.48, p=0.018); results were similar for patients with grade 1-2 (SMR=1.23) and grade 3a (SMR=1.29) disease. The survival deficit was eliminated in patients who achieved EFS12 (SMR=0.85, 95% CI: 0.66-1.09, p=0.20, Fig 1a), and so we did not pursue modeling EFS24. In contrast, patients with a non-death event (relapse, retreatment, or progression) within 12 months of diagnosis had inferior subsequent OS (SMR=3.90, 95% CI: 2.89-5.25, p=4.8x10-19, Fig 1b). These results were replicated in 153 FL patients from the Lyon registry: patients who achieved EFS12 had equivalent subsequent OS to the general French population (SMR=0.82, 95% CI: 0.39-1.72, p=0.60, Fig 1c), while patients who failed to achieve EFS12 had poor subsequent OS (SMR=4.16, 95% CI: 1.34-12.91, p=0.013, Fig 1d). In subset analysis of the MER, patients achieving EFS12 initially treated with IC (SMR=0.98, 95% CI: 0.63-1.54, p=0.93), RM (SMR=0.66, 95% CI: 0.31-1.38, p=0.27), or observation (SMR=0.73, 95% CI: 0.47-1.15, p=0.18) had equivalent OS to the population. In contrast, for patients not achieving EFS12, OS after event was inferior for those treated with IC (SMR=15.0, 95% CI: 10.22-22.05, p=2.0x10-43) or RM (SMR=4.96, 95% CI: 1.24-19.84, p=0.023), while trending towards inferior for those initially observed (SMR=1.55, 95% CI: 0.81-2.99, p=0.19). Summary: Events within the first 12 months of diagnosis are associated with poor OS in FL, especially in patients treated with IC, while patients achieving EFS12 have excellent subsequent survival, overall and in the main treatment subsets. Prognosis for FL patients should be recalibrated at 12 months from diagnosis. EFS12 will be useful in counseling and should be considered as an endpoint in studies of newly diagnosed FL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background: No approved treatment options are available to HR-MDS pts after HMA therapy. Study 04-21 (“ONTIME” trial) was a Phase III, randomized, controlled study of the efficacy and safety of rigosertib, a novel small molecule inhibitor of PI3-kinase and PLK pathways, in a heterogeneous population of MDS pts who had relapsed after, failed to respond to, or progressed during administration of HMAs. The study was conducted at 87 sites in the United States and 5 European countries. Methods:From Dec 2010 to Aug 2013, 299 HR-MDS pts [<30% bone marrow blasts (BMBL)] who had progressed on (37% of total enrollment), failed to respond to (25%), or relapsed after (38%) HMA treatment were stratified on BMBL count and randomized 2:1 to receive rigosertib (199 pts) or BSC (100 pts). Rigosertib was administered at 1800 mg/24 hr for 72-hr as a continuous intravenous (CIV) ambulatory infusion, every 2 weeks for the first 16 weeks, and then every 4 weeks. The primary endpoint was overall survival (OS), analyzed on an intention-to-treat (ITT) basis using the Kaplan-Meier method stratified on BMBL (5% to 19% vs. 20% to 30%). The trial had a 95% power to detect a 13-wk increase in median OS from 17 wks on BSC, with a 2-sided alpha = 0.05. The following results are based on 242 deaths: 161 in the rigosertib arm and 81 in the BSC arm. Results : Overall, the 2 arms were balanced in terms of baseline characteristics, with the majority of pts being male (66%), and White (82%). Age ranged from 50-90 yrs in the rigosertib arm and 55-86 years in the BSC arm (median, 74 yrs). The majority of pts (85%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. The median duration of the last HMA therapy was 8.8 months (mo) in the rigosertib arm and 10.3 mo in the BSC arm; 127 (64%) of rigosertib pts and 57% of BSC pts were classified as “primary HMA failure” (ie, they failed to respond to or progressed during HMA therapy, as defined by Prebet et al, J Clin Oncol, 2011). A 2.3-mo improvement in median OS was found in the overall (ITT) population (8.2 mo rigosertib vs. 5.9 mo BSC) (Figure 1). The ITT survival for rigosertib was similar to that noted in Phase I/II studies (35 weeks). The stratified log-rank p-value was 0.33. The stratified hazard ratio was 0.87, which was quite different from the ratio of medians (5.9/8.2 = 0.72), due to the fact that the 2 survival curves converged at 15 mo. Notably, among the 184 patients with primary HMA failure, the median OS was 8.6 mo in the rigosertib arm (N = 127) vs. 5.3 mo in the BSC arm (N = 57), HR= 0.69, p= 0.040 (Figure 2). Multivariate Cox regression, adjusting for pretreatment prognostic factors, showed little change in the treatment effect. The following subgroups were correlated with better OS: pts with failure of/progression on HMA treatment, pts with duration of HMA treatment ≤ 9 mo, pts < 75 years of age, and pts with very high risk per IPSS-R (Figure 3). Rigosertib was well tolerated, with a median dose intensity of 92%. There were no significant compliance or operations issues related to ambulatory continuous infusion. Protocol-defined dose reductions were reported in 5% of pts, with 24% experiencing dose delays of >7 days, mostly due to unrelated adverse events (AEs). No obvious differences between rigosertib and BSC were found in the incidence of AEs (rigosertib, 99%; BSC, 85%) or of ≥ Grade 3 AEs (rigosertib, 79%; BSC, 68%). In the rigosertib arm, AEs reported by ≥ 20% of pts, irrespective of severity or causality, were nausea (35%), diarrhea (33%), constipation (31%), fatigue (30%), fever (27%), anemia (22%), and peripheral edema (21%). Rigosertib had low myelotoxicity, consistent with previous clinical experience. Conclusions:Although the primary endpoint in this Phase III study of rigosertib vs BSC in pts with HR-MDS did not reach statistical significance in the ITT population, encouraging rigosertib treatment-related improvement in OS was noted in several subgroups of MDS pts, including those with “primary HMA failure and in patients in the IPSS-R Very High Risk category. CIV therapy with rigosertib had a favorable safety profile in this orphan population of elderly pts with MDS. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Fenaux: Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Roboz:Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Wilhelm:Onconova Therapeutics, Inc: Employment. Azarnia:Onconova Therapeutics, Inc: Employment. Maniar:Onconova Therapeutics, Inc: Employment.