Academic literature on the topic 'PS 15.5 UL 2017'

238 Background: Dual inhibition of the EGFR pathway using erlotinib and the monoclonal antibody panitumumab results in greater antitumor activity in preclinical pancreatic cancer models. A trial evaluating this approach was conducted. Methods: A safety analysis was initially performed with 6 patients at P 4 mg/kg every two weeks, E 100 mg daily, G 1000 mg/m2 weekly of a 28-day cycle. PGE was well tolerated with a grade 3 fatigue as only dose-limiting toxicity. Patients (pts) were then randomized to either PGE or GE alone. Eligibility included: no prior chemo, ECOG PS 0-1, bilirubin <2x UL, AST <2.5x UL. CT scans every 2 cycles. Results: 93 pts (46-GE; 47-PGE) were randomized from January to August, 2010. Median age 61 years and 65% male. ECOG PS 0 (51%) and PS 1 (49%). No significant differences in baseline characteristics observed between treatment arms. 81 pts evaluable for AEs; 37 (46%) had a maximum grade 3 (at least possibly related to treatment), and 12 (15%) maximum grade 4 or 5. Treatment arms similar with respect to the overall AEs with exception grade 1-3 acneiform rash, GE (65%) vs. PGE (85%). Commonly occurring grade 4 AEs (at least possibly related) consisted of thrombosis (3 pts) and thrombocytopenia (2 pts). Two grade 5 events occurred in PGE arm—duodenal hemorrhage (possibly related) and pancolitis with multisystem failure (unlikely). An additional PGE pt died 30 days off study (grade 5 CHF, possibly). 54 patients (67%; 31-GE, 23-PGE) ended treatment; 38 (70%) for disease progression (24-GE; 14-PGE). Other reasons for treatment discontinuation: AEs (9; 17%), pt refusal (4; 7%), death on study (2; 4%), other (1). In 81 pts with at least 1 cycle of chemotherapy, the median PFS for GE 2.0 months and 3.3 months for PGE. Accrual for the study was recently completed and overall and 6-month survival data will be presented. Conclusions: This study involved an initial run-in design to define tolerable doses of dual EGFR inhibitors, PGE, in pancreatic cancer patients. Although preliminary, the randomized phase II portion has been completed and differences between GE and PGE in terms of relevant clinical outcomes, PFS, are observed. No significant financial relationships to disclose.

Abstract Background Treatment related toxicity complicates outcome in elderly patients with AML (Estey et al. Blood. 2006). Conventionally, 7+3 induction (anthracycline plus cytarabine) results in Complete Remission rate of about 30%. Regimens with less toxicity, such as 10-days (d) schedule of DAC, seem promising with CR rate of 47% (Blum et al. PNAS. 2010). In secondary MDS derived AML, response prediction could be derived from mutation status in epigenetic modifiers (IDH1, IDH2, DNMT3 A, TET2), transcriptional regulators (RUNX1, CBL), and genes in spliceosome machinery, such as SF3B1 and SRSF2 (Husseinzadeh et al. American Society of Hem Meeting. Abstract # 1698. 2012). IDH-1 mutation is known to induce hypermethylator phenotype (fig 1) (Figueroa et al. Cancer Cell. 2010) and might be present in conjunction with SRSF2 mutations, an unique unreported molecular subset, feasible for exploring azanucleoside response prediction. Herein, we report a case of trisomy 8 MDS derived IDH1 and SRSF2 mutated AML who underwent rapid morphological blast differentiation in the context of acute differentiation syndrome while treated with 10 days (d) of hypomethylating dose of DAC. Methods A 61-year-old male with performance status (PS) = 3 presented with leukocytosis of 18.9 K/uL (peripheral blast 90%). He had a history of low-grade MDS diagnosed 2 years before AML transformation. After morphological confirmation of M5 AML, fluorescent in situ hybridation (FISH) revealed 81% nuclei with trisomy 8. Extracted DNA was tested with a custom-designed Leukemia Cancer Gene Mutation Panel using AmpliSeq™ technology and showed IDH1 c.394C>T(p.R132C) mutation (Fig. 2B) and c.284C>T(p.P95L) mutation of SRSF2 gene (Fig. 2C). DAC was initiated at 15 mg/m2 for a total of 10 days every 28 d cycle. Results By day 5 of cycle (C)1 of DAC treatment, brisk and significant rebound leukocytosis of 60 K/uL (Fig. 3) was observed, along with shortness of breath, hypoxemia and radiological evidence of floppy bilateral pulmonary infiltrates suggestive of acute-like differentiation syndrome. In addition to broad-spectrum antimicrobial and antifungal, dexamethasone at 4 mg intravenously (IV) every 8-hour (h) and hydroxyurea at 1 g orally every 8 h resulted in progressive normalization of peripheral blood count and hypoxemia after 48 h. Patient (pt) recovered from C1 and proceeded with C2 of treatment. A similar episode of brisk/robust leukocytosis was observed by day 5 of C2 requiring dexamethasone and hydroxyurea. Progressive morphological differentiation was observed to full mature and morphologically normal monocytes and neutrophil (Fig. 4). Pt expired as result of severe clostridium difficile colitis during C3 of DAC. Conclusions In our case, we observed robust acute differentiation syndrome characterized by rapid increase of WBC, shortness of breath and hypoxemia associated with azanucleoside treatment. Beside a novel association of IDH-1 and SRSF2 mutations, acute differentiation might suggest potential feature for azanucleoside response phenotype. Our case adds body of evidence of connection between epigenetic regulator and spliceosome mutations. Further studies on the impact of dual mutations in epigenetic reprogramming, leukemia transformation, and azanucleoside response will allow improved decision algorithm and therapeutic design. Disclosures: No relevant conflicts of interest to declare.

Abstract Lenalidomide is an immunomodulatory drug that is FDA approved for treatment of 5q- myelodysplastic syndrome (MDS) and myeloma. It has also been tested as a salvage therapy of refractory/relapsed AML with encouraging activity, especially in patients (pts) who relapsed post allogeneic transplant (alloSCT). In this setting, it has been postulated that lenalidomide may re-activate donor immune system and enhance a graft-versus-leukemia effect. This hypothesis is also supported by evidence of increase graft-versus-disease (GVHD) observed in pts treated with lenalidomide post-alloSCT. Therefore, in order to prospectively study the safety, feasibility, and early impact on risk of disease relapse we performed a phase 1 dose escalation study of lenalidomide administered orally daily following reduced intensity conditioning (RIC) alloSCT in pts with leukemia and lymphoma eligible for transplant. Methods: Pts were enrolled on a two-step process, with initial enrollment prior to transplant followed by a re-registration evaluation post-transplant at day +60 (+/- 7 days) to ensure eligibility. At this screening, pts were required to demonstrate engraftment with ANC >1000/uL, platelet count ³50,000/uL, and T-cell chimerism ³40% by day +30. Pts were required to have a creatinine clearance ³50 mL/min, AST ²3 x ULN, and ECOG PS of 0-2. Grades 1 or 2 acute GVHD (aGVHD) were allowed if controlled on ² 20 mg of prednisone daily; pts with a history of grades 3 or 4 aGVHD were excluded. Lenalidomide was given orally daily for 28 days/cycle. Dosing escalation was performed using a standard 3 x 3 design, with dose level (DL) 1 = 5 mg , DL 2 = 10 mg, and DL 3 = 15 mg. Results: From 6/2011 to 10/2012, 17 pts with AML (n=13), CLL (n=1), and DLBCL (n=3) were enrolled (Table 1) and underwent RIC alloSCT. The majority of patients had a Disease Risk Index (Armand et al. Blood, 2014) of high or very high. Of enrolled pts, only 3 received lenalidomide. Of the pts who did not proceed to treatment at re-registration, 4 were ineligible due to relapse, 3 were ineligible due to elevated creatinine, 3 were ineligible due to GVHD, 2 declined, and 2 were not treated due to study closure. All pts who received lenalidomide were treated at DL 1. The first pt treated (00-06) received cycle 1 without toxicity. On cycle 2 day 9 he developed a skin rash consistent with acute GVHD and discontinued therapy. The second pt treated (00-11) developed skin rash and diarrhea on cycle 1 day 3 and was diagnosed with steroid refractory aGVHD of the GI tract. He expired from complications of treatment. The third pt treated (00-12) developed a skin rash and diarrhea on cycle 1 day 6. Lenalidomide was discontinued. Based on these outcomes, the study was closed due to concerns regarding the risk of severe aGVHD caused by lenalidomide. However, patients 00-06 and 00-12 remain alive and in CR days 958 and 751 post transplant, respectively. In the entire cohort, the median PFS was 103 days (range = 15-992) with median OS 103 days (range = 30-1085). Conclusion: Early administration of low-dose lenalidomide following alloSCT is not feasible due to potential increased risk of severe aGVHD and likelihood of elevated creatinine at this time point. However, 2 of 3 pts who received lenalidomide and responded to treatment for aGVHD remain in CR from their high-risk AML. Thus, an amended approach with lower/fewer dose of lenalidomide/cycle or alternatively, use in transplants that do not utilize calcineurin phosphatase inhibitors (such as T-cell depletion based approaches) warrants additional consideration. Abstract 3954. Table 1 PT Age Sex Diagnosis Disease Risk Index Comorbidity Index Lena Treatment Progression free survival (days) Overall survival (days) Cause of death 01 64 F AML High 3 Ineligible1 592 979 Relapse 02 64 M AML Very high 1 Ineligible1 140 229 Relapse 03 26 F AML High 6 Ineligible2 35 121 Relapse 04 39 M DLBCL Intermediate 0 Declined 789 1085 05 64 M DLBCL Intermediate 1 Declined 108 121 Relapse 06 36 M AML High 3 Yes 958 958 07 60 M AML High 3 Ineligible3 992 992 08 61 M CLL Low 0 Ineligible3 101 101 Acute GVHD 09 71 M AML High 1 Ineligible1 957 957 10 57 M AML High 5 Ineligible2 30 30 Regimen Related Toxicity 11 32 M AML Very High 2 Yes 103 103 Acute GVHD 12 50 F AML Very High 4 Yes 751 751 13 61 F AML Very High 4 Ineligible2 42 242 Relapse 14 60 M AML Very High 0 Ineligible2 15 160 Relapse 15 63 F AML High 3 Ineligible3 61 61 Acute GVHD 16 66 M AML High 3 Study closure 706 706 17 68 M DLBCL High 5 Study closure 72 72 Pneumonia 1 = elevated creatinine 2 = relapse 3 = GVHD Disclosures Off Label Use: Lenalidomide administration following allogeneic transplantation.. Blum:Celgene: Consultancy.

Abstract Introduction: Thrombotic thrombocytopenic purpura (TTP) is a catastrophic and potentially fatal disorder caused by systemic microvascular thrombosis due to von Willebrand factor (VWF)-platelet thrombi. TTP is caused by congenital or acquired deficiency of the plasma metalloprotease ADAMTS13. Based on an earlier study (Chen J et al., J Clin Invest 2011, 121:593-603), we proposed N-acetylcysteine (NAC) as an adjunct treatment for TTP. This study showed that NAC reduced the size and activity of VWF in vitro in human plasma and in vivo in a TTP mouse model. In 2013 and 2014, two case reports described treatment of refractory TTP patients with NAC, one receiving a low dose of NAC [300 mg/kg (total 15 g) for the 1st 24 hrs, followed by 2.5 g/day for two weeks concurrently with plasma exchange] (Shortt J et al., N Engl J Med 2013, 368: 90-92; Shortt J et al., Transfusion 2014, 54:2362-2363) and the other receiving high-dose NAC [300 mg/kg/day (11 g/day) for 10 days between plasma exchanges] (Li GW et al. Transfusion 2014, 54: 1221-1224). The patient treated with high-dose NAC improved rapidly (the patient woke up from coma 18 hr after NAC treatment was initiated), but the patient treated with lower dose NAC did not appear to respond. Thus, it is as yet unclear whether NAC is an effective treatment for TTP. Therefore, more clinical studies and detailed analyses are required to examine the effects of NAC in TTP patients. Here we report the results of clinical and biochemical studies on two patients with relapsed TTP treated with NAC. Before, during, and after NAC treatment, we determined the concentrations of NAC, cysteine, and glutathione in plasma; VWF concentration, multimer structure, and functions; ADAMTS13 concentration and activity; and platelet counts and activation status (P-selectin expression and phosphatidylserine exposure). Methods: Two females with a history of prior episodes of TTP presented with acute TTP [ADAMTS13 < 10%, positive for ADAMTS13 inhibitors, platelet count ≤ 10,000/uL, lactate dehydrogenase (LDH) > 600 IU/L] and both were treated with NAC per IRB-approved protocol [150 mg/kg bolus over 1 hr and 150 mg/kg as continuous infusion until the next therapeutic plasma exchange (TPE)]. They received daily TPE until their platelet counts normalized, and intravenous NAC during days 2-5. Blood was collected daily for 8 days for research assays. ADAMTS13 concentrations in patient plasma were measured by ELISA. ADAMTS13 activity was measured using HRP-conjugated A2 peptide substrate (Wu J-J et al. J Thromb Haemost 2006, 4:129-136). Concentrations of NAC, total cysteine, and total free thiols (free thiol cysteine and free thiol NAC) in plasma were determined by mass spectrometry. Plasma VWF multimer patterns were analyzed by 1.5% agarose gel electrophoresis followed by western blotting with an HRP-conjugated polyclonal VWF antibody. Platelets in whole blood were labeled for platelet markers (CD41a or CD42b) together with one of the activation markers, P-selectin or phosphatidylserine (lactadherin). The labeled platelets were analyzed by flow cytometry. Results: Platelet counts in both patients started to increase 1 day after NAC infusion and continued to increase after discontinuation of NAC and TPE. After NAC infusion, the free thiol concentration (NAC and cysteine) in plasma increased 4 and 59 fold in patients 1 and 2, respectively. This was accompanied by increasing ADAMTS13 specific activity (ADAMTS13 activity/ADAMTS13 antigen). In patient 1, the specific activity increased from 127% (prior to NAC infusion but after TPE) to 270% during NAC infusion; in patient 2, the specific activity increased from 56% to 86%. In patient 1, the VWF multimer size decreased during NAC treatment and the VWF multimers migrated slightly faster. NAC also appeared to inhibit platelet activation. Before NAC infusion, the platelets in both patients were positive for phosphatidylserine (PS, > 30%) and P-selectin (> 15%), compared to 2% and 5%, respectively, in a normal control. The percentages of PS- and P-selectin-positive platelets decreased to less than 18% and 10% respectively, during NAC treatment. Summary: NAC treatment of two patients with TTP in conjunction with TPE was well tolerated and associated with recovery of platelet count and LDH, increased ADAMTS13 specific activity and total free thiol concentration in plasma, reduced platelet activation, and decreased VWF multimer size in one patient. Disclosures Konkle: CSL Behring: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; Octapharma: Research Funding; Novo Nordisk: Consultancy.

Abstract Introduction Non-Hodgkin lymphoma responds to single agents such as cyclophosphamide, combination therapy such as CVP and immunotherapy with monoclonal antibodies such as rituximab. There is no consensus on the optimal treatment for relapsed low grade or mantle cell lymphoma. Based on the success and tolerability of combining alkylating agents with proteasome inhibitors in multiple myeloma, a phase II clinical trial of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBor-D) was designed to explore the efficacy and safety of this combination in relapsed low grade and mantle cell lymphoma (MCL). Methods This trial enrolled relapsed patients at Mayo Clinic from October 2008 to March 2014. Eligibility required age≥18; biopsy proven follicular grades 1 or 2 lymphoma (FL), MCL, small lymphocytic lymphoma/chronic lymphocytic leukemia, marginal zone B-cell lymphoma, or Waldenström’s macroglobulinemia (WM); life expectancy >3 months; ECOG PS 0, 1 or 2; measurable disease; Hb ≥8g/dl, ANC ≥1200/uL, platelet ≥75,000/uL, creatinine ≤1.5xULN, total bilirubin ≤1.5xULN, alkaline phosphatase ≤3xULN, AST ≤3xULN; and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Treatment included rituximab 375 mg/m2 IV on day 1 and oral cyclophosphamide 300 mg/m2, IV bortezomib 1.3 mg/m2, and oral dexamethasone 40 mg on days 1, 8, 15, and 22 in a 28-day cycle. Treatment was continued two cycles beyond best response or a maximum of 12 cycles. Allopurinol 300 mg on days 0-14 for the first cycle was strongly recommended. Results 21 patients were enrolled prior to study closure due to slow accrual. Bortezomib was initially given on days 1, 4, 8, and 11 in the first 16 patients, but was subsequently modified to days 1, 8, 15, and 22 due to significant peripheral neuropathy (PN). Median age was 69 years (range 51-80) and 13 (62%) were male. 62% had stage IV disease and 17 (81%) had 2 or more prior treatments with 3 (14%) having prior autologous stem cell transplantation. Histologies included FL-I (n=6), FL-II (n=2), MCL (n=8), and WM (n=5). Patients completed a median of 4 cycles of treatment (range 1-12), discontinuing due to 9 (43%) completion per protocol, 4 (19%) progression, 5 (24%) adverse events, 1 (5%) patient refusal, and 2 (10%) other reasons. Median follow-up is 32.8 months (0.9-54.8). CR or PR as best response was observed in 13 (62%, 95% CI 38-82%; 4 CR [19%], 9 PR [43%]) patients. By histology, CR or PR was observed in 7 (88%) FL patients (4 CR, 3 PR); 2 (25%) MCL patients (both PR), and 4 (80%) WM patients (all PR). CR or PR was observed in 10/16 (62%; 4 CR, 6 PR) before and 3/5 (60%; all PR) after the change in bortezomib schedule. Among 13 patients with CR or PR, median duration of response was 25.9 months (95% CI 8.0-not reached). Median PFS and OS were 11.6 months (95% CI 3.8-not reached) and 54.8 months (95% CI 24.6-54.8), respectively. At least one Gr≥3 adverse event at least possible related was observed in 14 (67%) patients, the most common being leucopenia (7, 33%), neutropenia (7, 33%), thrombocytopenia (6, 29%), anemia (5, 24%), PN (5, 24%), and fatigue (3, 14%). Peripheral sensory neuropathy at least possibly related was Gr1, Gr2, and Gr3 in 5 (24%) patients each, with a lower rate observed for patients after the change in bortezomib schedule (before 13/16 [81%] Gr≥1, after 2/5 [40%] Gr≥1). Among 14 patients who completed a baseline and at least one post-baseline FACT/GOG-NTX additional concerns questionnaire, 10 (71%) reported clinically meaningful (≥3-point) worsening in patient-reported neurotoxicity (8/11 [73%] before and 2/3 [67%] after the change in bortezomib schedule). Conclusions Our results suggest R-CyBor-D is a safe and effective combination in patients with relapsed low grade and mantle cell lymphomas. High response rates were seen in FL and WM. The majority of significant AE’s were hematologic. However, sensory neuropathy was common with twice weekly dosing of bortezomib and lessened with weekly dosing. Determination of optimal treatment regimens in this population remains an unmet need. Additional clinical trials including larger patient numbers are necessary to confirm these observations. This trial was sponsored by Millennium Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Tiedemann:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.

Abstract Abstract 608 Common eligibility criteria for most clinical trials in MDS and AML include acceptable performance status, renal and hepatic functions and lack of other comorbidities including other concomitant malignancies or HIV infection. Median survival without therapy at MD Anderson in this group of pts is less than 60 days. To study the impact of therapy in patients not eligible for clinical trials, we conducted a phase II of the combination of 5-azacitidine and the histone deacetylase inhibitor vorinostat. The combination of these two agents is known to be safe and to have significant activity in MDS and AML. An interim report of this study was presented at ASH 2010. Here, we report the final data on the study. Eligible pts included those with previously untreated MDS (INT-1 or above) or AML and any of these: creatinine or bilirubin greater than 2 mg/dL, ECOG performance status (PS) more than 2 or not eligible for any other protocol. Pts with HIV disease or concomitant malignancies were also eligible. Pts with CBF abnormalities were excluded. Therapy was 5-azacitidine 75 mg/m2 IV daily × 5 every 3 to 6 weeks and vorinostat 200 mg orally three times a day on days 1 to 5 with 5-azacitidine. The clinical trial was designed to stop if expectations for survival at 60 days and/or achievement of complete remission (CR) rates were not achieved based on priors derived from historical experience at MD Anderson. The study was to stop if the # pts alive at > 60 days was < 0/3, 2/6, 3/9, 5/12, 6/15, 8/18, 10/21,11/24, or 13/27 evaluable or if the number of pts with no CR was > 6/6, 11/12, 16/18,21/24, 26/30. A maximum of 30 pts could be treated if none of the stopping rules was met. Operating characteristics targeted a 20% improvement in response and survival. As pharmacodynamic endpoints, global and gene specific hypomethylation, induction of histone acetylation, TET2 mutations and miRNA 29b levels were evaluated. The study has been completed. In total 30 patients were treated. The characteristics are as follows: median age 74 years (range 44–83), median WBC 3 K/uL (range 0.6–112), median % bone marrow blasts 10% (range 1–78), complex cytogenetics in 16 pts (53%), Flt-3 or Ras mutated 4 (13%), median creatinine 0.9 mg/dL (range 0.3–2.4), median bilirubin 0.7 mg/dL (range 0.3–4.1). Using WHO criteria, 16 pts (53%) had MDS, 2 CMML and the rest AML. Eligibility criteria included: presence of another malignancy 16 pts (53%) and others including: liver cirrhosis, liver failure, cardiac dysfunction, severe COPD and poor PS (ECOG 4). Treatment was well tolerated with only 1 pt (3%) developing severe (nausea, vomiting) non-heme related toxicity. Only 1 (5%) pt died during induction therapy. The first pt was enrolled on 9/09 and the last 12/10. The median number of cycles administered was 3.5+ (1 to 11+). All 30 patients were evaluable for survival and 24 (80%) survived longer than 60 days (median survival 7 months: range 1 to 16). Therapy was active: 8 patients achieved a complete remission and 1 had a complete marrow response for an overall response rate of 9 (30%). Of the 16 non-responding patients, 8 had stable disease for more than 8 weeks. At the present time 9 of the 30 patients are alive. All deaths were related to primary disease progression (other than leukemia). We calculated comorbidity score using the ACE-27 scale: 3 patients had 0 points, 7 1 point, and 20 2–4 points. No association between response and survival was documented with ACE-27. TET2 mutation and miRNA29 levels were analyzed at baseline. Of the 17 pts analyzed, 5 harbored a TET2 mutation but only 1 had achieved response. Baseline miRNA29b levels were not different in responders versus non responders. Global and gene specific hypomethylation was observed with therapy. In summary, the study did not meet the stopping rules for survival and response. No significant toxicity was documented. The combination of 5-azacitidine and vorinostat is safe and active in this poor prognosis population resulting in levels of activity and safety similar to those observed in populations eligible for clinical trials. These results support treatment of these pt population and question current eligibility for phase I/II trials. Disclosures: No relevant conflicts of interest to declare.

Introduction Venetoclax (VEN), a potent BCL2 inhibitor, demonstrated favorable outcomes combined with hypomethylating agents and low dose cytarabine (AraC) in elderly patients (pts) newly diagnosed (ND) with acute myeloid leukemia (AML). In order to improve both remission rates and survival in fit AML pts, we evaluated the combination of VEN with FLAG-IDA regimen in fit pts with ND or relapsed/refractory (R/R) AML. Objectives This phase (Ph) Ib/II single center clinical trial has dual primary objectives: (1) Safety and tolerability of the combination for pts with R/R AML (Ph Ib), and (2) Overall response rate (ORR) by modified IWG AML criteria in pts ND or R/R AML (Ph II). Secondary analyses include duration of response (DOR) and overall survival (OS). Methods Eligibility includes medically fit, ND or R/R AML pts of any age with adequate organ function, PS ≤ 2, and WBC &lt; 25x109/L. Only R/R AML pts were eligible for Ph Ib dose escalation. Pts receive FLAG-IDA induction/consolidation (ind/cons), with VEN orally daily. The original FLAG-IDA ind consisted of fludarabine 30 mg/m2 IV D2-6, AraC 2 g/m2 IV D2-6, idarubicin 6 mg/m2 IV D4-6 (8 mg/m2 IV D4-6 for ND pts), and filgrastim 5 mcg/kg daily D1-7 (or pegfilgrastim 6 mg after day 5 to replace remaining injections). The 3+3 algorithm was applied for dose escalation. The first cohort (dose -1, n=8) received FLAG-IDA with VEN 200 mg on days 1-21 of ind, incorporating a 2-day VEN dose ramp up. After the observation of gram negative bacteremia and/or sepsis in 5 of 6 pts during cycle 1 nadir, an amended dose level -1 ind was designed with reduced AraC 1.5 g/m², with VEN 200 mg on D1-14 and dose level 0 with VEN 400mg on D1-14. After completion of ind/cons, single agent VEN at 400 mg continuously is provided as maintenance for pts not proceeding to alloSCT. The data cutoff was 6.10.2019. Results At data cutoff, 34 pts with a median age of 47 yrs (range, 21-72) have been enrolled: 16 pts in the Ph Ib, and 18 pts in Ph II (11 in ND, and 7 in R/R cohort). 23 pts had R/R AML with a median of 2 (range, 1-4) prior therapies, and 10 (43%) pts had received prior alloSCT. Additional demographics including molecular profile at study enrollment are provided in Table 1. The median number of cycles received is 2 (range, 1-4). VEN 400 mg on D1-14 was considered safe for Ph II dose expansion. Serious adverse events regardless of causality were infections (n=26), bacteremia (n=12), sepsis (n=5), hypotension (n=4) and typhlitis (n=3). No tumor lysis syndrome was identified. 30-day mortality was 0%, 60-day mortality was 0% in ND cohort and 13% in R/R cohort (2 pts died from progression and 1 pt from fungal pneumonia). All enrolled pts were evaluable for response. Of 23 R/R pts, 17 pts (74%) achieved a best response of CR/CRi (12 CR, 5 CRi: 3 CRh + 2 CRp). 12 (52%) pts attained MRD negative status by flow cytometry. 15 pts attained a best response after one cycle, and two attained blast reduction after cycle 1 followed by CR after re-induction. Among responders, 9 pts proceeded to alloSCT, 2 remain on study, 3 pts relapsed, and 3 pts died in CR at 1.7, 3.4 and 4.6 months on treatment. Median time to ANC recovery &gt; 500/ul and platelet recovery &gt; 50K in responders was 27 days (range, 20-90) and 33 days (range, 20-54) respectively. With a median follow-up of 5 months, median DOR is not reached and OS is 7.1 months. Median OS for pts in salvage 1, 2, and ≥ 3 is 9.4, 10, and 4.9 months, respectively. Of 11 ND pts, 10 pts (91%) achieved ORR (9 CR, 1 CRh) and all 10 pts became MRD negative by flow cytometry: 3 pts proceeded to alloSCT, and 7 pts remain on active treatment. Median time to ANC and platelet recovery with induction was 23 days (range, 19-31) and 25 days (range, 18-31) respectively. Both DOR and OS are not estimable. Of interest, responding pts demonstrated higher apoptosis priming, as shown by depolarization in response to Bid, PUMA and Bim peptides by BH3 profiling (Fig 1). Conclusions FLAG-IDA with VEN demonstrates notable activity in both R/R and ND medically fit pts. Improved safety and tolerability without decreasing efficacy was achieved by decreasing AraC to 1.5 g/m2, and administering VEN for 14 days in ind, and 7 days in cons cycles. Neither prolonged cytopenias nor early mortality were observed. Ph II portion for R/R and ND pts is ongoing. Correlative studies with genomic annotation, CyTOF analysis and BH3 profiling are being analyzed, with higher apoptosis priming identified in responding pts. Longer follow-up is necessary to establish long term survival benefit. Table 1 Disclosures Konopleva: Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Calithera: Research Funding; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding. Kadia:Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Biopath: Consultancy; BiolineRx: Consultancy, Research Funding; Merus: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy, Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding. DiNardo:celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; syros: Honoraria; abbvie: Consultancy, Honoraria; medimmune: Honoraria; jazz: Honoraria.

Background: Guadecitabine (G) is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a large global randomized phase 3 study of G vs Treatment Choice (TC) with azacitidine (AZA), decitabine (DEC), or low dose Ara-C (LDAC) in 815 TN AML patients unfit for IC (ASTRAL-1 study). The primary ITT results were previously presented (Fenaux et al, EHA abstract S879, 2019). Clinical guidelines for single agent HMAs recommend a minimum of 4 to 6 treatment cycles for maximum benefit. We describe here the results of the study based on number of treatment cycles administered. M ethods: TN-AML patients ineligible for IC due to age ≥ 75 y, or coexisting morbidities, or ECOG PS 2-3 were randomized 1:1 to either G (60 mg/m2/d SC for 5-days Q28 days) or a preselected TC of AZA, DEC, or LDAC at their standard dose/schedule. AML diagnosis and response status were assessed by an independent central pathologist blinded to randomization assignment. Complete response (CR) and overall survival (OS) were co-primary endpoints. We analyzed patients' characteristics, number of treatment cycles, reasons for treatment discontinuation, CR, and OS including analyses by number of cycles received including prospective subgroups, and OS analyses of responders and non-responders. Results: 815 patients were randomized to G (408) or TC (407). Preselected TCs prior to randomization were DEC (43%), AZA (42%), and LDAC (15%). Baseline variables were well balanced across the 2 treatment arms. For G vs TC respectively, age ≥75 y in 62% vs 62.4%, PS 2-3 in 50.5% vs 50.4% (including 10.8% vs 8.8% PS 3), and poor risk cytogenetics in 34.3% vs 34.6%. Most patients were assigned to an HMA at randomization (759, 93%) with only 56 patients (7%) randomized to receive LDAC. Both CR (19.4% for G and 17.4% for TC), and OS Hazard Ratio (0.97; 95% CI 0.83-1.14) were similar and not significantly different between G and TC. Many patients in both arms did not receive the recommended minimum of 4 cycles (42.4% vs 40.8% for G vs TC respectively), or 6 cycles (54.2% vs 53.8% for G vs TC). The proportions were well balanced between the 2 treatment arms. Characteristics of patients who received at least 4 or 6 cycles were also well balanced between the 2 treatment arms for age, PS 2-3, secondary AML, poor risk cytogenetics, BM blasts >30%, and proliferative AML (total white cell count ≥20,000/uL). The primary reasons and proportions for treatment discontinuation were similar for the 2 treatments arms. For patients with <4 and <6 cycles respectively they are, in descending order, early deaths (16.7% and 20.7% of the overall ITT population), progression (7.6% and 11.7%), adverse events (5.8% and 6.9%), and patient decision (5.5% and 7.1%). In patients who received at least 4 cycles more patients achieved CR on G (33.6%) vs TC (28.6%), and median OS was longer on G (15.6 months for G vs 13 for TC, HR 0.78, 95% CI 0.64-0.96, log-rank p 0.02, Fig 1). Similarly, in patients who received at least 6 cycles, there were more CR on G (40.1%) vs TC (36.2%) and median OS was longer on G (19.5 months for G vs 15.0 for TC, HR 0.69, 95% CI 0.54-0.88, log-rank p 0.002, Fig 2). Subgroup analyses of OS in patients who received at least 4 or 6 cycles showed that survival benefit from G over TC was consistent in all prospective subgroups including against each of the 3 TCs (AZA, DEC, and LDAC). OS analyses in patients who received at least 4 or 6 cycles also favored G vs TC in both responders (CR, CRp, CRi, or PR) and non-responders with maximum benefit in patients who received at least 6 cycles (G vs TC OS HR 0.66, 95% CI 0.45-0.96, log-rank p 0.028 for responders, and HR of 0.73, 95% CI 0.53-1.00, log-rank p 0.048 for non-responders). Summary/Conclusions: In a large global 815-patient randomized study of G vs TC composed mainly of first generation HMAs, G was at least as effective as TC based on the primary ITT analysis of CR and the narrow 95% CI of OS HR (0.83-1.14). Analyses of patients by number of treatment cycles showed that those who received at least 4 or 6 cycles achieved longer OS in G vs TC with the largest benefit in those who received at least 6 cycles. The benefit was observed in all subgroups, and in both responders and non-responders. Treatment with single agent guadecitabine should continue as long as the patient can still benefit and for at least 6 cycles to gain the maximum survival benefit. Disclosures Roboz: Trovagene: 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; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: 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; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Krauter:Pfizer: Honoraria. Robak:Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding. Kantarjian:Agios: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Ariad: Research Funding. Novak:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel,Accommodations; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel,Accommodations. Jedrzejczak:Takeda: Consultancy; Amgen: Consultancy, Other: travel support for hematology meetings; Celgene: Other: travel support for hematology meetings; Novartis: Research Funding; Roche: Other: travel support for hematology meetings. Thomas:PFIZER: Honoraria; ABBVIE: Honoraria; DAICHI: Honoraria; INCYTE: Honoraria. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Brandwein:Jazz Pharma: Consultancy, Honoraria; Otsuka: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Novartis: Consultancy, Honoraria. Demeter:Angelini: Other: Advisory Board; Pfizer: Other: Advisory Board; Novartis: Other: Advisory Board; Bristol Myers Squibb: Other: Advisory Board; Amicus: Other: Advisory Board; Amgen: Other: Advisory Board; Roche: Other: Advisory Board. Griffiths:Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Persimmune: Consultancy; Persimmune: Consultancy; Genentech, Inc.: Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; New Link Genetics: Consultancy; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Abbvie, Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; New Link Genetics: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial. Yee:Agensys, Astex, Hoffman La Roche, MedImmune, Merck, Millenium, Roche/Genentech: Research Funding; Novartis, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas, Celgene, Otsuka, Shire, Takeda: Membership on an entity's Board of Directors or advisory committees. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

447 Background: While ICI prolong OS after platinum chemotherapy in aUC, outcomes vary based on clinical confounders. We aimed to develop a prognostic model in pts receiving ICI in a non-clinical trial setting. Methods: We used a hypothesis driven approach of clinician selected covariates to develop a new prognostic model. Data source was a retrospective cohort of pts treated with ICI at 19 institutions. Demographics, clinicopathologic data, treatment patterns, and OS were collected. Univariate (UVA) Cox regression was done on 24 variables hypothesized to be associated with OS. Variables were retained for multivariate analysis (MVA) if they had statistical relationship with OS (p<0.2) and were included in the final model if p<0.05 on MVA. Each retained covariate was assigned 1 point in the final prognostic model. Stratified median OS and c-statistic were calculated. Results: 415 pts with mean age 69, 26% female, 66% ever smokers, 69% pure UC, 15% upper tract UC, 54% with prior extirpative surgery, Bellmunt risk factors 17%, 51%, 28% and 4% for 0, 1, 2, 3, respectively were included. Non-White race, ECOG PS≥1, albumin<3.5g/dL (lower limit of normal), hemoglobin<10g/dL, absolute neutrophil count (ANC)>8x106/ul (upper limit of normal), and presence of bone or liver metastases (mets) were all associated with worse OS on UVA Cox regression; albumin<3.5 g/dL, ANC>8x106/uL, presence of bone or liver mets remained significant on MVA and were included in the prognostic model. Median (m)OS by new model and Bellmunt are shown in table. C-statistic of the new model was 0.67. Conclusions: Albumin<3.5 g/dL, ANC >8x106/ul, presence of bone or liver mets were negative prognostic factors in pts with aUC treated with ICI. This has comparable features to recently reported 5-factor model using clinical trial data, including LDH (unavailable in our cohort). External validation is being pursued. The proposed model may be used for prognostication, clinical trial design, eligibility and stratification. [Table: see text]

Abstract INTRODUCTION: There is a lack of data on early mortality in aggressive lymphomas, particularly HIV-related lymphomas. Patients who present with advanced disease and poor performance status are at a higher risk of adverse outcomes and are not offered clinical trial enrollment. Factors that may contribute to early mortality have not been delineated. In this retrospective analysis, we sought to identify causes and predictors of early mortality, occurring within 180 days of index diagnosis, in patients with HIV-positive and negative DLBCL, at an academic medical center. METHODS: We reviewed an electronic database to identify patients with a diagnosis of HIV-related DLBCL, treated at our center between January 1, 2005 and December 31, 2017. We further identified patients with non-HIV positive DLBCL diagnosed from January 1, 2015 to December 31, 2017. Data on patient demographics, clinical outcomes and treatment was collected. We defined early mortality as those patients who died within 180 days of diagnosis. RESULTS: HIV-NEGATIVE DLBCL: There were 103 HIV-negative patients with DLBCL, with a mean age of 65 years. N=17 (16.5%) patients expired within 180 days of diagnosis. In univariate analysis, factors predicting increased risk of mortality included poor ECOG performance status (PS) 3-4, presence of B-symptoms and higher international prognostic index (IPI) scores (Table 1). In multivariate analysis, poor PS (HR 4.86, p<0.03) and B-symptoms (HR 5.9, p<0.02) remained significant predictors of early mortality. Age, cell of origin and Hepatitis B/C positivity were not found to be predictive. The leading cause of death in the first 180 days was sepsis, attributing for 53% of mortality (Figure 1). Other commonly identified causes included progressive disease (23%), tumor lysis and cardiac complications (12%). HIV-POSITIVE DLBCL: We identified 82 patients with HIV-positive DLBCL and divided patients into Cohort A (N=25) patients who expired within 180 days and Cohort B (N=57), patients who were alive beyond 180 days. 9 patients died within the first 30 days, 20 patients within 90 days and 25 patients within 180 days of index diagnosis. Both groups predominantly consisted of African-Americans with advanced stage DLBCL with a mean age of 53 and 48 years respectively (p=0.02). In univariate analysis, more patients in Cohort A had Stage 3-4 DLBCL (100% vs. 86%), poorer ECOG PS of 3-4 (52% vs. 7%), higher IPI scores (56% vs. 11%), lower CD4 counts (median of 70 cells/uL vs. 140 cells/uL) and higher LDH (544 U/L vs. 270 U/L). In multivariate analysis, we found that poor ECOG PS (HR 2.4, p<0.0001), higher LDH (HR 1, p<0.008) and older age (HR 1.07, p<0.023) were associated with an increased risk of mortality at 180 days. The leading causes of death within 180 days were progressive disease in 48%, and sepsis in 32% of patients. We wanted to examine whether the time period of diagnosis affected mortality from HIV-related DLBCL in patients. Group 1 patients were diagnosed from January 2005 to December 2010 (N=20) and Group 2 from January 2011 to December 2017 (N=29). We found that in Group 1, 50% of patients died from progressive disease and 15% of patients died from an acute event. Meanwhile, in Group 2, 38% of patients died from progressive disease, and 52% died from an acute event. Sepsis was the most common acute event in both groups. CONCLUSION: Preventing early mortality in aggressive lymphomas is crucial to improving overall survival. For patients with non-HIV related DLBCL, we found poor ECOG PS and presence of B-symptoms to be predictors of early mortality. In patients with HIV-positive DLBCL, poor ECOG PS, higher LDH and older age were contributing factors. The leading cause of death in both HIV-positive and HIV-negative patients (2011- 2017) was sepsis followed by progressive disease at 180 days after diagnosis. Although sepsis is a major factor contributing to early mortality and morbidity, it is preventable with prophylaxis against opportunistic infections. In order to decrease sepsis related mortality, we propose early initiation of antimicrobial therapy in patients at high risk based on independent clinical variables identified in this study. A prospective study preventing sepsis in high risk patients is warranted to decrease early mortality in patients with aggressive lymphoma. Disclosures Janakiram: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.