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Supplementary Figure 1.Baseline 4EBP1 and outcomes.

Purpose: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL).Experimental Design: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD.Results: The median age of patients was 25 years (range, 11–64) and median number of prior treatments was 2 (range, 1–7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P ≤ 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders.Conclusions: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL. Clin Cancer Res; 21(12); 2704–14. ©2015 AACR.

Supplementary Figure 2. OS and EFS by salvage status.

Supplementary material and methods, Tables 1-3. Supplementary table 1. Changes in the expression of proteins and their phosphorylated forms with everolimus treatment analyzed by RPPA; Supplementary table 2. Results of binomial analysis showing direction of changes in the expression of proteins and their phosphorylated forms, analyzed by RPPA, for individual patients; Supplementary Table 3. Major everolimus pharmacokinetic parameters in cycles 1 and 2a.

Summary Background Hypomethylating agents, such as decitabine, are the standard of care for older patients with newly diagnosed acute myeloid leukaemia. Single-arm studies have suggested that a 10-day schedule of decitabine cycles leads to better outcomes than the usual 5-day schedule. We compared the efficacy and safety of these two schedules. Methods Eligible patients were aged 60 years or older with acute myeloid leukaemia but unsuitable for intensive chemotherapy (or ClinicalTrials.gov , number NCT01786343 . Findings Between Feb 28, 2013, and April 12, 2018, 71 patients were enrolled. 28 received decitabine for 5 days and 43 for 10 days, and all were assessable for efficacy and safety. The primary endpoint was achieved in similar proportions of patients in the two treatment groups (12 [43%] of 28 in the 5-day schedule group, 95% credible interval 26–60, and 17 [40%] of 43 in the 10-day schedule group, 26–54, p=0·78; difference 3%, −21 to 27). Total follow-up was 38·2 months, during which the median duration of overall survival was 5·5 months (IQR 2·1–11·7) in the 5-day group and 6·0 months (1·9–11·7) in the 10-day group. 1-year overall survival was 25% in both groups. Complete remission, CRp, CRi, and overall survival did not differ between groups when stratified by cytogenetics, de-novo versus secondary or therapy-related acute myeloid leukaemia, or TP53mut status. The most common grade 3–4 adverse events were neutropenic fever (seven patients [25%] in the 5-day group and 14 [33%] in the 10-day group) and infection (five [18%] and 16 [37%], respectively). One patient (4%) died from sepsis in the context of neutropenic fever, infection, and haemorrhage in the 5-day group, and in the 10-day group six patients (14%) died from infection. Early mortality was similar in the two groups. Interpretation In older patients with newly diagnosed acute myeloid leukaemia, efficacy and safety did not differ by the 5-day or the 10-day decitabine schedule. Funding University of Texas MD Anderson Cancer Center and National Cancer Institute Specialized Programs of Research Excellence.

Based on our previous study of the combination of sorafenib with 5-azacytidine (AZA) in relapsed/refractory patients with FLT3 mutated acute myeloid leukemia (AML), we hypothesized that the combination would be efficacious and well tolerated in untreated patients with FLT3 mutated AML who are unsuitable for standard chemotherapy due to advanced age or lack of fitness. Newly diagnosed patients with untreated FLT3 mutated AML who underwent frontline therapy on 2 separate protocols of AZA plus sorafenib were analyzed. The clinical trials were registered at clinicaltrials.gov (NCT02196857 and NCT01254890). Overall, 27 patients with untreated FLT3 mutated AML (median age of 74 years, range, 61-86) were enrolled. The overall response rate was 78% (7 [26%] CR, 12 [44%] CRi/CRp, and 2 [7%] PR). Patients received a median of 3 treatment cycles (1-35). The median duration of CR/CRp/CRi is 14.5 months (1.1-28.7 months). Three (11%) responding patients (1 CR, 2 CRi) proceeded to allogeneic stem cell transplant. The median follow-up for surviving patients was 4.1 months (3.0-17.3 months). The median overall survival for the entire group was 8.3 months, and 9.2 months in the 19 responders. The regimen was well tolerated in elderly patients with untreated FLT3 mutated AML with no early deaths.

Background: Prior work from our group has shown that fibrocytes, the cells driving bone marrow (BM) fibrosis in patients with primary myelofibrosis (PMF), are neoplastic (clonal) and derived from monocytes (Verstovsek, J Exp Med 2016). These findings led to the clinical development of PRM-151 (recombinant human pentraxin-2) as an anti-fibrotic agent for patients with myelofibrosis (MF) (Verstovsek, EHA 2019). Our observations were extended by others to show that thrombopoietin receptor (MPL) activation induces fibrocyte differentiation and that blood monocytes highly expressing MPL and signaling lymphocyte activation molecule family member 7 (SLAMF7) were possible fibrocyte precursors (Maekawa, Leukemia 2018). Furthermore, patients with JAK2V617F+ MF have a significantly elevated SLAMF7 high monocyte percentage, which correlates with the JAK2V617F allele burden (Maekawa, Blood 2019). Finally, elotuzumab, a SLAMF7-targeting monoclonal antibody, inhibited the differentiation of MF patient-derived fibrocytes in vitro and romiplostim-induced MF and splenomegaly in vivo. Study design and methods: This is a single-institution, investigator-initiated, pilot phase 2 study of elotuzumab monotherapy in patients with JAK2V617F+ PMF or post-polycythemia vera/essential thrombocythemia MF who need treatment but are not candidates for JAK inhibitor therapy. Baseline BM fibrosis grade must be 2 or 3 per the European consensus (Thiele, Haematologica 2005). Prior JAK inhibitor treatment is permitted. Elotuzumab is dosed intravenously weekly at 10 mg/kg per dose for the first 8 doses, followed by 20 mg/kg every 4 weeks, per the label for its use in multiple myeloma in combination with pomalidomide and dexamethasone. Patients may continue elotuzumab until disease progression or unacceptable toxicity, up to a maximum of 36 cycles. Premedication and management of infusion reactions are carried out according to the elotuzumab package insert. Spleen and liver sizes are measured by palpation and the MPN-SAF-TSS questionnaire (Emanuel, J Clin Oncol 2012) is administered on day 1 of each cycle. Patients receive a BM biopsy at screening and every 6 cycles while on-study. Plasma cytokines are measured at baseline and every 3 cycles while on-study. The primary endpoint is overall response rate according to the revised IWG-MRT-ELN criteria (Tefferi, Blood 2013). A total of 15 patients are planned to be enrolled. Elotuzumab is provided by Bristol-Myers Squibb. Adverse events are graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The method of Thall, Simon and Estey (Thall, Stat Med 1995) is used for toxicity monitoring. Correlative studies: These include quantification of SLAMF7 highCD16 neg circulating monocytes by flow cytometry, measurement of serum interleukin-1 receptor alpha (IL-1Rα) concentrations and correlation of these with each other and with the mutant JAK2 allele burden, culture of human fibrocytes from peripheral blood mononuclear cells (PBMCs) in vitro, engraftment of BM cells from patients in non-obese diabetic, severe combined immunodeficient gamma (NSG) mice, and quantitation of fibrocytes in the BM of participants at baseline and every 6 cycles. Current status: The study (clinicaltrials.gov identifier: NCT04517851) is ongoing; 2 participants have been enrolled and treated thus far. Updated enrollment information will be provided. Disclosures Bose: Astellas: Research Funding; Sierra Oncology: Honoraria; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Blueprint Medicines: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Pfizer: Research Funding. Jain: TG Therapeutics: Honoraria; Janssen: Honoraria; Servier: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Cellectis: Honoraria, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding. Pemmaraju: Roche Diagnostics: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Springer Science + Business Media: Other; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Sager Strong Foundation: Other; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Plexxicon: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Kantarjian: Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Daiichi-Sankyo: Research Funding; Jazz: Research Funding; Immunogen: Research Funding; BMS: Research Funding; Astellas Health: Honoraria; AbbVie: Honoraria, Research Funding; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Verstovsek: Blueprint Medicines Corp: Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Sierra Oncology: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Elotuzumab is a monoclonal antibody targeting SLAMF7, previously known as CS-1. It is approved for the treatment of multiple myeloma in combination with an IMiD and dexamethasone. This trial studies it as a single agent in patients with myelofibrosis.

Background Anemia is common in patients (pts) with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF). Furthermore, anemia is an on-target effect of therapeutic Janus kinase 2 (JAK2) inhibition, and may be the most frequent cause of ruxolitinib (rux) discontinuation (d/c) in clinical practice (Kuykendall, Ann Hematol 2018). Current therapies for anemia of MF (erythropoietin and analogs, danazol, IMiDs®) are unsatisfactory. Sotatercept (ACE-011) is a first-in-class, activin receptor type IIA ligand trap that may improve anemia by sequestering stromal transforming growth factor beta superfamily ligands that suppress terminal erythropoiesis (Iancu-Rubin, Exp Hematol 2013). Methods This is a phase 2, investigator-initiated, open-label, single institution study of sotatercept, administered subcutaneously every 3 weeks, in 2 cohorts of anemic pts (Hgb Results A total of 53 pts have been treated; one pt received only 0.3 mg/kg of sotatercept and is not considered further. Thirty one pts received sotatercept alone and 21 in combination with rux. Baseline characteristics appear in Table 1, panel A. Sixteen TD and 15 non-TD pts received sotatercept alone for a median of 5 (1-67) cycles. Thirteen pts received 0.75 mg/kg and 18, 1 mg/kg. Seven of 24 (29%) evaluable pts responded. Of these, 4 were anemia responses; 3 TD pts achieved TI. Five responses occurred at the 0.75 mg/kg dose, and 2 at the 1 mg/kg dose. Median time to response (TTR) was 21 (1-22) days and median duration of response (DOR) 13 (3.9-56.4) months. Seven pts (22.6%) received The combination cohort comprised 15 non-TD pts and 6 TD pts. The median number of cycles was 8 (2-43). Five of 17 (29%) evaluable pts in the combination cohort responded, all non-TD pts. Median TTR was 14 (7-147) days and median DOR 34.6 (3.1-47.9) months. Four pts (19%) received Several non-response-evaluable pts in both cohorts achieved ≥1.5 g/dl increments in Hgb from baseline that were not sustained for ≥12 wks because of early d/c of sotatercept. An additional pt in the combination cohort required a rux dose increase, leading to failure to sustain a ≥1.5 g/dl Hgb improvement. Across both cohorts, several responding pts required multiple protocol-specified drug holidays because of Hgb levels ≥11.5 g/dl, with resumption of sotatercept once Hgb was Sotatercept was well-tolerated (Table 1, panel B). Grade 3 adverse events possibly related to sotatercept were HTN (n=7), limb (bone/muscle/joint) pain (n=3) and headache (1). Conclusions Sotatercept is safe and effective against anemia of MPN-associated MF, both in non-TD and TD pts, with a response rate of 29% both when used alone and in conjunction with a stable dose of rux. A total of 60 pts are planned to be treated on this trial (NCT01712308). Disclosures Bose: Blueprint Medicines Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding. Pemmaraju:Samus Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; SagerStrong Foundation: Other: Grant Support; Roche Diagnostics: Honoraria; Pacylex Pharmaceuticals: Consultancy; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; Incyte Corporation: Honoraria; Cellectis: Research Funding; Blueprint Medicines: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; DAVA Oncology: Honoraria. Daver:Fate Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: 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; ImmunoGen: Research Funding; Novartis: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: 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. Jabbour:BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Kadia:Astellas: Research Funding; Pulmotec: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; JAZZ: Honoraria, Research Funding; Cyclacel: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Cellenkos: Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Astra Zeneca: Research Funding. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Cortes:Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding; Novartis: Consultancy, Research Funding. Jain:BMS: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Borthakur:Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Cyclacel: Research Funding; GSK: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding. Alvarado:Sun Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding. Huynh-Lu:Incyte Corporation: Speakers Bureau. Nguyen-Cao:Incyte Corporation: Speakers Bureau. Garcia-Manero:Acceleron Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; Onconova: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding. Kantarjian:Oxford Biomedical: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Delta Fly: Honoraria; Janssen: Honoraria; Ascentage: Research Funding; BioAscend: Honoraria; Amgen: Honoraria, Research Funding; Aptitute Health: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Adaptive biotechnologies: Honoraria; Abbvie: Honoraria, Research Funding. Verstovsek:Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding.

Tumor hypoxia causes resistance to radiation and chemotherapy. Evofosfamide (TH-302) has exhibited specific hypoxia-dependent cytotoxicity against primary acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples in vitro. Based on these findings, a Phase I study of evofosfamide was designed for patients with relapsed/refractory leukemia (NCT01149915). In this open-label study, patients were treated with evofosfamide as a 30-60 min/day infusion on Days 1-5 of a 21-day cycle (Arm A, n = 38) or as a continuous infusion over 120 hr over Days 1-5 of a 21-day cycle (Arm B, n = 11). Forty-nine patients were treated including 39 (80%) with AML and 9 (18%) with ALL. Patients had received a median of five prior therapies. In Arm A, the dose-limiting toxicities (DLTs) were grade 3 esophagitis, observed at a dose of 550 mg/m(2) . The maximum tolerated dose (MTD) was a daily dose of 460 mg/m(2) . In Arm B, the DLTs were grade 3 stomatitis and hyperbilirubinemia, observed at a daily dose of 460 mg/m(2) . The continuous infusion MTD was a daily dose of 330 mg/m(2) . Hypoxia markers HIF-1α and CAIX were highly expressed in leukemic bone marrow and were significantly reduced after evofosfamide therapy. The combined overall response rate in Arms A and B was 6% (2 CR/CRi and 1 PR), with all responses seen in Arm A. Evofosfamide has shown limited activity in heavily pretreated leukemia patients. Further evaluation investigating evofosfamide in combination with cytotoxic or demethylating agents is warranted. Am. J. Hematol. 91:800-805, 2016. © 2016 Wiley Periodicals, Inc.

Based on our previous study of the combination of sorafenib with 5-azacytidine (AZA) in relapsed/refractory patients with FLT3 mutated acute myeloid leukemia (AML), we hypothesized that the combination would be efficacious and well tolerated in untreated patients with FLT3 mutated AML who are unsuitable for standard chemotherapy due to advanced age or lack of fitness. Newly diagnosed patients with untreated FLT3 mutated AML who underwent frontline therapy on 2 separate protocols of AZA plus sorafenib were analyzed. The clinical trials were registered at clinicaltrials.gov (NCT02196857 and NCT01254890). Overall, 27 patients with untreated FLT3 mutated AML (median age of 74 years, range, 61-86) were enrolled. The overall response rate was 78% (7 [26%] CR, 12 [44%] CRi/CRp, and 2 [7%] PR). Patients received a median of 3 treatment cycles (1-35). The median duration of CR/CRp/CRi is 14.5 months (1.1-28.7 months). Three (11%) responding patients (1 CR, 2 CRi) proceeded to allogeneic stem cell transplant. The median follow-up for surviving patients was 4.1 months (3.0-17.3 months). The median overall survival for the entire group was 8.3 months, and 9.2 months in the 19 responders. The regimen was well tolerated in elderly patients with untreated FLT3 mutated AML with no early deaths.

Background: Single-arm studies have suggested that a 10-day schedule of decitabine (DAC) may result in better outcomes than the standard 5-day schedule in older patients (pts) with acute myeloid leukemia (AML), particularly in pts with TP53 mutations. We therefore designed a randomized phase II study to evaluate the relative safety and efficacy of these two different schedules of DAC in this older population. Methods: Adults ≥60 years of age with newly diagnosed AML were randomized using a Bayesian adaptive design to receive DAC at a dose of 20 mg/m2 IV daily for either 5 or 10 consecutive days as induction. Pts Results: Between 2/2013 and 4/2018, 71 pts were randomized to receive DAC for either 5 days (n=28) or 10 days (n=43). Baseline characteristics of the 2 arms were well-balanced and are shown in Table 1. The median age of the entire cohort was 78 years (range, 57-94 years). TP53 mutations were detected in 7/24 pts (29%) in the 5-day arm and in 17/41 pts (41%) in the 10-day arm. The composite CR + CRp + CRi rate was similar in both arms (12/28 [43%] in 5-day arm vs 17/43 [40%] in the 10-day arm; P=0.78). CR rates were 29% and 30%, respectively. Given the similar response rates, this trial terminated early for futility. There was a trend towards earlier responses with the 10-day schedule (P=0.09). No significant differences in response rates were observed by disease subgroups (cytogenetics, de novo vs. secondary AML, or TP53 mutation). The 30-day mortality rates for the 5-day and 10-day arms were 4% and 9%, and the 60-day mortality rates were 21% and 25%, respectively. The median duration of follow-up was 38.2 months. The median remission duration for the 5-day and 10-day schedules was 9.4 and 6.4 months, and 1-year continuous remission rates were 26% and 33%, respectively (P=0.98; Figure 1A). The median OS was 5.5 and 6.0 months, respectively, and 1-year OS rates were 25% in both arms (P=0.47; Figure 1B). No significant difference in OS was observed between schedules when stratified by disease subgroups. Median OS for pts with TP53-mutated AML was 5.5 months for the 5-day arm and 4.9 months for the 10-day arm (P=0.55). There were no differences in baseline TP53 variant allelic frequency (VAF) in pts who responded to DAC compared to those who did not (P=0.70). Responding pts had a significant decline in TP53 VAF at the end of cycle 1 (mean ± SD baseline VAF 53.2% ± 19.7% vs end-of-cycle 1 VAF 27.5% ± 23.9%, P Conclusions: In older adults with newly diagnosed AML, DAC given for either 5 or 10 consecutive days resulted in similar response rates, early mortality and survival. No differences in response or survival were observed in any subgroup, including TP53-mutated AML. Disclosures Short: Takeda Oncology: Consultancy. Kadia:Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy; BMS: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding. Daver:Incyte: Research Funding; Pfizer: Consultancy; Kiromic: Research Funding; Otsuka: Consultancy; Karyopharm: Consultancy; BMS: Research Funding; Karyopharm: Research Funding; Incyte: Consultancy; ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; ImmunoGen: Consultancy; Alexion: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Sunesis: Consultancy; Novartis: Consultancy; Sunesis: Research Funding. DiNardo:Celgene: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Abbvie: Honoraria; Karyopharm: Honoraria; Bayer: Honoraria. Maiti:Celgene Corporation: Other: Research funding to the institution. Bose:Blueprint Medicines Corporation: Research Funding; Celgene Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy, Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Pemmaraju:Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Jain:Abbvie: Research Funding; Celgene: Research Funding; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Verastem: Research Funding; ADC Therapeutics: Research Funding; Cellectis: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Seattle Genetics: Research Funding; Astra Zeneca: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Infinity: Research Funding; BMS: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Ravandi:Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Xencor: Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Sunesis: Honoraria; Sunesis: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Jazz: Honoraria.

Patients received 5-azacytidine (AZA) 75 mg/m(2) intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ~1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsed AML and FLT-3-ITD. This trial was registered at clinicaltrials.gov as #NCT01254890.

Purpose We conducted a phase II study of pegylated interferon alfa-2a (PEG-IFN-α-2a) in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Patients and Methods Seventy-nine patients (40 with PV and 39 with ET) have been treated. Median time from diagnosis to PEG-IFN-α-2a was 54 months in patients with PV and 33 months in patients with ET. Eighty-one percent of patients had received prior therapy. The first three patients received PEG-IFN-α-2a at 450 μg weekly. As a result of poor tolerance, this dose was decreased in a stepwise manner to a current starting dose of 90 μg weekly. Seventy-seven patients are evaluable and have been observed for a median of 21 months. Results The overall hematologic response rate was 80% in PV and 81% in ET (complete in 70% and 76% of patients, respectively). The JAK2V617F mutation was detected in 18 patients with ET and 38 patients with PV; sequential measurements by a pyrosequencing assay were available in 16 patients with ET and 35 patients with PV. The molecular response rate was 38% in ET and 54% in PV, being complete (undetectable JAK2V617F) in 6% and 14%, respectively. The JAK2V617F mutant allele burden continued to decrease with no clear evidence for a plateau. The tolerability of PEG-IFN-α-2a at 90 μg weekly was excellent. Conclusion PEG-IFN-α-2a resulted in remarkable clinical activity, high rates of molecular response, and acceptable toxicity in patients with advanced ET or PV. The ability of PEG-IFN-α-2a to induce complete molecular responses suggests selective targeting of the malignant clone.

Purpose: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Experimental Design: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD. Results: The median age of patients was 25 years (range, 11–64) and median number of prior treatments was 2 (range, 1–7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P ≤ 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders. Conclusions: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL. Clin Cancer Res; 21(12); 2704–14. ©2015 AACR.

7029 Background: Sorafenib plus 5-azacytidine (AZA) is observed to be safe and effective in relapsed / refractory FLT3-ITD mutated acute myeloid leukemia (AML) patients (pts). Hypothesis: Combining sorafenib with AZA is safe and effective in older untreated FLT3-ITD mutated AML pts. Methods: Eligibility included: untreated FLT3-ITD mutated AML (≥10% mutation burden), age ≥60 yrs, adequate organ function, and ECOG performance status ≤ 2. The regimen was: AZA 75 mg/m2daily x 7 days and sorafenib 400 mg twice daily for 28 days. Results: 26 pts with untreated AML [median age 73 (61-86)] were enrolled: 16 (62%) pts had normal karyotype, 2 (8%) complex karyotype, 4 (15%) other miscellaneous abnormalities, and 4 (15%) with insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in all pts with a median allelic ratio of 0.3735 (0.009-0.885). The overall response rate (ORR) in 25 evaluable pts was (76%) [7 (28%) with CR, 10 (40%) CRi/CRp, and 2 (8%) PR]. Pts underwent a median of 3 (1-35) treatment cycles. The median number of cycles to response was 2 (1-4), and the median time to achieve response, 1.77 months (mos) (0.689-4.271 mos). The median duration of CR/CRp/CRi is 14.5 mos (1.18—28.74). Three (18%) responding pts (CR, CRp, CRi) have proceeded to allogeneic stem cell transplant. With a median follow-up of 6.8 mos (0.2-18.8), 6 pts are alive, 3 in remission (CR/CRP/CRi). The median overall survival (OS) for the entire group is 8.3 mos; 9.2 mos in 17 responders. Evaluable pts treated with AZA + sorafenib (n = 25) were compared to a matched cohort of historical FLT3-ITD mutated pts > 60 yrs, but treated with hypomethylator-based (HMA) therapy without sorafenib (n = 20); the respective ORR (CR, CRp, CRi, PR) (76% vs. 70%, p = 0.653) and median OS (8.3 and 9.4 mos, p = 0.69) were similar. The remission duration for the responding pts treated with AZA+sorafenib was significantly longer (14.5 mos) than those on other HMA regimens without sorafenib (3.8 mos) (p = 0.01). Adverse events possibly attributable to the regimen included: grade (Gr) 1/2 nausea (n = 3), Gr 1/2 diarrhea (n = 2), Gr 1 dyspnea (n = 1), and Gr 1 breast pain (n = 1). Conclusions: The combination of AZA and Sorafenib is both well tolerated and effective in older untreated FLT3-ITD mutated AML. Clinical trial information: NCT02196857;NCT01254890.

Background: The combination of 5-azacytidine (AZA) and sorafenib has been reported to be a safe and effective strategy in patients with relapsed and/or refractory FLT3-ITD mutated acute myeloid leukemia (AML). We hypothesized that combining sorafenib with AZA, may be used effectively in older patients with untreated AML whose leukemic cells harbor the mutation. Methods: Patients were eligible if they had untreated AML with a FLT3-ITD clone detectable by polymerase chain reaction (at least 10% mutation burden), were 60 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. The treatment regimen included AZA 75 mg/m2daily for 7 days combined with sorafenib 400 mg twice daily for 28 days. Cycles were repeated approximately every 4 to 5 weeks. Dose adjustments of both agents, and delay of AZA, based on toxicity were allowed. Results: Overall, 23 patients with untreated AML with a median age of 74 yrs (range, 61-86 yrs) were enrolled. They included 14 (61%) patients with normal cytogenetics, 2 (9%) with complex karyotype, 4 (17%) with other miscellaneous abnormalities, and 3 (13%) with insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in all patients with a median allelic ratio of 0.35 (range, 0.01-0.89). The overall response rate in 22 evaluable patients was (77%) including 7 (32%) with CR, 9 (41%) CRi/CRp, and 1 (5%) PR. Patients have received a median of 3 (range, 1-35) treatment cycles with the median number of cycles to response being 2 (range, 1-5) and the median time to achieve response, 1.9 months (range, 0.7-4.3 months). The median duration of CR/CRp/CRi is 14.5 months (range, 1.2-28.7 months). Two (9%) patients have proceeded to allogeneic stem cell transplant. With a median follow-up of 4.2 months (range, 0.9-61.4), 8 patients remain alive, 7 still in remission (CR/CRP/CRi). The median overall survival for the entire group is 8.8 months, and 9.2 months in the 17 responding patients (Figure 1). Treatment-related grade 3/4 adverse events included: grade 3 diarrhea (n=2), grade 3 pneumonitis (n=3), grade 4 sepsis (n=2), grade 3 infections (n=3). When patients treated with AZA + sorafenib (n=23) were compared to a matched cohort of historical patients older than 60 years who were treated with hypomethylator-based therapy without sorafenib (n=20), overall response rates (including CR, CRp, CRi, and PR) were statistically similar (77% vs.31%, respectively; p=0.6). The median overall survival for the two groups were 8.8 months and 9.4 months (p=0.67), respectively. The remission duration for the responding patients treated with AZA+sorafenib was significantly longer (16 months) than those on other hypomethylator-based regimens without sorafenib (3.8 months)(p=0.008) (Figure 2). Conclusions: The combination of AZA and Sorafenib is effective and well tolerated in older patients with untreated FLT3-ITD mutated AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Ariad: Research Funding. Burger:Roche: Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

BACKGROUND The hypomethylating agents decitabine and 5-azacytidine are commonly used for the initial treatment of acute myeloid leukemia (AML) in elderly patients deemed unfit to receive standard cytotoxic induction chemotherapy. Decitabine at the approved schedule of 20 mg/m2daily for 5 days was shown to be superior to supportive care or low dose cytarabine. (Kantarjian H, JCO; 30(21):2670, 2012). An extended 10-day schedule of decitabine was reported to have a significantly higher response rate (Blum W, PNAS; 107(16):7473, 2010) OBJECTIVES The primary objective of the current study was to compare the response rates of the two schedules of decitabine in patients with AML aged 60 years or older who were deemed ineligible to receive standard cytotoxic induction chemotherapy. Secondary objectives were to compare response durations, survival outcomes, and toxicities between the two schedules. METHODS Patients with AML aged 60 years or older were randomized using a Bayesian adaptive design to receive decitabine at a dose of 20 mg/m2intravenously daily for either 5 days or 10 days. Responding patients could receive up to 24 cycles repeated every 4 to 8 weeks. Patients on the 10-day schedule could receive 5-day dosing after achieving a response or earlier if clinically indicated. The primary efficacy outcome was complete remission (CR), CR with incomplete count recovery (CRi), or CR with incomplete platelet recovery (CRp) after three cycles. RESULTS Fifty-seven patients with a median age of 77 years (range 62-90 years) were enrolled on the 5-day (23 patients, 40%) and 10-day (34 patients, 60%) schedules. Thirty-nine patients (68%) were male. The median WBC count in the 5-day and 10-day arms were 2 × 109/L (range 0.7-36.5) and 3 × 109/L (range 0.6-17.7), respectively (p=not significant, NS). The median pre-treatment platelet count for the 5-day and 10-day arms were 24 x 109/L (range 7-162) and 39.5 x 109/L (range 2-213), respectively (p = 0.04) but all other pre-treatment characteristics including the distribution of cytogenetics risk group were similar between the two groups. Pre-treatment cytogenetic findings included complex in 29 patients (51%), diploid in 17 (30%), and intermediate or miscellaneous in 7 (12%), and cytogenetic analysis was not performed in 4 patients (7%). One patient in the 5-day arm received prior treatment for myelodysplastic syndrome and 2 patients in the 10-day arm received prior treatments for chronic myeloid leukemia and post-essential thrombocythemia myelofibrosis (none with hypomethylating agents). Overall and complete response rates did not differ between the two arms (Table 1). Median overall survival was 4.9 months for the 5-day arm and 9.3 months for the 10-day arm (p = 0.88; Figure 1). Median event-free survival was 3.1 months for the 5-day arm and 4.6 months for the 10-day arm (p = 0.92). The median response duration was 9.4 months for the 5-day arm and 6.4 months for the 10-day arm (p = 0.68; Figure 2). CONCLUSION Response rates, response durations, and overall survival were not statistically different between the two schedules of decitabine in elderly patients with AML ineligible for cytotoxic induction regimens. These findings should be considered in the design of trials investigating combinations of hypomethylating agents with molecularly targeted agents. Overall Survival in Patients on the 5-day (n = 23) and 10-day (n = 34) schedules Overall Survival in Patients on the 5-day (n = 23) and 10-day (n = 34) schedules Figure 1 Response Duration in Patients achieving CR/CRp/CRi, on the 5-day (n = 11) and 10-day (n = 14) schedules Figure 1. Response Duration in Patients achieving CR/CRp/CRi, on the 5-day (n = 11) and 10-day (n = 14) schedules Figure 2 Figure 2. Disclosures Daver: Kiromic: Research Funding; Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Sunesis: Consultancy, Research Funding; Ariad: Research Funding; Otsuka: Consultancy, Honoraria. DiNardo:Agios: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Wierda:Genentech: Research Funding; Gilead: Research Funding; Acerta: Research Funding; Abbvie: Research Funding; Novartis: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

KIT D816V mutation has been observed in more than 90% of patients with systemic mastocytosis (SM). This mutation constitutively activates the mammalian target of rapamycin (mTOR) signaling pathway. We tested the efficacy of everolimus (RAD001), a novel oral mTOR inhibitor, at a dose of 10 mg daily in an open label, non-comparative Phase II trial for patients with SM. Ten patients were enrolled from April 2007 to October 2008. Median age was 55 years, four were males, seven had indolent and three aggressive SM, and six were previously treated with other agents. Median duration of therapy was 4 months (range 0.2-18). No objective responses were noted. Four patients had a short-lasting subjective improvement in symptoms for a median duration of 3 months (range 3-15). Grade 1-3 diarrhea, mucositis, and neutropenia were the most common adverse effects. No Grade 4 toxicity was noted. In conclusion, everolimus does not result in appreciable clinical activity in patients with SM.

BACKGROUND. Interferon-alpha (IFN-α) has shown significant activity in the treatment of BCR-ABL–negative myeloproliferative disorders (MPDs), particularly essential thrombocythemia (ET) and polycythemia vera (PV). PEG-IFN-α-2b is a pegylated IFN-α-2b with a significant advantage over nonpegylated form in that it is administered once a week. METHODS. Thirty-eight patients with BCR-ABL–negative MPDs were treated with PEG-IFN-α-2b, given subcutaneously weekly, at the starting dose of 3 μg/kg/wk for the first 14 patients and then 2 μg/kg/wk for the next 24 patients, with intent to treat patients as long as they benefited from the therapy. RESULTS. Median age was 54 years. Patient diagnoses were: 13 (34%) ET; 11 (29%) primary myelofibrosis (PMF); 5 (13%) BCR-ABL–negative chronic myeloid leukemia (CML); 4 (10.5%) hypereosinophilic syndrome (HES); 4 (10.5%) PV; and 1 (3%) unclassified myeloproliferative disease (uMPD). Recorded grade 3–4 toxicities were related to fatigue, myelosuppression, and musculoskeletal pain. Ten (26%) patients stopped treatment because of toxicity. Thirteen (34%) patients achieved a complete remission, and 4 (11%) achieved a partial response. Only 1 patient with PMF responded. Median time to response was 5 months. Median duration of response was 20 months. Three patients had a sustained response for >24 months. CONCLUSIONS. PEG-IFN-α-2b, with proper dose modifications, is effective in controlling disease in a significant proportion of BCR-ABL–negative MPD patients, particularly ET and PV. However, toxicities encountered with PEG-IFN-α-2b therapy are similar to those obtained with conventional IFN-α, thus limiting the duration of therapy. Cancer 2007. © 2007 American Cancer Society.

Introduction The outcomes of patients (pts) with relapsed/refractory acute lymphoblastic leukemia (ALL) remain poor. Dysregulation of the PI3K/AKT/mTOR signal transduction pathway is central to leukemic cell growth and survival. Everolimus is an orally active inhibitor of mTOR approved for the treatment of pts with several tumor types. Aim The purpose of this phase I/II study was to establish the safety and efficacy of everolimus in combination with hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) in pts with relapsed/refractory ALL and lymphoblastic lymphoma (LL). Methods Pts ≥ 10 years of age with relapsed/refractory ALL or LL, ECOG performance status 2 2 and adequate organ function were eligible. Pts were treated with oral everolimus at 5 or 10 mg (phase 1 dosing) continuously concurrently with 8 cycles of the standard hyper-CVAD regimen, starting day 0 of course 1. Everolimus 5 mg daily was established as maximum tolerated dose (MTD) after 2 cycles. Comprehensive proteomic profiling of 10 proteins along with their phosphorylated forms was performed using reverse-phase protein arrays (RPPA). Total RNA was isolated from patient samples using TRIzol reagent and gene expression analysed using a HumanHT-12 v4 gene expression chip from Illumina (N = 5). Pharmacokinetic (PK) studies were performed on day 0 and day 15 of course 1 (N = 8). Background Twenty pts were enrolled between April 2010 and June 2013, with accrual ongoing. Clinical characteristics included 9 pts in first salvage, 2 in second salvage and 9 beyond second salvage (Table 1). Median (Med) number of cycles given was 2 (1-5). Med follow-up was 19 months (1-35). Seven of 20 pts responded for an overall response rate of 35% with complete remission (CR) in 6 pts (30%), CR with incomplete count recovery (CRi) in 1 (5%), and partial remission (PR) in 2 (10%). Six of 9 pts (66%) in first salvage achieved CR, and one of 2 pts in second salvage achieved CRi. Four pts proceeded to stem cell transplant in CR. Med event-free survival (EFS) and med overall survival (OS) were 6 and 7 months, respectively, for pts in 1st salvage, and 2 and 4 months, respectively for pts in second salvage and beyond (P=0.01 and P=0.002). The 1-year OS is 47% for 1st salvage pts and 9% for pts in second salvage and beyond. Grade 3 mucositis was dose-limiting toxicity. Other grade 3/4 toxicities including infections, transaminitis, diarrhea, headache, and increased bilirubin occurred in 18 (90%), 6 (30%), 2 (10%), 2 (10%), and 2 (10%) pts. Among the 10 pts profiled by RPPA, inhibition of mTOR signaling (p-pS6K) was observed in 7/10 (70%). Everolimus significantly inhibited phosphorylation of S6K on both, pS235-S236 and pS240-S244 sites (P=0.007 and P=0.01, respectively). Inhibition of pS6 was observed at both 5 mg and 10 mg doses. No statistically significant difference in phosphorylation of 4EBP1, AKT or other proteins was noted. Gene set enrichment analysis performed in paired PB samples from 5 pts showed enrichment of the ABC transporter gene set in pts who failed to respond. Analysis of PB samples 24 hrs post everolimus exposure was associated with reduction of the signature for miR-21, miR-30 and miR-507 gene sets, irrespective of a biological response to mTOR inhibition as assessed by S6K phosphorylation. PK analysis showed that area under the curve (AUC) for everolimus was dose-dependent with higher AUC at 10 mg versus 5 mg. Those achieving CR had significantly higher AUC and lower clearance at steady state compared to pts with PR/no response (Fig. 1, P=0.025), but it was not associated with toxicity. Conclusion The combination ofhyper-CVAD plus everolimus was well tolerated, and findings indicate that further testing of mTOR inhibitors with standard chemotherapy in the frontline therapy of ALL and LL is warranted. Disclosures: Kantarjian: Sanofi-Aventis: Research Funding. Ravandi:Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Teva: Consultancy, Honoraria; Pfizer: Honoraria; Merck: Research Funding; Bayer/Onyx: Consultancy, Honoraria; EMD Serono: Research Funding; Medimmune: Research Funding; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria.

Background TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard designed to be selectively activated in hypoxic conditions. Preclinical data in mice with acute lymphoblastic leukemia (ALL) have demonstrated marked expansion of hypoxia in areas of marrow leukemia infiltrates (Benito et al., PLoS One 2011). TH-302 also exhibited specific hypoxia-dependent cytotoxicity when tested against primary ALL and acute myelogenous leukemia (AML) samples in vitro (Benito et al., ASH 2012). Based on these findings, a phase 1 study of TH-302 was designed for advanced leukemias. Methods Eligible patients had ECOG ≤ 3, relapsed/refractory leukemias for which no standard therapy options were available, and acceptable hepato-renal function. A standard 3+3 dose-escalation design was used with 40% dose increments. TH-302 was administered IV over 30-60 min daily, either by 30 min-bolus administration or as a continuous infusion on days 1-5 of a 21-day cycle. The objectives were to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of TH-302 with these schedules and to assess preliminary clinical activity of TH-302. Results A total of 49 patients with previously treated AML (n=39), ALL (n=9) or CML in blast phase (n=1) received TH-302 at bolus doses of 120 (n=4), 170 (n=4), 240 (n=3), 330 (n=3), 460 (n=20), 550 (n=4) mg/m2 or continuous doses of 330 (n=8) or 460 (n=3) mg/m2. Two of 3 evaluable patients treated with bolus TH-302 (550 mg/m2) experienced DLTs of grade 3 esophagitis; bolus administration MTD was established at 460 mg/m2. Two of 3 patients treated with continuous infusion of TH-302 (460 mg/m2) experienced DLTs of grade 3 mucositis or grade 3 hyperbilirubinemia; continuous administration MTD was established at 330 mg/m2. Thirteen patients received greater than 1 cycle. Generally, a significant rapid cytoreduction was evident early in the cycle, but was not maintained prior to initiation of the next cycle. Two AML patients who received 550 mg/m2 bolus TH-302 had complete resolution of leukemia cutis. One AML patient at 550 mg/m2 bolus TH-302 had a complete response with incomplete platelet recovery (CRp), and one AML patient at 440 mg/m2 bolus TH-302 had a CR. Conclusions In patients with advanced leukemias, MTDs were established for daily bolus infusion and 5-day continuous infusion of TH-302 at 460 mg/m2 and 330 mg/m2, respectively. Increased incidence of skin and mucosal toxicity were observed at higher dose levels with both administration schedules. Clinical activity of single-agent TH-302 has been noted with a few objective responses, but the majority of cytoreductions were transient. Disclosures: Konopleva: Threshold Pharmaceuticals: Research Funding. Handisides:Threshold Pharmaceuticals: Employment, Equity Ownership. Kroll:Threshold Pharmaceuticals: Employment, Equity Ownership. Kantarjian:Ariad: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

24 Background: Outcome of patients with relapsed acute myeloid leukemia (AML) with FLT3-ITD mutation is poor. Elevated FLT3 ligand levels (FL) secondary to cytotoxic chemotherapy is a putative mechanism of resistance to the FLT3 kinase inhibitors. We hypothesized that FL levels will be lower when combining sorafenib with less intensive therapy such as 5-Azacytidine (5-Aza). This study was conducted to evaluate the efficacy and tolerability of the combination of sorafenib and 5-Aza in patients with refractory or relapsed AML with FLT3-ITD mutation. Methods: Patients were eligible if they had relapsed or refractory AML and were 18 years of age or older. They received 5-Aza 75 mg/m2 IV daily x 7 days and sorafenib 400 mg PO BID continuously; cycles were repeated in approximately one month intervals. Results: 38 patients with AML with a median age of 60 years (range, 24-87) were enrolled. 4 were inevaluable as they never received therapy or discontinued it before response assessment. FLT-3-ITD was detected in 30 (88%) patients. They had received a median of 2 prior treatments (range, 0-6); 13 (38%) had received ≥ 3 prior regimens and 8 had failed prior FLT3 kinase inhibitor. Response rate was 41%, including 6 (17%) with CRi, 4 (12) with CRp, 3 (9%) with CR, and 1(3%) PR. The median time to achieving CR/CRi was 2 cycles (Range, 1-6) and the median duration of CR/CRi was 3 months (Range, 1–12). Conclusions: Combination of 5-Aza and sorafenib is effective for patients with relapsed AML with FLT-3-ITD mutation.

6558 Background: The outcome of patients with relapsed acute myeloid leukemia (AML) with FLT3-ITD mutation is poor. Sorafenib is an inhibitor of FLT-3 kinase activity in nanomolar concentrations. We conducted this phase II study to evaluate the efficacy and tolerability of the combination of Sorafenib and 5-Aza for the treatment of patients with refractory or relapsed AML with the particular emphasis on those with FLT3-ITD mutation. Methods: Patients were eligible if they had relapsed or refractory AML and were 18 years of age or older. They received 5-Aza 75 mg/m2 daily x 7 together with Sorafenib 200 mg BID X 28 days; cycles were repeated in approximately 1-month intervals. Responses were assessed after first cycle and then at the discretion of the treating physician at the time of the best peripheral blood response. Results: 32 patients with AML with a median age of 61 years (range, 24-87) were enrolled. They included 13 (41%) with diploid cytogenetics, 9 (28%) with complex cytogenetics, and 10 (31%) with miscellaneous chromosomal abnormalities. FLT-3-ITD was detected prior to the initiation of treatment in 30/32 patients. Patients had received a median of 2 prior treatments (range, 1-6). 12 (38%) patients had received ≥3 prior regimens and 11 had failed therapy with a FLT3 kinase inhibitor (6 with AC220, 1 with PKC412, and 5 with sorafenib, either as monotherapy or with plerixafor); 2 had failed 2 prior FLT3 inhibitors. 10 patients were inevaluable as they never received therapy or discontinued it before response assessment at one month. The overall CR/CRi rate among the 22 evaluable patients is 50%, including 9 (41%) with CRi and 2 (9%) with CR; with a median of 3 (range, 1-9) treatment cycles. The median time to achieving CR/CRi was 3 months (range, 1-4) and the median duration of CR/CRi was 3 months (range

6585 Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard designed to be selectively activated in hypoxic conditions. Preclinical data in mice with ALL have demonstrated marked expansion of hypoxia in areas of marrow leukemia infiltrates (Benito et al., PlosOne, in press). TH-302 also exhibited specific hypoxia-dependent cytotoxicity when tested against primary ALL and AML samples in vitro. Based on these findings, a phase 1 study of TH-302 was designed for advanced leukemias. Methods: Eligibility: ECOG ≤ 3, relapsed/refractory leukemias for which no standard therapy options were available, and acceptable hepatorenal function. A standard 3+3 dose escalation design was used with 40% dose increments. TH-302 was administered IV over 30-60 minutes daily on Days 1-5 of a 21-day cycle. The objectives were to determine the MTD and PK profile of TH-302 with this schedule and to assess preliminary clinical activity of TH-302. Results: 34 subjects with previously treated AML (n=26), ALL (n=6) or CML in blast phase (n=1) received TH-302 at doses of 120 (n=4), 170 (n=4), 240 (n=3), 330 (n=3), 460 (n=16) or 550 (n=4) mg/m². No skin or mucosal toxicity was noted in participants treated with TH-302 doses ≤240 mg/m2. At 330 mg/m2, grade 2 dermatological toxicities included skin ulcer (n=1) and hand/foot syndrome (n=1). Grade 2 mucositis (n=3) and grade 2 skin toxicity (e.g. skin rash, skin ulcers; n=3) were reported at 460 mg/m2; none were dose-limiting. Two of 3 evaluable subjects treated at the 550 mg/m2 cohort experienced DLTs of grade 3 esophagitis. Eight subjects had stable disease or better after 1 cycle. One ALL subject (at 120 mg/m2) cleared marrow blasts with persistent neutropenia. One AML subject (at 550 mg/m2) achieved CRp after 1 cycle with resolution of leukemia cutis. Conclusions: TH-302 administered daily for 5 consecutive days every 3 weeks is well-tolerated with increased incidence of skin and mucosal toxicity at higher dose levels. Clinical activity has been noted with a few objective responses, but majority of cytoreductions in the AML subset were transient. Clinical trials combining TH-302 with various chemotherapeutics with established efficacy in AML and ALL are planned.

The conventional management of patients (pts) with high-risk Philadelphia chromosome-negative (Ph-negative) MPD revolves around the administration of cytoreductive agents such as hydroxyurea, anagrelide, and recombinant human interferon alpha (IFN-a). IFN-a has shown significant activity in the treatment of Ph-negative MPD, particularly essential thrombocythemia (ET) and polycythemia vera (PV). PEG-Intron is a pegylated IFN-a that has a significant advantage over regular IFN-a in that it is administered once a week. We are reporting the final results of a phase II study evaluating the efficacy and tolerability of PEG-Intron in pts with Ph-negative MPD treated at M. D. Anderson Cancer Center, Houston, Texas. PEG-Intron was given subcutaneously weekly with intent to treat pts as long as they benefit from the therapy. Forty pts were enrolled, 26 males (65%), with a median age of 54 years (range 28 to 81). Pts diagnoses were: 14 ET (35%); 11 myelofibrosis (MF; 27%); 6 Ph-negative chronic myeloid leukemia (CML; 15%); 4 hypereosinophilic syndrome (HES; 10%); 4 PV (10%); and 1 myelodysplastic syndrome/myeloproliferative disease (MDS/MPD; 3%). Thirty-four pts are evaluable for response evaluation, as they have received minimum of 3 months of therapy, and have received more than 50% of the medication during the time on study: complete remission (CR) was achieved in 13 pts (38%) while partial response (PR) was noted in 4 pts (12%); 17 pts (50%) had no response. Six pts were not evaluable for response: 2 refused therapy before starting; 3 stopped therapy early due to toxicity, and 1 had progression of the disease before 3 month response evaluation. Of the 17 responders 12 (71%) achieved their best response by 3 months on the therapy. Overall response among all the patients enrolled varied by the type of diagnosis: of the 14 ET pts 7 achieved CR and 2 achieved PR (64% overall response rate); of the 11 MF pts one achieved CR; of the 6 Ph-negative CML 2 achieved CR; of the 4 pts with HES one achieved CR; of 4 PV pts 2 achieved CR and 2 PR; and 1 MDS/MPD pt was not evaluable for response. Initially, starting dose of PEG-Intron was 3 mcg/kg per week. However, of the first 14 pts on the study all but 1 had to reduce the dose at least once within the first 3 months, and therefore the starting dose of PEG-Intron was reduced to 2 mcg/kg per week. Most of the pts maintained the 2 mcg/kg per week throughout their time on the therapy. Recorded grade 3 toxicities were related to myelosuppression, disturbance of GI tract, and musculo-skeletal system (22 pts). Grade 4 toxicities were recorded in 4 pts: 1 developed anemia and the other 3 developed thrombocytopenia. Of the 38 pts that have received any therapy 5 (4 in CR and 1 in PR) are still receiving therapy for a median duration of 28+ months (range, 21+ to 41+). Of the 33 pts that stopped the therapy 17 stopped because of no response, 6 due to unrelated medical reasons, 5 due to toxicity, 2 due to other reasons, 1 was lost to follow-up, 1 lost response, and 1 progressed to acute myeloid leukemia. After a median follow-up of 24 months (range, 1 to 42) 26 pts are alive. In conclusion, PEG-Intron, with proper dose modifications, is effective in controlling disease in a significant proportion of Ph-negative MPD pts, particularly patients with ET and PV. However, toxicities encountered with PEG-Intron therapy are still significant.

Patients (pts) with high-risk Philadelphia chromosome-negative myeloproliferative disorders (MPDs) are customarily treated with cytoreductive agents such as recombinant human interferon-alpha (IFN-α), hydroxyurea (HU), and anagrelide (AG). Despite the significant activity of IFN-α in MPDs, responses have been frequently limited by poor tolerance and inconvenient dosing schedules. PEG-IFN-α is formulated by covalently attaching polymers of ethylene glycol to the native IFN-α molecule, which results in increased serum half-life, decreased renal excretion, thus allowing for weekly administration while maintaining acceptable toxicity profile. Based on the superior pharmacokinetic and pharmacodynamic profile of PEG-IFN-α relative to IFN-α we designed a phase II study of subcutaneous (sc) PEG-IFN-α-2a (Pegasys™) for pts with ET and PV. A total of 23 pts have been enrolled so far (13 ET, 10 PV). First 3 pts received PEG-IFN-α-2a at 450mcg weekly but experienced toxicity and had to reduce the dose; next 3 pts started at 360mcg weekly and again had to reduce the dose due to toxicity; last 17 pts started at 270mcg weekly and tolerated therapy well. Dose modifications of 90 mcg are allowed according to response or toxicity. Median age is 54 years (range, 23 to 73), time from diagnosis to PEG-IFN-α-2a therapy 64 months (range, 1 to 282), Hb 13.5 g/dL (range, 8.9 to 18.5), WBC 5×109/L, (range, 4.3 to 49), platelets 592×109/L (range, 298 to 1000). All pts had prior therapies (median 2, range 1–6), including HU (n=17), AG (n=13), IFN-α (n=6: 4 oral and 2 sc), imatinib mesylate (n=2) and others (n=3). In addition, 8 PV pts had received phlebotomies. The JAK2 V617F mutation was detected in 6 (46%) of 13 ET pts and in 9 (90%) of 10 PV pts. All pts had diploid cytogenetics. After a median follow-up of 6 months (range, 1 to 15), 11 of 13 (85%) ET pts have achieved a complete response (platelets 2 weeks). Overall, 17 pts (74%) reduced the dose so far, while 6 pts (all on 270mcg weekly) remain at the same initial dose. Only 2 pts (1 ET, 1 PV) discontinued therapy, due to retinal infiltrates and depression after 8 and 6 months on therapy, respectively. In summary, therapy with PEG-IFN-α-2a has an acceptable toxicity profile and significant activity in pts with ET and PV. Updated clinical and molecular results will be presented.