Blast Reduction Research Articles

Blast Percentage of Bone Marrow Aspirate on Day 14 of Induction Chemotherapy Predicts Adult Acute Lymphoblastic Leukemia Treatment Outcomes

The prognosis of adult acute lymphoblastic leukemia is much worse than that of pediatric acute lymphoblastic leukemia, even when patients achieve complete remission. Early response to treatment can be an important alternative indicator of treatment outcomes. The purpose of our current study was to identify the prognostic value of the blast percentage of the induction interim bone marrow, which might predict relapse-free survival and overall survival in patients with adult acute lymphoblastic leukemia. A retrospective analysis was performed on 80 adult patients diagnosed with Philadelphia chromosome-negative acute lymphoblastic leukemia from 1994 to 2011. Complete remission was observed in 75 (93.8%) patients after induction chemotherapy. On multivariate analysis, a reduction of blasts to a level of 5% or less in the induction interim bone marrow and CD20 positivity were significant prognostic predictors of relapse-free survival (hazard ratio, HR = 2.88, p = 0.006, and HR = 2.67, p = 0.010) and overall survival (HR = 2.10, p = 0.033, and HR = 2.39, p = 0.013). The blast percentage of the induction interim bone marrow may be a useful prognostic factor to predict outcome.

A phase 1 dose escalation study of the IDH1m inhibitor, FT-2102, in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

7009 Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients (pts) and 3% of MDS pts. FT-2102 is a highly potent, selective small molecule inhibitor of IDH1m without anticipated CYP or QTc liabilities at the recommended phase 2 dose. Methods: A Phase 1/2 study was initiated to evaluate the safety, PK/PD, and clinical activity of FT-2102 alone or in combination with azacitidine (AZA) or cytarabine in IDH1m AML/MDS pts. Safety for all pts and efficacy for evaluable pts are reported. Results: At the data cutoff, 35 pts with a median of 2 prior regimens (range 1-9) had received FT-2102 in dose-escalation, including 22 single-agent (SA) and 13 AZA combination (CO) pts. Sixteen pts remain on treatment (SA, n = 10; CO, n = 6) with a median of 2 treatment cycles (range 1-16); 4 pts discontinued for transplant. FT-2102 has been well tolerated both as SA and in combination with AZA. Overall, regardless of causality, most treatment emergent AEs (TEAEs) were grade (gr) 1/2; most common ( > 20%) TEAEs were fatigue (34%), nausea (29%), and febrile neutropenia (23%). The most common ( > 15%) gr 3/4 TEAEs were febrile neutropenia (23%), anemia (20%), and pneumonia (17%). Five (14%) pts had gr 3 differentiation syndrome that was manageable and did not result in discontinuation. Steady-state exposure that exceeded the target IC90 of IDH1m was achieved at 150 mg BID, resulting in a reduction of 2-HG to normal levels in the majority of pts. Best response in all evaluable SA pts (n = 16) included: 2 (13%) complete remissions (CR), 4 (25%) complete remissions with incomplete hematologic recovery (CRi), and 5 (31%) clinical benefit (CB; stable disease lasting ≥8 weeks), including 2 with > 50% reduction of marrow blasts (MB). Best response in evaluable CO pts (n = 11) included: 2 (18%) CR, 1 (9%) CRi, and 5 (45%) CB, including 2 with > 50% reduction of MB. Conclusions: FT-2102 has shown favorable safety, PK/PD, and clinical activity in IDH1m AML/MDS with a single agent complete response rate (CR/CRi) of 38% and a complete response rate of 27% in combination with AZA. Current data support the continued evaluation of 150 mg BID in the expansion and Phase 2 stages of the study. Clinical trial information: NCT02719574.

Liposomal Grb2 antisense oligodeoxynucleotide (BP1001) in patients with refractory or relapsed haematological malignancies: a single-centre, open-label, dose-escalation, phase 1/1b trial

Activating mutations of tyrosine kinases are common in leukaemias. Oncogenic tyrosine kinases use the growth factor receptor-bound protein 2 (Grb2) for signal transduction, leading to activation of mitogen-activated protein kinase (MAPK) 1 and MAPK3 (ERK2 and ERK1). We hypothesised that inhibition of Grb2 would suppress ERK1 and ERK2 activation and inhibit leukaemia progression. To inhibit Grb2, a liposome-incorporated antisense oligodeoxynucleotide that blocks Grb2 protein expression, BP1001, was developed. We report the first phase 1 findings of BP1001. In this single-centre, open-label, dose-escalation phase 1/1b trial, we enrolled participants (aged ≥18 years) with refractory or relapsed acute myeloid leukaemia, Philadelphia-chromosome-positive chronic myeloid leukaemia (in chronic, accelerated, or blast phase), acute lymphoblastic leukaemia, or myelodysplastic syndrome, at MD Anderson Cancer Center (Houston, TX, USA). We used a 3 + 3 dose escalation strategy, with at least three patients enrolled at each dose level. We administered BP1001 intravenously, twice weekly, for 28 days, with a starting dose of 5 mg/m2. If two or more patients developed toxic effects of grade 3 or higher, that dose level was deemed toxic. The dose was escalated if it did not produce dose-limiting toxic effects, and patients would be sequentially enrolled into cohort 2 (10 mg/m2), cohort 3 (20 mg/m2), cohort 4 (40 mg/m2), cohort 5 (60 mg/m2), or cohort 6 (90 mg/m2). After completion of monotherapy, we assessed the safety and toxicity of BP1001 (60 or 90 mg/m2) in combination with 20 mg low-dose cytarabine (twice-daily subcutaneous injections) in a phase 1b study in patients with refractory or relapsed acute myeloid leukaemia (ie, those who were refractory to at least one previous therapy regimen and no more than one previous salvage regimen). The objectives of this study were to establish the toxicity and tolerance of escalating doses of BP1001 monotherapy in patients with refractory or relapsed leukaemia, to assess the maximum tolerated dose of BP1001, and to determine the optimal biologically active dose of BP1001, defined as a 50% reduction in Grb2 expression in circulating leukaemia cells. We also aimed to assess the in-vivo pharmacokinetics of BP1001 and tumour response. The study is completed and is registered with ClinicalTrials.gov, number NCT01159028. Between July 23, 2010, and Feb 23, 2016, we enrolled and treated 39 patients, of whom 27 were assessable for dose-limiting toxicity. The first patient treated had mucositis and hand-foot syndrome, which were assessed as possibly related to BP1001 and counted as a dose-limiting toxicity. We noted no other dose-limiting toxicities, and a maximum tolerated dose was not identified. The highest tested dose of BP1001 was 90 mg/m2. The most common grade 3-4 adverse events were cardiopulmonary disorders (25 [64%] of 39 patients), and fever (including neutropenic fever) and infections (17 [44%] patients). Grade 5 adverse events were cardiopulmonary disorders (two [5%] of 39 patients), fever (including neutropenic fever) and infections (two [5%] of 39 patients), and multi-organ failure (one [3%] of 39 patients). Nine (33%) of 27 patients who had peripheral blood blasts at the start of therapy had a reduction of 50% or more in peripheral blood blasts while receiving BP1001 montherapy. Three (10%) of 29 patients who had bone marrow blasts at the start of therapy had a reduction in bone marrow blasts of 50% or more while receiving BP1001 monotherapy. Per investigator's assessment, seven (22%) of 32 patients benefited from BP1001 monotherapy and had extended cycles of treatment. Of seven patients receiving BP1001 plus low-dose cytarabine combination therapy, two had complete remission, one had complete remission with incomplete haematological recovery, and two had stable disease with no dose-limiting toxicity; one patient died and one withdrew, both because of disease progression. There were eight deaths; none were treatment related. BP1001 is well tolerated, with early evidence of anti-leukaemic activity in combination with low-dose cytarabine. To further explore this anti-leukaemic activity, the efficacy of BP1001 plus low-dose cytarabine combination is being investigated in an ongoing phase 2 study in patients with previously untreated acute myeloid leukaemia who are ineligible for intensive induction therapy. Bio-Path Holdings Inc.

Preliminary Results of a Phase 1 Study of Flotetuzumab, a CD123 x CD3 Bispecific Dart® Protein, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Background: Acute myeloid leukemia (AML) blast and leukemic stem cells highly express CD123, which is associated with high-risk disease and disease progression. CD123 expression on normal hematopoietic stem cells is minimal, enabling a strategy of preferential ablation of AML with a CD123-targeted approach. Flotetuzumab (MGD006/S80880) is a novel T-cell redirecting (CD123 x CD3) bispecific DART® protein being tested in a phase 1 study in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods: This phase 1 dose-escalation study is designed to define the safety profile, maximum tolerated dose and schedule (MTDS), and preliminary anti-leukemic activity of flotetuzumab. Relapsed/refractory (R/R) AML or intermediate-2/high-risk MDS patients (pts) are treated on 28-day cycles at doses from 3-1000ng/kg/day on one of 2 dosing schedules (4-day on/3-day off or a continuous 7-day on schedule). To mitigate cytokine-release syndrome (CRS), a one-step lead-in dose (LID) (100ng/kg/day for 4 days) or two-step LID (30 ng/kg/day for 3 days followed by 100ng/kg/day for 4 days) was instituted during Cycle 1/Week 1 (C1W1), followed by the cohort target dose (300-1000ng/kg/day) on either of the dosing schedules on W2-4. Cycle 2 and beyond, all pts were treated on a 4-day on/3-day off schedule at the cohort target dose for a maximum of 12 cycles, with 2 cycles after a complete response or complete remission with incomplete blood count recovery. Steroid-sparing, anti-cytokine therapy was used, if clinically indicated, to manage CRS symptoms. Disease status was assessed by International Working Group (IWG) criteria. Samples were collected for pharmacokinetics, anti-drug antibodies (ADA) and cytokine analysis, including IL-2, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma and GM-CSF. Results: 45 pts with R/R AML/MDS (89% AML and 11% MDS) have been treated with flotetuzumab, median age of 64 (29-84), and 44% female. The MTDS has been reached at 500ng/kg/day. Overall flotetuzumab has demonstrated manageable toxicity; drug-related adverse events ≥G3 were observed in 20/45 (44%) pts; infusion-related reaction/CRS (IRR/CRS), the most common toxicity, was observed in 34/45 (76%) pts (G3 in 6/45, 13%). The most frequent CRS symptoms were pyrexia (15), chills (10), tachycardia (10), and hypotension (4). Cytokine levels were higher in pts with CRS than in pts without (median IL-6, 116.2 vs. 67.9 pg/mL; IL-8, 191.1 vs. 144.6 pg/mL; IL-10, 867.6 vs. 348.7 pg/mL) and were generally higher with increasing CRS grade. A two-step LID during week 1 appeared to decrease the severity of CRS grade (mean grade reduction 0.54) compared to pts that received a one-step LID during cycle 1. In addition, lower median peak cytokine levels are observed with two-step LID during W1 and after achieving W2 target dose. Fourteen pts treated at the threshold 500 ng/kg/day dose cohort and beyond (700ng/kg/day dose cohort) have completed at least one cycle of treatment and had a post-treatment bone marrow (BM) biopsy. Anti-leukemic activity was documented in 57% (8/14) pts, 6/14 reached IWG criteria (3 CR, 1 CRi, 1 MLF, 1 PR) for an overall response rate (ORR) of 43%, and 2 pts had stable disease and bone marrow (BM) blast reduction of 20 and 25% from baseline, respectively. Blast reduction occurred rapidly, often within one cycle of therapy, and extended beyond flotetuzumab discontinuation. Multispectral immunohistochemistry analysis of BM samples showed flotetuzumab in situ with a significant increase (in CD-8 T cells (1.58-fold increase, p=0.0013). Consistent with T-cell activation, CD-25, CD-69 and PD-1 upregulation on both CD-4 and CD-8 T-cells was also observed in peripheral blood samples. Conclusions: Flotetuzumab in R/R AML and MDS demonstrated evidence of anti-leukemic activity (ORR 43%) with a manageable safety profile. This program advances an immune-activating agent in treating AML and continues to enroll patients in cohort expansion (24 AML and 24 MDS patients at the MTDS) in the US and Europe. clinicaltrials.gov NCT02152956. Disclosures Uy: Boehringer Ingelheim: Consultancy; GlycoMimetics: Consultancy; Novartis: Consultancy, Other: Travel Suppport. Foster: Macrogenics: Research Funding; Shire: Honoraria; Pfizer: Research Funding; Amgen: Honoraria; Incyte: Honoraria; Celgene: Research Funding; Celator: Research Funding. Arellano: Cephalon Oncology: Research Funding. Rizzieri: Shire: Research Funding; Erytech: Research Funding. Topp: Roche: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Research Funding; Macrogenics: Consultancy, Research Funding; Celgene: Other: Travel; Regeneron: Consultancy, Honoraria, Research Funding. Martinelli: Incyte, Pfizer, MSD, Abbvie, JJ MacroGenics: Employment, Equity Ownership, Patents & Royalties. Sun: Macrogenics Inc: Employment, Equity Ownership. Baughman: MacroGenics, Inc.: Employment. Shannon: MacroGenics, Inc.: Employment. Fox: Bristol Myers-Squibb: Consultancy, Research Funding; AstraZeneca/MedImmune: Consultancy, Research Funding; PerkinElmer: Consultancy, Research Funding; Janssen/Johnson and Johnson: Consultancy, Research Funding; Argos: Consultancy; Bayer: Consultancy; Definiens: Consultancy; OncoSec: Consultancy, Research Funding; PrimeVax: Consultancy, Equity Ownership; Peregrine: Consultancy; UbiVac: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Other: Co-Founder and managing Member of LLC; Ventana/Roche: Consultancy; Viralytics: Consultancy, Research Funding. Bonvini: MacroGenics, Inc.: Employment, Equity Ownership, Research Funding. Wigginton: MacroGenics: Employment, Equity Ownership. Davidson-Moncada: MacroGenics: Employment, Equity Ownership.

Preliminary Results from a Phase Ib Study Evaluating BCL-2 Inhibitor Venetoclax in Combination with MEK Inhibitor Cobimetinib or MDM2 Inhibitor Idasanutlin in Patients with Relapsed or Refractory (R/R) AML

Preliminary Results from a Phase Ib Study Evaluating BCL-2 Inhibitor Venetoclax in Combination with MEK Inhibitor Cobimetinib or MDM2 Inhibitor Idasanutlin in Patients with Relapsed or Refractory (R/R) AML

Remissions of Acute Myeloid Leukemia and Blastic Plasmacytoid Dendritic Cell Neoplasm Following Treatment with CD123-Specific CAR T Cells: A First-in-Human Clinical Trial

The current treatment of relapsed or refractory AML is associated with low rates of complete response (CR) and considerable complications. As a result, only a minority of patients (pts) proceed to allogeneic hematopoietic stem cell transplantation (alloHSCT) with curative intent. Furthermore, outcomes for AML pts with disease relapse after alloHSCT are dismal. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and incurable blood cancer with a median survival of <18 months and no standard of care. Thus, there are clear unmet therapeutic needs in both these conditions. CD123 is overexpressed on AML blasts and leukemic stem cell (LSC)-enriched cell subpopulations compared to normal hematopoietic stem cells and myeloid progenitors. High levels of CD123 expression is also one of the diagnostic hallmarks for BPDCN. All these features make CD123 an attractive target for T cell based adoptive immunotherapy.We have previously demonstrated preclinically the anti-AML activity of CD123-chimeric antigen receptor (CAR) T cell therapy (Mardiros, Blood 2013). The CD123CAR contains an anti-CD123 single-chain variable fragment, an optimized IgG4 CH2CH3 linker, a CD28 co-stimulatory domain, and a CD3 zeta signaling domain and is used to engineer T cells for patients enrolled on a single center, first-in-human phase I dose escalation clinical trial open at our Institution (NCT02159495). The primary objective is to test the safety and activity of escalating doses of CD123CAR T cells for patients with relapsed or refractory AML (cohort 1) and BPDCN (cohort 2). Donor-derived or autologous T cells from leukapheresed peripheral blood mononuclear cells were lentivirally transduced with the CD123CAR vector. Prior to T cell infusion, all patients undergo a lymphodepleting regimen including fludarabine 25-30 mg/m2 daily for 3 days and cyclophosphamide 300 mg/m2 daily for 3 days. Pts receive a single dose of CD123CAR T cells with an option for a second infusion if they continue to meet safety and eligibility criteria and still have CD123+ disease. To date, 14 patients have been enrolled and 7 treated (6 AML, 1 BPDCN).All 6 patients in the AML cohort had refractory AML following alloHSCT, and a median of 4 (range: 4-7) prior lines of therapy. Of the 2 pts treated at dose level (DL) 1 (50M CAR+ T), 1 achieved a morphologic leukemic-free state, which lasted 2 months. She received a second infusion 3 months later with subsequent blast reduction from 77.9% to 0.9% (flow cytometry) after 35 days. Of the 4 pts on DL 2 (200M CAR+ T), 1 achieved CR and became transfusion independent. She proceeded to a second alloHSCT on day 70. Restaging on day +161 post-transplant showed she has remained in MRD-negative CR with good engraftment and 100% donor chimerism. Another pt with CR prior to treatment remained in CR at day 28 and has proceeded to a second alloHSCT. The remaining 2 patients had reductions in blast counts, but did not achieve remission. All toxicities were reversible and manageable: cytokine release syndrome (CRS; 4 grade 1, 1 grade 2); 1 adenoviral pneumonia requiring intubation; and 1 grade 3 rash due to drug hypersensitivity. There were no dose limiting toxicities and no treatment-related cytopenias. One pt with prior alloHSCT had mild recurrent cutaneous GVHD, which occurred after the completion of CAR T treatment. Correlative studies including T cell persistence and CD123 expression are underway and will be reported.In the BPDCN cohort, 1 pt has been treated so far, a 74-year-old man with a persistent bulky subcutaneous mass after clinical trial treatment with a CD123 antibody-drug conjugate. Following lymphodepletion, he received a single dose of 100M autologous CD123CAR T cells and continues to be in CR at 60 days post-infusion. Skin biopsies at the tumor site on days 14 and 28 showed no evidence of disease. Restaging work-up at day 28 revealed disease-free bone marrow, no new masses by CT scan, normalized blood counts, and complete resolution of clinical symptoms. The pt tolerated the treatment well with no CRS or neurologic toxicity.In this first-in-human clinical trial of CD123CAR T cell therapy, we have demonstrated the feasibility and safety of targeting CD123. We have also observed promising anti-leukemic activity in both AML and BPDCN. Importantly, no myeloablative effects have been observed, supporting further testing of this immunotherapeutic strategy in both transplant eligible and ineligible patients. DisclosuresStein:Stemline: Consultancy; Amgen: Consultancy, Speakers Bureau.

A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia

This Phase 1/2, dose-escalating study of rigosertib enrolled 22 patients with higher-risk myelodysplastic syndromes (MDS) (n=9) and acute myeloid leukemia (AML; n=13) who had relapsed or were refractory to standard therapy and for whom no second-line therapies were approved. Patients received 3- to 7-day continuous intravenous infusions of rigosertib, an inhibitor of Ras-effector pathways that interacts with the Ras-binding domains, common to several signaling proteins including Raf and PI3 kinase. Rigosertib was administered at doses of 650–1700mg/m2/day in 14-day cycles. Initial dose escalation followed a Fibonacci scheme, followed by recommended phase 2 dose confirmation in an expanded cohort. Rigosertib was well tolerated for up to 23 cycles, with no treatment-related deaths and 18% of patients with related serious adverse events (AEs). Common AEs were fatigue, diarrhea, pyrexia, dyspnea, insomnia, and anemia. Rigosertib exhibited biologic activity, with reduction or stabilization of bone marrow blasts and improved peripheral blood counts in a subset of patients. Ten of 19 evaluable patients (53%) demonstrated bone marrow/peripheral blood responses (n=4 MDS, n=1 AML) or stable disease (n=3 MDS, n=2 AML). Median survival was 15.7 and 2.0 months for responders and non‐responders, respectively. Additional studies of rigosertib are ongoing in higher-risk MDS (NCT00854646).

Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation.

Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways. Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28-day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3-inhibitory activity in FLT3-mutant cell lines. Among 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose-limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3-inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)-mutant cells. Cabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD- and F691 TKD-altered tyrosine kinases. Cancer 2018;124:306-14. © 2017 American Cancer Society.

Abstract 2642: Preclinical efficacy of daratumumab in acute lymphoblastic leukemia

Abstract Targeted immunotherapy has become critical for the successful treatment of many forms of cancer, particularly therapeutic antibodies with cytotoxic abilities. No safe and effective immunotherapies have been developed for T-cell acute lymphoblastic leukemia (T-ALL). CD38 is a transmembrane glycoprotein found on the cell surface of activated T cells, terminally differentiated B cells, but relatively low levels on normal lymphoid and myeloid cells. Daratumumab (dara) (Darzalex, Janssen Biotech, Inc.) is a human IgG1κ monoclonal antibody that binds to a unique CD38 epitope and was recently FDA approved for the treatment of refractory multiple myeloma. In order to ensure CD38 is a relevant target in T-ALL and surface expression does not change with chemotherapy, we evaluated CD38 expression by flow cytometry (FACS) from 21 patients with T-ALL (10 early T-cell precursor (ETP) and 11 non-ETP) at diagnosis and after one month of induction chemotherapy. All of the samples had detectable CD38 expression which did not change significantly after induction (mean CD38 MFI at diagnosis vs end-induction: 3.27 log vs 3.19 (S.I.; p = 0.25). Therefore we hypothesized that targeting CD38 with dara would be effective against T-ALL. In order to test this hypothesis, we xenografted primary ALL blasts from 15 different patients, including 7 with ETP-ALL and 8 with non-ETP T-ALL. Mice were randomized to dara (200 μg /mouse intraperitoneally (IP) weekly) vs control (isotype control at 200 μg/mouse IP weekly; 5 mice per arm for each sample) after they developed &amp;gt;1% peripheral blood (pb) blasts by FACS. Disease burden was assessed by FACS enumeration of pb blasts weekly and splenic blasts at sacrifice. We demonstrate striking efficacy of dara monotherapy in 6 of 7 ETP-ALL samples with reduction of pb and splenic blasts. Mice treated with high disease burden from 5 of the 8 non-ETP samples were moribund immediately after dara injection, possibly from aggregates of antibody bound to tumor cells leading to pulmonary embolism or tumor lysis, and were therefore inevaluable. We have since repeated the experiments for 3 of the samples, treating the mice after injection but before detectable engraftment of peripheral blasts. Dara was effective in all 3 samples. Experiments are ongoing for the other 2 samples. Overall, we have found Dara was effective in 4 of 6 evaluable non-ETP T-ALL samples. In summary, we found dara is a highly effective novel monotherapy for T-ALL in preclinical models. Based on these results, we are developing an early phase trial for children and young adults with relapsed/refractory T-ALL. Note: This abstract was not presented at the meeting. Citation Format: Karen Lee Bride, Tiffaney Vincent, Soo-Yeon L. Im, Tori Fuller, Theresa Ryan, David M. Barrett, Shannon L. Maude, Mignon L. Loh, Michelle L. Hermiston, Stephan A. Grupp, Brent L. Wood, David T. Teachey. Preclinical efficacy of daratumumab in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2642. doi:10.1158/1538-7445.AM2017-2642

Systemic reduction of rice blast by means of photosensitizers

Systemic disease resistance of plants may be induced by exogenous reactive oxygen species or their sources. Certain compounds (photosensitizers) produce ROS at the expense of light energy. Of them, this study used photodynamic dyes bengal rose and methylene blue, which yield singlet oxygen, and mercaptopyridine-N-oxide, which yields hydroxyl radical. The goals were to find out whether they can systemically protect rice (Oryza sativa L.) from blast caused by the fungus Magnaporthe oryzae Conouch et Kohn and whether ROS is involved in defense mechanisms. The tested compounds were placed on the fourth (uppermost) leaf. When the fifth leaf developed (in approximately 7 days), it was inoculated with virulent fungal strain. We found that almost all the chemical treatments altered the fourth leaf and all of them reduced disease symptoms on the fifth leaf. Antioxidants combined with the tested substances compromised the disease control. Photosensitizers applied to the fourth leaf increased superoxide production in drop diffusates of healthy and, to larger extent, infected fifth leaf. In these diffusates, fungitoxicity also increased, which was diminished by antioxidants added to the diffusates. Besides, treatment with mercaptopyridine-N-oxide systemically weakened the endogenous antioxidative (H2O2-decomposing) activity of a diffusate. It is suggested that the oxidative burst in the treated leaves induced the systemic disease resistance, whose accomplishment might include the secondary oxidative burst in systemic leaves suppressing the pathogen’s development.

Phase I study of lurbinectedin (PM11083) in patients with advanced AML and MDS.

e18521 Background: The FDA-approved drug trabectedin is a DNA minor groove binder (MGB) with activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB, with activity against myeloid leukemia cells. A phase I clinical trial was initiated to determine recommended doses in MDS/AML. Further assessment of its safety, tolerability, and pharmacogenetics were studied. Methods: In total, 42 patients with relapsed/refractory MDS/AML received lurbinectedin, using a 3+3 study design. It was administered as a 1-hour IV infusion first at 3.5, 5, 6, and 7mg per dose on days 1 and 8. Subsequently, it was administered on days 1, 2, and 3, using 1, 1.5, 2, or 3mg per dose per patient. Results: Three patients had dose-limiting toxicities (DLTs), which were rhabdomyolysis (up to gr 4), hyperbilirubinemia (gr 3), and oral herpes (gr 3). All DLTs occurred in the 6 and 7mg cohorts. Adverse events included febrile neutropenia/infections (n = 3), GI (n = 6) and pulmonary (n = 2) toxicity, hyperhidrosis (n = 1), and QT prolongation (n = 1). Overall, 33 of 42 patients (79%) had reduction of blasts in peripheral blood (PB) or bone marrow (BM) at nadir, including 23 (55%) with &gt; 50% reduction in PB blasts alone (n = 18) or both BM and PB blasts (n = 5). One patient had PR, 2 patients had morphologic leukemia-free survival, and most (n = 30) were discontinued for progressive disease. Early deaths occurred from disease-related causes, not attributable to lurbinectedin. Thirty-two patients treated at MD Anderson were analyzed for clinical characteristics and responses. Notably, among patients with follow-up bone marrow biopsy, those with a cytogenetic abnormality at chromosome 11q21-23 had significantly greater bone marrow blast reduction than those without such abnormality (change in percentage blasts: -31±14% [n = 4] vs. 8±8% [n = 16], respectively; P= 0.04). Conclusions: Lurbinectedin is generally safe and tolerated at dose levels tested. While no sustained remissions &gt; 3 cycles were observed in these highest-risk patients, single-agent lurbinectedin was transiently leukemia suppressive for some patients, including some with abnormal chr11q or TP53 mutation. Rational combinations and situational uses of lurbinectedin are under consideration. Clinical trial information: NCT01314599.

Ruxolitinib (RUX) in combination with azacytidine (AZA) in patients (pts) with myelodysplastic/myeloproliferative neoplasms (MDS/MPNs).

7064 Background: Clinical trials exclusively focusing on pts with MDS/MPNs are lacking. Combining RUX and AZA may target distinct manifestations of MDS/MPNs. Methods: Pts were treated with single-agent RUX 15 mg or 25 mg (based on platelets count) orally twice daily continuously in 28-day cycles for the first 3 cycles. AZA 25 mg/m2 (day 1-5) was added on each cycle starting cycle 4 and could be increased to 75 mg/m2 (maximum) or started earlier than cycle 4 and/or at higher dose in pts with proliferative features or high blasts. Results: 35 pts with med age 70 years (range, 43-79) were enrolled (MDS/MPN-U, n = 14; CMML, n = 17; atypical CM (aCML), n = 4), 28 (80%) were Int-2/High per MF DIPSS, 14 (41%) had splenomegaly &gt; 5 cm, and 12 (34%) had EUMNET MF-2/MF-3 fibrosis. Common mutations on a 28-gene sequencing panel included JAK2 (29%), RAS (27%), ASXL1 (21%), TET2 (18%), and DNMT3A (12%). All 35 pts were evaluable for response per MDS/MPN IWG criteria and 17 (49%) responded. 6/17 (35%) IWG responses occurred after the addition of AZA (med time after AZA = 1.8 months). JAK2 mutated pts had a trend to higher responses vs those with non-mutated pts (8/10 vs 9/25, P = 0.19). Ten pts had &gt; 5% pretreatment BM blasts and 7 achieved a reduction in blasts to &lt; 5% (70%). A &gt; 50% reduction in palpable spleen length reduction at 24 weeks was seen in 9/12 (75%) pts. New grade 3/4 anemia and thrombocytopenia occurred in 18 pts (51%) and 19 (54%) pts but were manageable with dose modifications. Only one pt discontinued therapy due to cytopenias. At a med follow-up of 17.4 mo (range, 1.2-36.8+), 14 (40%) pts died: pneumonia (n = 4), sepsis (n = 4), progression to AML (n = 4), and cardiac arrest (n = 1). The med survival for all pts was 16.6 mo (1.0 - 36.8). Compared to CMML and aCML, MDS/MPN-U pts had significantly better med survival (26.4+ vs 15.0+ vs 1.5+ mo, respectively; p = 0.01). Conclusions: The combination of RUX and AZA showed an IWG-response rate of 49% in pts with MDS/MPNs, and was well-tolerated. The benefit appears more profound in pts with MDS/MPN-U. This study is ongoing. (ClinicalTrials.gov Identifier: NCT01787487).

Phase IB/II study of nivolumab with azacytidine (AZA) in patients (pts) with relapsed AML.

7026 Background: Blocking PD-1/PD-L1 pathways enhances anti-leukemia responses in murine AML (Zhang et al, Blood 2009). PD-1 positive CD8 T-cells are increased in bone marrow (BM) of pts with AML (Daver et al, ASH 2016). AZA up-regulates PD-1 in AML (Yang et al., Leukemia 2013). Methods: Pts were eligible if they had AML and failed prior therapy, had adequate performance status (ECOG ≤ 2), and organ function. AZA 75mg/m2Days 1-7 with nivolumab 3mg/kg on Day 1 and 14 was established as the recommended phase II dose. Courses were repeated every 4-5 weeks indefinitely. Responses were evaluated at the end of 3 courses. Results: 53 pts with med age 68 years (range, 44 – 90), secondary AML (43%), poor risk cytogenetics (43%), med prior regimens 2 (range, 1-7) have been enrolled. Common mutations included DNMT3A (n = 11), TP53 (n = 11), TET2 (N = 8), CEBPA (n = 8), ASXL1(n = 8). All 53 pts are evaluable for response: 11 (21%) achieved CR/CRi and 7 (14%) had hematologic improvement (HI) for an overall response rate of 35%. Additionally, 14 (26%) had ≥50% BM blast reduction, 3 (6%) had stable disease &gt; 6 months, and 12 (23%) had progression. The CR/CRi have been durable with 9 of 11 (82%) pts with CR/CRi alive at 1 year, after censoring for SCT. Med survival for the 53 evaluable pts was 5.7 months (range, 0.9 – 16.2) and in the 27 salvage 1 pts was 9.3 months (range, 1.6 – 16.2). These compare favorably to historical survival with AZA-based salvage protocols at MDACC. Grade 3/4 and Grade 2 immune toxicities were observed in 7 (14%) and 6 (12%) pts, respectively. These responded rapidly to steroids and 12 of 13 pts were successfully rechallenged with nivolumab. Multicolor flow-cytometry data were available on pretherapy, end of cycle 1, and end of cycle 2 BM aspirates in 9 CR/CRi and 22 non-responders. Pts who achieved CR/CRi had higher pre-therapy total CD3 (P = 0.02) and higher CD8+ T-cells (P = 0.07) infiltrate in the BM. Responders demonstrated progressive increase in BM CD8+ and CD4+ infiltrate. Both responders and non-responders had increase in CTLA4+ CD8+ cells on therapy. Conclusions: Full dose AZA and nivolumab are tolerable and may produce durable responses in relapsed AML. Up-regulation of CTLA4 may be a mechanism of resistance to PD1 based therapies in AML. Clinical trial information: NCT02397720.

Clofarabine-based chemotherapy as a bridge to transplant in the setting of refractory or relapsed acute myeloid leukemia, after at least one previous unsuccessful salvage treatment containing fludarabine: a single institution experience.

For refractory or relapsed acute myeloid leukemia patients, allogeneic hematopoietic stem cell transplantation is the only curative treatment option, but the disease must be in remission before this can be attempted. "Salvage" therapy regimens containing high-dose cytarabine plus fludarabine or cladribine with or without anthracyclines or plus mitoxantrone and etoposide fail in 30-50% of cases. We report the outcome of 14 patients treated with a clofarabine-based treatment administered after at least one failed fludarabine-based "salvage" attempt in a "real life" (outside a clinical trial) context. No death related to the clofarabine-based treatment was observed. Four of the 14 patients (29%) reached complete remission and one (7%) achieved a reduction of marrow blasts to fewer than 10%. Three of these five patients were successfully transplanted and have shown a long-term survival. The small number of this group of patients does not permit the identification of clinical features clearly related to a favorable outcome, but we note that all the three long-term survivals were FLT3 wild type. Clofarabine-based "salvage therapy" in patients with very poor expectancy is feasible even after a fludarabine-based salvage attempt, albeit with success only in a small percentage of cases (3/14=21%).

Simple matters in complex times.

Simple matters in complex times.

Bone marrow cellularity at day 14 is the most important predictive factor for response in patients with AML who require double‐induction chemotherapy: Analysis from a large, single institution experience

In patients with acute myeloid leukemia (AML), the presence of residual disease at day 14 after primary induction therapy warrants consideration of a second induction cycle. However, data to guide retreatment decisions in such patients are presently limited. Here, we retrospectively reviewed data from 176 patients with AML treated at our institution with a second induction chemotherapy regimen because of day 14 residual disease. Clinical variables and nadir bone marrow features were assessed for correlations with complete remission (CR) and overall survival (OS). In our patient group, 59% achieved CR after a second induction course. Median OS for the entire group was 12.40 months (95% CI, 9.90-14.90) but 19.07 months (95% CI, 13.13-25.01) for those who attained a CR. Nadir marrow hypocellularity (P < 0.001) at day 14, absolute blast reduction of >50% (P = 0.030), and de novo disease status (P = 0.018) were significantly correlated with CR achievement after re-induction. Marrow hypocellularity at day 14 was the most significant predictor of CR on multivariate analysis (P < 0.001). Nadir marrow features did not independently correlate with OS when accounting for CR status. Re-induction was successful in achieving CR in most patients. Study patients who did not achieve CR were more likely to have nonhypocellular marrows.

The Potential of Streptomyces as Biocontrol Agents against the Rice Blast Fungus, Magnaporthe oryzae (Pyricularia oryzae).

Rice is a staple food source for more than three billion people worldwide. However, rice is vulnerable to diseases, the most destructive among them being rice blast, which is caused by the fungus Magnaporthe oryzae (anamorph Pyricularia oryzae). This fungus attacks rice plants at all stages of development, causing annual losses of approximately 10–30% in various rice producing regions. Synthetic fungicides are often able to effectively control plant diseases, but some fungicides result in serious environmental and health problems. Therefore, there is growing interest in discovering and developing new, improved fungicides based on natural products as well as introducing alternative measures such as biocontrol agents to manage plant diseases. Streptomyces bacteria appear to be promising biocontrol agents against a wide range of phytopathogenic fungi, which is not surprising given their ability to produce various bioactive compounds. This review provides insight into the biocontrol potential of Streptomyces against the rice blast fungus, M. oryzae. The ability of various Streptomyces spp. to act as biocontrol agents of rice blast disease has been studied by researchers under both laboratory and greenhouse/growth chamber conditions. Laboratory studies have shown that Streptomyces exhibit inhibitory activity against M. oryzae. In greenhouse studies, infected rice seedlings treated with Streptomyces resulted in up to 88.3% disease reduction of rice blast. Studies clearly show that Streptomyces spp. have the potential to be used as highly effective biocontrol agents against rice blast disease; however, the efficacy of any biocontrol agent may be affected by several factors including environmental conditions and methods of application. In order to fully exploit their potential, further studies on the isolation, formulation and application methods of Streptomyces along with field experiments are required to establish them as effective biocontrol agents.

A Phase I Study of the Multi-Targeted Tyrosine Kinase Inhibitor Cabozantinib in Patients with Acute Myeloid Leukemia

Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) of FLT3, MET, AXL, VEGFR, and KIT, all of which are implicated in the pathogenesis of acute myeloid leukemia (AML). Cabozantinib has been studied in clinical trials of solid tumors, and is FDA approved for use in medullary thyroid and renal cell carcinoma. Despite multiple relevant targets, cabozantinib has not been previously studied in AML. Given up-regulation of these key enzymes and related pathways in AML, we sought to assess the safety and tolerability of cabozantinib in this population.The primary objective of this phase I, 3+3 cohort dose-escalation study was to define the maximum tolerated dose (MTD) of cabozantinib in patients with AML. Eligibility included adults ≥ age 18, with relapsed or refractory (R/R) AML, or those aged ≥ 70, with new diagnosed AML but ineligible for or declining conventional therapy. Study treatment required a white blood cell count (WBC) of < 30,000/mm3, but concurrent treatment with hydroxyurea was allowed to control WBC during the first 15 days of cycle 1. The first dose level was 40MG by mouth daily (QD), a dose previously demonstrated to be well-tolerated in solid tumor malignancies. Cabozantinib was administered in 28 day cycles, and dose escalation occurred via 3 cohorts (40MG QD, 60MG QD, 80MG QD). Escalation to each successive dose level was guided by incidence of dose limiting toxicity (DLT) during cycle 1 of study treatment. Pharmacodynamic evaluation of serial plasma samples obtained from patients, by use of a plasma inhibitory assay (PIA), was used to assess FLT3 inhibitory activity in FLT3-ITDcell lines. Response was determined by bone marrow biopsy after the first cycle of treatment, and those achieving complete or partial remission, or with stable disease and clinical benefit, could continue on study until disease progression, intolerable toxicity, or upon receipt of 12 cycles.18 patients were enrolled on study. The median age was 68 (range 27-85); 12 (67%) were male, and 14 (78%) were Caucasian. FLT3-ITD mutations were detected in 5 (23%) patients, and NPM1 mutations in none. 16 patients (89%) had R/R AML, and 2 patients (11%) had newly diagnosed disease. The majority (75%) of those with R/R AML had been treated with two or more lines of prior treatment. 3 patients were enrolled at the first dose level (40MG QD), of whom one experienced >G3 transaminitis, thought unrelated to cabozantinib, but could not be dosed for this reason and was therefore replaced. No DLTs were detected at the first dose level among the 4 studied patients. However, two of the three patients enrolled at the second dose level (60MG QD) experienced DLT, one with grade 3 pancreatitis and the other with grade 3 transaminitis. Three patients were then enrolled at the next lower level, dose level 1 (40MG QD), of whom two could not complete the DLT period, one because of disease progression and the other due to an infected aortic ulceration unrelated to study treatment. These two patients were replaced, and no additional DLTs were noted. 40MG daily was therefore determined to be the MTD, and 6 patients were subsequently treated in an expansion cohort at this dose. Additional ≥ grade 2 toxicities, possibly or probably related to cabozantinib, each affected 3 or less patients, and included fatigue, nausea, anorexia, constipation, oral mucositis, palmar-plantar erythrodysesthesia, transaminitis, and electrolyte imbalance. Fifteen patients could be assessed for response on study. No patients had a marrow response per formal criteria. Four patients had a reduction in peripheral blasts during treatment, of whom 2 transiently cleared their circulating blasts (one with FLT3-ITD). One patient experienced a reduction in marrow blasts, and one had stable marrow disease. FLT3 inhibitory activity of serially collected patient plasma samples, as determined by the ex vivo PIA, consistently revealed potent and sustained inhibition of FLT3 auto-phosphorylation in FLT3-ITDmutant cell lines by day 8 of cycle 1.Cabozantinib, a multi-targeted TKI, is well-tolerated in patients with AML at the MTD of 40 MG daily. In this molecularly heterogeneous, heavily pre-treated population of AML patients, clinical response to cabozantinib monotherapy was limited. However, we found that cabozantinib inhibits FLT3-ITD tyrosine kinase in a potent and sustained fashion. Additional clinical study of cabozantinib among patients with FLT3 mutant AML is therefore warranted. DisclosuresFathi:Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Agios Pharmaceuticals: Other: Advisory Board participation; Bexalata: Other: Advisory Board participation. Levis:Millennium: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding. Avigan:Astex: Research Funding; DCPrime: Research Funding. Hobbs:Constellation: Other: Advisory Board participation; Incyte: Other: Advisory Board participation.

Pilot Study of Combined Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib with Sorafenib in Pediatric Patients with Relapsed/Refractory FLT3+Ve AML

Background: Crenolanib is a novel type I pan-FLT3 inhibitor, which inhibits both FLT3-ITD, as well as FLT3 tyrosine kinase domain (TKD) activating mutations. Combination of crenolanib (Type I) and sorafenib (Type II) has been shown to have synergistic apoptotic effects in FLT3+ve AML blasts derived from patients (pts) who have relapsed after prior sorafenib treatment. We hypothesized that the combination of crenolanib and sorafenib may provide enhanced FLT3 inhibition by targeting both inactive as well as active FLT3 kinase conformations. We here report the results of a dose finding study of sorafenib given with fixed doses of crenolanib in pediatric pts with FLT3+ve AML.Design: This pilot study was designed to assess the tolerability of escalating doses of sorafenib with full doses of crenolanib (66.7 mg/m2 TID) in pediatric pts with relapsed or refractory FLT3+ve AML. Crenolanib was administered continuously at 66.7 mg/m2 TID starting on d1. Sorafenib was administered continuously starting from d8 at 150 mg/m2/d (dose level 1). The rolling-6 design was used and if no DLTs were seen, sorafenib was escalated to 200 mg/m2/d (dose level 2). Additionally, triple intrathecal therapy with methotrexate, hydrocortisone, and cytarabine was given on d8 and continued weekly in pts with CNS leukemia until CSF was free of blasts.Results: From April 2015 to March 2016, 7 children (median age, 9yrs; range, 5-14yrs) have been enrolled. All pts had progressed after a median of 3 prior AML therapies (range, 1-7). Four pts had progressed after frontline treatment, which included sorafenib maintenance; the other 3 pts had progressed after standard chemotherapy. Two pts had undergone prior allo SCT. Median WBC count prior to therapy was 1.7 x 109/L (range 0.7-7.5 x 109/L) with median blast percentage of 15% (range 0-60%). All 7 pts had a FLT3-ITD (mutant to wild-type FLT3 ratio ranged from 0.048 to 22, with one pt not having any wild type FLT3 allele). At the time of study entry, 2 pts had active CNS leukemia and required additional intrathecal therapy.Crenolanib 66.7 mg/m2 TID was well tolerated with no pt requiring crenolanib dose reduction. Sorafenib was administered to the first 3 pts at 150 mg/m2 QD from d8 onward. As no DLTs were observed at 150 mg/m2 QD dose, sorafenib was dose escalated to 200 mg/m2 QD for the next 4 pts. No DLTs were observed at either of the sorafenib doses. The combination of crenolanib/sorafenib was well tolerated with most AEs being grade 1 and 2 in severity. Rash was frequently seen in pts following the addition of sorafenib and one pt developed grade 2 hand-foot syndrome which resolved within 5d on the same dosing regimen. No grade 4 LFT elevations were seen in any pt.During cycle 1 of therapy, crenolanib/sorafenib combination resulted in clearance of peripheral blood blasts in 5/6 pts and 1 pt without blasts at baseline had resolution of extramedullary neck mass. Reduction of bone marrow blasts was seen in 4/7 pts. By Cheson criteria, one patient achieved a CR (with FLT3 negativity), two had a PR, and one had a marrow response of CRi but with persistent CNS disease. Three pts had NR although 2 had transient benefit from crenolanib on day 8 as determined by BM blast percentage. Peripheral blood and bone marrow blast percentages are summarized in Figure 1 and Table 1, respectively. Median overall survival was 221d (Figure 2) with 2 pts currently still alive.Conclusions: Crenolanib 66.7 mg/m2 TID can be safely combined with sorafenib at 200 mg/m2 QD. Even in pts with prior exposure to sorafenib, this combination showed clinical benefits, represented by rapid reduction of bone marrow or peripheral blasts, and was able to have improved quality of life. Although dual TKI combinations targeting the same receptor have not been tried in AML, such strategies have been shown to have efficacy in other diseases like HER2+ve breast cancer. Pharmacokinetics of crenolanib and sorafenib and FLT3-TKD mutation analysis will be presented. Accrual to this trial continues. [Display omitted] [Display omitted] [Display omitted] DisclosuresInaba:Arog: Research Funding. Eckardt:Arog: Employment, Equity Ownership.

Ruxolitinib (RUX) in Combination with Azacytidine (AZA) in Patients (pts) with Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs)

Background:Clinical trials exclusively focusing on pts with MDS/MPN are lacking.AZA is a DNA methyltransferase (DNMT) inhibitor approved for the therapy of MDS while RUX is a JAK inhibitor approved as therapy for myelofibrosis and polycythemia vera. RUX and AZA may target distinct clinical and pathological manifestations of MDS/MPNs.Aim:To determine the efficacy and safety of RUX + AZA in pts with MDS/MPN requiring therapy including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia BCR-ABL1 negative (aCML), and myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U)(ClinicalTrials.gov Identifier: NCT01787487).Methods:A sequential approach with single-agent RUX 15 mg orally twice daily (if platelets 100-200) or 20 mg twice daily (if platelets >200) continuously (pts with platelets below 50 were not eligible) in 28-day cycles for the first 3 cycles followed by the addition of AZA 25 mg/m2 on days 1-5 of each 28-day cycle starting cycle 4 was adopted. The AZA dosage could be gradually increased to a maximum of 75 mg/m2. The AZA could be started earlier than cycle 4 and/or at a higher dose in pts with proliferative disease or elevated blasts.Results: 34 pts were enrolled between March 1, 2013 and June 30, 2016. Baseline characteristics are summarized in table 1. 21 pts remain alive after a median (med) follow-up of 14.2 months (range, 0.5-32.7+).Responses were evaluated by the MDS/MPN IWG response criteria (Savona et al., Blood 2015, 125(12):1857-65). 32 pts were enrolled before April 1 2016 wereevaluable for response. Responses were noted in 16 (50%) pts. Details of responses are shown in table 2. Med time to IWG response was 1.8 mos (range, 0.7-11.0+) and the med duration of response is 7 mos (range, 2.3-31.8+). Seven (44%) of the IWG responses occurred after the addition of the AZA. There was a trend to higher IWG-responses in JAK2 mutated versus non-mutatedpts (7/8 versus 9/24 responses, P=0.18). Additionally, 9 pts had >5% pretreatment BM blasts and 7 achieved a reduction in blasts to <5% with a med time to blast reduction of 5.5 mos (range, 2.6-11.2+). Serial evaluation of bone marrow biopsies documented reduction in EUMNET fibrosis score in 5 of 20 (25%) evaluable pts after a med of 5.5 mos (range, 2.0-5.6+) on therapy. The reduction in fibrosis was by one grade in all 5 cases.Oneptexperienced grade 3/4 non-hematological toxicity of limb edema. New onset grade 3/4anemiawas seen in 24 pts [71%; of which 7 (21%) had a >/=2+ grade change] and new onset grade 3/4 thrombocytopenia in 18 (53%) pts, respectively.The AZA was started in cycle 4 in 14 pts (41%). The AZA was started earlier due to leukocytosis or increased blasts in 16 pts (47%): in cycle 1 (n=8), cycle 2 (n=5), and cycle 3 (n=3); 2 never started AZA due to low counts and 2 pts are too early to start AZA.23 (68%) pts have discontinued protocol therapy due to leukocytosis (n=7), progression to AML (n=5), stem cell transplant (n=3), lack of response (n=2), progressive thrombocytopenia (n=1), pneumothorax (n=1), concurrent T-cell neoplasm (n=1), and loss of insurance (n=1).Thirteen (38%) pts have died: pneumonia (n=4), sepsis (n=4), progression to AML (n=4), and uncontrolled leukocytosis in oneptwith Ph- CML. The med overall survival (OS) for all 34 pts is 25.4mos+ (range, 1.0-32.7+). The MDS/MPN-U patients had a significantly better med OS (26.4+ months) as compared to the CMML (15.0+ months) andaCML(1.5+ months)pts, respectively (P=0.01).Conclusion: Concomitant administration of RUX with AZA demonstrated an IWG-response rate of 50% in pts with MDS/MPNs, with expected myelosuppression as the only significant toxicity. The benefit seems to be more profound in pts with MDS/MPN-U and MDS/MPNpts with JAK2 mutations. This combination warrants further evaluation. [Display omitted] DisclosuresCortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Verstovsek:Pfizer: Research Funding; Geron: Research Funding; Roche: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Galena BioPharma: Research Funding; Promedior: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Lilly Oncology: Research Funding; NS Pharma: Research Funding; Genentech: Research Funding; Gilead: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; CTI BioPharma Corp: Research Funding.