Teva Pharmaceutical Industries Research Articles

Metabolic Function in 5,047 Adults with Type 2 Diabetes on Metformin Alone Based on Oral Glucose Tolerance Test (OGTT) Data from the GRADE Cohort

Little data exist on the relationship between glycemic variables, insulin sensitivity and insulin and C-peptide responses in subjects with T2DM. We assessed these relationships using baseline OGTT data from the Glycemia Reduction Approaches in Diabetes, A Comparative Effectiveness study (GRADE) cohort. Eligibility included T2DM <10 y, HbA1c 6.8-8.5% treated with metformin alone. Glucose, insulin and C-peptide were measured at 0, 15, 30, 60, 90 and 120 minutes in 5047 OGTTs. Insulin sensitivity was measured by HOMA-S and insulin and C-peptide responses were estimated using δhormone/δglucose0-30 and incremental area under the curve (incAUC) hormone/glucose0-120. Subjects were 63.6% men, 57.2±10 y old (mean±SD), with HbA1c 7.5±0.5% and T2DM duration 4.2±2.8 y. Insulin and C-peptide responses were inversely associated with HOMA-S in a curvilinear manner (p<0.001 for all). Glycemic variables were all inversely associated with HOMA-S and insulin and C-peptide responses (Table, p<0.001 for all). The weakest association was between HbA1c and HOMA- S and the strongest between 2h glucose and incAUC C-peptide. Even in established diabetes there is measurable β-cell function and these measures remain proportional to glycemic responses. We plan to use these baseline measures of β-cell function as potential determinants of treatment outcomes in GRADE. Table: Adjusted Regression DataHOMA-SδI/δG0-30δCP/δG0-30incAUC I/G0-120incAUC CP/G0-120Fasting glucose-0.28-0.20-0.21-0.28-0.322hr glucose-0.18-0.25-0.27-0.34-0.44incAUC-G0-120-0.10-0.16-0.16-0.16-0.18HbA1c-0.07-0.10-0.09-0.13-0.15Regression models are presented as signed R2 adjusted for sex, age, race, BMI, T2DM duration, eGFR and metformin dose. I = insulin, G = glucose, CP = C-peptide Disclosure K. Utzschneider: Consultant; Self; Novo Nordisk Inc. M. Banerji: Speaker's Bureau; Self; Merck & Co., Inc. J.I. Barzilay: Stock/Shareholder; Self; AbbVie Inc., AstraZeneca, Celgene Corporation, DuPont, Merck & Co., Inc., Teva Pharmaceutical Industries Ltd.. E.V. Gonzalez: None. F. Ismail-Beigi: None. K.J. Mather: Research Support; Self; Merck & Co., Inc., Sanofi-Aventis, Novo Nordisk A/S, Abbott. Advisory Panel; Self; Merck & Co., Inc. P. Raskin: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc., GlaxoSmithKline plc.. N. Younes: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Research & Development, Merck & Co., Inc., Novo Nordisk A/S. G. Research Group: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung, and Blood Institute. Other Relationship; Self; Bristol-Myers Squibb Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi-Aventis, Roche Diagnostics Corporation, Becton, Dickinson and Company, Centers for Disease Control and Prevention, National Diabetes Education Program.

Does the Shape of the OGTT Glucose Curve Reflect Metabolic Function in Individuals with Type 2 Diabetes? Baseline Data from the GRADE Cohort

In nondiabetic subjects a biphasic (rise, fall, rise) vs. monophasic (rise then fall) glucose pattern on OGTTs has been associated with better metabolic parameters, but data in T2DM are limited. We categorized the shape of the glucose curve from baseline OGTTs performed in the Glycemia Reduction Approaches in Diabetes Study (GRADE) into monophasic, biphasic or continuous rise and analyzed their relationship with metabolic parameters. GRADE eligibility included T2DM <10 y, HbA1c 6.8-8.5% with metformin treatment alone. OGTT glucose and insulin were measured at 0, 15, 30, 60, 90 and 120 minutes (n=5047 adults: age 57.2±10 y, 63.6% male, HbA1c 7.5±0.5%, duration T2DM 4.2±2.8 y). Most glucose profiles were monophasic. HbA1c did not differ between groups. Those with a monophasic shape were more likely to be men, had higher BMI, fasting glucose and incAUC glucose, and lower HOMA-S and disposition index (Table). Compared to the monophasic group, those with a continuous rise shape had lower fasting glucose and higher HOMA-S, but the highest 2 h glucose. Those with a biphasic pattern had intermediate insulin sensitivity, but the highest disposition index. Thus, a biphasic glucose pattern reflects better β-cell function, similar to that observed in nondiabetic subjects. Whether glucose patterns predict response to GRADE interventions will be determined on study completion.Table. Phenotypic and metabolic characteristics by OGTT glucose curve shapeMonophasicBiphasicContinuousP valueN (%)3212 (64.0)283 (5.6)1523 (30.4)Sex (%male)70.359.750.2<0.001Age (years)56.5±9.958.0±10.558.5±9.9<0.001BMI (kg/m2)35±732±633±7<0.001HbA1c (%)7.5±0.57.5±0.57.5±0.50.6Fasting glucose (mmol/L)8.5±1.78.4±1.68.3±1.7<0.0012 hour glucose (mmol/L)15.4±2.915.8±3.117.1±3.0<0.001incrementalAUC0-120 glucose (mmol/L)6.4±1.55.3±1.75.7±1.5<0.001HOMA-S (mU.mmol/L-2)0.22±0.230.25±0.210.28±0.41<0.001δInsulin/δGlucose0-30 (mU/mmol)5.3±4.46.5±5.65.1±6.10.002Disposition index (mmol/L-1)0.34±0.640.46±0.430.38±0.370.005Mean±SD. 23 had missing data and 6 were excluded with a triphasic pattern. Disposition index = δI/δG0-30 x HOMA-S. Disclosure K. Utzschneider: Consultant; Self; Novo Nordisk Inc. M. Banerji: Speaker's Bureau; Self; Merck & Co., Inc. J.I. Barzilay: Stock/Shareholder; Self; AbbVie Inc., AstraZeneca, Celgene Corporation, DuPont, Merck & Co., Inc., Teva Pharmaceutical Industries Ltd.. E.V. Gonzalez: None. F. Ismail-Beigi: None. K.J. Mather: Research Support; Self; Merck & Co., Inc., Sanofi-Aventis, Novo Nordisk A/S, Abbott. Advisory Panel; Self; Merck & Co., Inc. P. Raskin: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc., GlaxoSmithKline plc.. N. Younes: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Research & Development, Merck & Co., Inc., Novo Nordisk A/S. G. Research Group: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung, and Blood Institute. Other Relationship; Self; Bristol-Myers Squibb Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi-Aventis, Roche Diagnostics Corporation, Becton, Dickinson and Company, Centers for Disease Control and Prevention, National Diabetes Education Program.

The Association between Inpatient Hyperglycemia and Thirty-Day Mortality Is Modified by Type 2 Diabetes History

Background: There is a well-established association between inpatient hyperglycemia (HG) and mortality. However, evidence is inconsistent regarding whether this association is differential among those with and without type 2 diabetes mellitus (T2DM). Most studies results are limited by selected patient populations and many did not adjust for comorbidities. We aimed to examine if the association between inpatient HG and 30-day mortality is modified by T2DM status among a population-based cohort with over 15 years of medical history. Methods: A retrospective cohort study of individuals who were first hospitalized between 2012-2015. Thirty-day mortality was assessed during the inpatient stay up to 30 days post discharge. The adjusted association between inpatient HG and mortality was first assessed with logistic regression models. Then, four interaction terms were entered into the model to assess if the association of HG with mortality significantly differed by pre-hospital glycemic status (T2DM, prediabetes, unscreened and non-T2DM). Results: The multivariate model demonstrated a 2.18-fold risk of mortality associated with HG (OR [95% CI]: 2.18 [2.07-2.29]). After including the interaction terms between HG and pre-hospital glycemic status the model yielded the following results: the odds of mortality, compared to T2DM group with HG, were 1.43 [1.27-1.62] in non-T2DM group, 1.32 [1.16-1.52] in prediabetes group, and 1.28 [1.02-1.60] in unscreened group. This relationship remained robust throughout all sensitivity analyses that we conducted. Conclusion: The findings indicate that inpatient HG is positively associated with mortality and the group without T2DM is at highest risk. Glucose targets should be reconsidered for this group during their inpatient stay and their transition to the outpatient setting needs to be more closely monitored. Prospective research is needed to examine the efficacy of lowering their glucose targets on short-term mortality. Disclosure H. Rayyan Assi: None. B.S. Feldman: None. M. Leventer-Roberts: None. I. Raz: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Stock/Shareholder; Self; DarioHealth. Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Orgenesis Inc., Pfizer Inc., Sanofi R&D, SmartZyme Biopharma. Consultant; Self; Bristol-Myers Squibb Company. Speaker's Bureau; Self; Bristol-Myers Squibb Company, Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Novartis Pharma K.K., Sanofi-Aventis. Consultant; Self; FuturRx Ltd, Insuline Medical,Camereyes Ltd, Exscopia, Medial EarlySign Ltd. Stock/Shareholder; Self; Glucome Ltd, InsuLine Medical Ltd.. Consultant; Self; Dermal Biomics Inc. Stock/Shareholder; Self; Orgenesis Inc.. Speaker's Bureau; Self; Teva Pharmaceutical Industries Ltd.. Advisory Panel; Self; Concenter BioPharma/Silkim Ltd, Camereyes Ltd. Stock/Shareholder; Self; CameraEyes Ltd. Advisory Panel; Self; Breath of Life PharmaLtd, Panaxia.

Intervention of the Flash Glucose Sensing Technology on Glycemic Control and Treatment Satisfaction in Patients with Type 2 Diabetes Treated Intensively by Insulin—A Randomized Controlled Trial

Objective: To determine the satisfaction from treatment and effectiveness of flash glucose monitoring system (FGM) in patients with type 2 diabetes. Design and Methods: 101 individuals with type 2 diabetes on multiple daily insulin injection (MDI) therapy for ≥1 year (mean duration 21.81±7.65 years) and HbA1c 7.4-10.2% (57-88 mmol/mol) were randomized to the intervention (n=53) or the standard care group (n=48). Those in the intervention group were instructed to use FGM and once a week 7-points BG assessment to confirm any a symptomatic hypoglycemia. The control group continued the routine BG measurement as before the study and add once a week 7-points BG measurement at constant day. For 12 weeks, both groups were instructed to adjust insulin dose in the frequent face-to-face and telephone visits. Satisfaction from treatment, quality of life, comfort using FGM, HbA1c and hypoglycemia events were evaluated. Results: The mean age was 66.75 ± 7.55; 64.35% were male. Total treatment satisfaction increased in the intervention group (p=0.053). At the 12 week of the study, subjects in the intervention group found treatment significantly more flexible (p=0.019), convenient (p=0.052), and would recommend it more to their counterparts (p=0.023). The mean HbA1c was 8.51 ± 0.81%. After 10 weeks, HbA1c changes were -0.82% in the intervention group and -0.29% in the control (p=0.0013). 67.9% subjects from the intervention study and 27.1% from the control group reduced HbA1c ≥0.5% HbA1c (p<0.001); and 39.6% subjects from the intervention and 16.7% from the control group reduced HbA1c≥1.0% (p=0.0076) without increasing frequency of hypoglycemia. Conclusion: FGM potentially produces a modification of behavior/life style and improves treatment satisfaction. It improves glycemic control in subjects with type 2 diabetes treated by MDI without increased frequency of hypoglycemia. Disclosure M. Yaron: None. E. Roitman: Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; GlucoMe. Stock/Shareholder; Self; GlucoMe. G. Aharon-Hananel: None. Z. Landau: None. T. Ganz: None. M. Karp: None. M. Ish-Shalom: None. J. Singer: None. J. Wainstein: None. I. Raz: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Stock/Shareholder; Self; DarioHealth. Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Orgenesis Inc., Pfizer Inc., Sanofi R&D, SmartZyme Biopharma. Consultant; Self; Bristol-Myers Squibb Company. Speaker's Bureau; Self; Bristol-Myers Squibb Company, Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Novartis Pharma K.K., Sanofi-Aventis. Consultant; Self; FuturRx Ltd, Insuline Medical,Camereyes Ltd, Exscopia, Medial EarlySign Ltd. Stock/Shareholder; Self; Glucome Ltd, InsuLine Medical Ltd.. Consultant; Self; Dermal Biomics Inc. Stock/Shareholder; Self; Orgenesis Inc.. Speaker's Bureau; Self; Teva Pharmaceutical Industries Ltd.. Advisory Panel; Self; Concenter BioPharma/Silkim Ltd, Camereyes Ltd. Stock/Shareholder; Self; CameraEyes Ltd. Advisory Panel; Self; Breath of Life PharmaLtd, Panaxia.

Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial

Rasagiline, a monoamine oxidase B inhibitor with neuroprotective potential in Parkinson's disease, has shown a disease-modifying effect in the SOD1-Gly93Ala low-expressing mouse model of amyotrophic lateral sclerosis, both alone and in combination with riluzole. We sought to test whether or not rasagiline 1 mg/day can prolong survival in patients with amyotrophic lateral sclerosis also receiving riluzole. Patients with possible, probable, or definite amyotrophic lateral sclerosis were enrolled to our randomised, placebo-controlled, parallel-group, double-blind, phase 2 trial from 15 German network for motor neuron diseases (MND-NET) centres (university hospitals or clinics). Eligible patients were aged at least 18 years, had onset of progressive weakness within the 36 months before the study, had disease duration of more than 6 months and less than 3 years, and had a best-sitting slow vital capacity of at least 50%. After a 4-week screening period, eligible patients were randomly assigned (1:1) to receive either rasagiline (1 mg/day) or placebo in addition to riluzole (100 mg/day), after stratification for site of onset (bulbar or spinal) and study centre. Patients and all personnel assessing outcome parameters were masked to treatment allocation. Patients were followed up 2, 6, 12, and 18 months after randomisation. The primary endpoint was survival time, defined as the time to death or time to study cutoff date (ie, the last patient's last visit plus 14 days). Analyses of primary outcome and safety measures were done in all patients who received at least one dose of trial treatment (intention-to-treat population). The trial is registered with ClinicalTrials.gov, number NCT01879241. Between July 2, 2013, and Nov 11, 2014, 273 patients were screened for eligibility, and 252 patients were randomly assigned to receive rasagiline (n=127) or placebo (n=125). 126 patients taking rasagiline and 125 taking placebo were included in the intention-to-treat analysis. For the primary outcome, the survival probability at the end of the study was 0·43 (95% CI 0·25-0·59) in the rasagiline group (n=126) and 0·53 (0·43-0·62) in the placebo group (n=125). The estimated effect size (hazard ratio) was 0·91 (one-sided 97·5% CI -infinity to 1·34; p=0·31). Rasagiline was well tolerated, and most adverse events were due to amyotrophic lateral sclerosis disease progression rather than treatment; the most frequent of these were dysphagia (32 [25%] taking rasagiline vs 24 [19%] taking placebo) and respiratory failure (25 [20%] vs 31 [25%]). Frequency of adverse events were comparable between both groups. Rasagiline was safe in patients with amyotrophic lateral sclerosis. There was no difference between groups in the primary outcome of survival, although post-hoc analysis suggested that rasagiline might modify disease progression in patients with an initial slope of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised greater than 0·5 points per month at baseline. This should be confirmed in another clinical trial. Teva Pharmaceutical Industries.

Teva will cut 14,000 jobs worldwide

Kåre Schultz, the new CEO of Teva Pharmaceutical Industries, is making good on his promise to launch a major restructuring of the indebted generic-drug giant. Schultz aims to reduce Teva’s costs around the globe by $3 billion by 2019. To do that, Teva will slash 25% of its workforce, about 14,000 employees, and shutter many of its R&D facilities, manufacturing plants, and offices worldwide next year. The Israeli firm’s stock spiked 16% upon the news.

Drugmakers cut jobs

Novartis will cut 250 positions in the U.S., most of them in East Hanover, N.J. In addition, the drug company plans 500 job cuts or relocations at its Basel, Switzerland, headquarters during the next 18 months. The jobs are associated with coordination, development, and production. But the firm says it will also add 350 Swiss posts, mostly across its biotech activities. Meanwhile, Israel’s Teva Pharmaceutical Industries will close a plant in Gödöllő, on the outskirts of Budapest, if it can’t sell it. The facility employs 500 people.

Pregnancy Outcomes from the Branded Glatiramer Acetate Pregnancy Database.

Appropriate counseling and treatment for women with multiple sclerosis (MS) who may become pregnant requires an understanding of the effects of exposure to disease-modifying therapies (DMTs) during pregnancy. Current reports and studies are limited in their usefulness, mostly by small sample size. Branded glatiramer acetate (GA) is a DMT approved for the treatment of relapsing forms of MS. For more than 2 decades, it has been shown to be efficacious and to have a favorable safety profile. The Teva Pharmaceutical Industries Ltd global pharmacovigilance database comprises data from more than 7000 pregnancies, during which women with MS were exposed to treatment with branded GA. We analyzed data from Teva's global pharmacovigilance database. Pregnancy outcomes for patients treated with branded GA were compared with reference rates of abnormal pregnancy outcomes reported in two large registries representing the general population. Pregnancies exposed to branded GA were not at higher risk for congenital anomalies than what is expected in the general population. These data provide evidence that branded GA exposure during pregnancy seems safe, without teratogenic effect.

A phase 2 study of temozolomide in patients affected by pretreated metastatic colorectal cancer with MGMT promoter methylation.

629 Background: Presently few options are available for pts with mCRC who failed standard treatments and prognosis remains grim. MGMT promoter methylation is a frequent and early event in CRC tumorigenesis. This epigenetic silencing is a predictor of response to the alkylating drug TMZ in glioblastoma. Preclinical evidences and a couple of clinical cases showed TMZ activity in pts affected by mCRC with MGMT silencing. We designed a study to evaluate the efficacy and safety of TMZ in pts with refractory mCRC harboring MGMT promoter methylation. While the trial was ongoing three analogous studies, reporting discordant results, were published. Methods: This was a 3-institutional, single arm, phase 2 trial, planned according to a 2-stage Simon’s optimal design. The primary endpoint was ORR. Secondary outcomes included DCR, OS, PFS and safety. A first cohort of 21 pts was accrued: if more than 1 response was observed a second cohort of 20 pts would be enrolled; if 4 or fewer responses were observed by the end of stage two, then no further investigation would be warranted. MGMT promoter methylation was assessed on archival tissue samples by MS-PCR. Patients affected by MGMT methylated mCRC, who failed 2 or more prior treatments, received TMZ, provided by TEVA Pharmaceutical Industries, at a dose of 150-200 mg/mq/day once a day on days 1-5 every 28 days. Results: From July 2012 to June 2016, 225 pts were screened and 80 showed MGMT promoter methylation, among those 42 met the inclusion and exclusion criteria and were enrolled. ORR was 10% with no CR and 4 (10%) PR. SD was achieved in 9 (22%) pts, accounting for a DCR of 32%. At a median FU of 9 months all pts experienced PD and 88% died. Median PFS and OS were 2.6 months (95% CI 2.1-3.2) and 7.1 months (95% CI 5.1-9.2) respectively. Overall, any-grades AEs were reported in 75.6% pts, most of them were G1-2 (84%). The most frequent AE were nausea (56%) and platelet count decreased (39%). 4 pts discontinued study treatment due to AE. No SAE neither toxic death was recorded. Conclusions: The study did not meet its primary endpoint, however an interesting DCR (32%) and 4 PR were achieved. The role of TMZ in mCRC treatment remains still controversial and might warrant further analysis. Clinical trial information: 2012-002766-13.

Teva to pay record fine over bribery charges

Teva Pharmaceutical Industries agreed to pay $519 million to settle U.S. criminal and civil allegations that it paid bribes to government officials in Russia, Ukraine, and Mexico between 2002 and 2012 to secure business for its medications. The Israel-based company, which is the world’s largest manufacturer of generic drugs, will pay the biggest criminal fine ever imposed by the U.S. government against a pharmaceutical company for violating the Foreign Corrupt Practices Act. The law, jointly enforced by the Justice Department and the Securities & Exchange Commission, prohibits the payment of bribes to foreign officials to assist in obtaining or retaining business. Teva allegedly made more than $214 million in illicit profits by bribing officials to increase its market share, obtain regulatory approvals, and gain favorable drug purchase and prescription decisions, according to the federal government. The improper conduct did not involve U.S. sales. “While the conduct that resulted in this

CREATING LABORATORY TECHNOLOGY OF GENERIC EPIRUBICIN PHARMECEUTICAL DOSAGE FORM

Introduction. Governments around the world seek to reduce rapidly rising health care costs. Using the same high quality and often cheaper than the original brands, generics greatly reduces costs while providing an adequate quality of care. Therefore the development of generic medicines is an important task. The purpose of the study - the reproduction of the pharmaceutical dosage form for creation of national drug-generic epirubicin. Materials and methods. The study used a substance epirubicin (Ph. Eur current edition, Teva Pharmaceutical Industries Ltd., Israel); “Farmorubicin”, production “Pfizer Italia Srl” for “Pfizer Inc.”, Italy / US and excipients conforming to with relevant regulatory documents. Mice transplanted tumor: lymphocytic leukemia P388. Methods: technological, pharmaco-analytical, biological and pharmacological. Results. Pharmaceutical analysis of reproduced generic-drug “Epirubicin-RONC®” showed that itfully meets the requirements of manufacturer’s monograph. The results of “acute” toxicity study in rats and observations of the experimental animals within 30 days after a single administration suggest that both drugs have similar toxicological properties and are almost identical. Generic “Epirubicin RONC®” and “Farmorubicin” in lyophilized dosage form for injection 10.0 mg/vial, administered once, shows equal antitumor effect at two administration routes in mice with transplantable tumor: lymphocytic leukemia P-388. Conclusion. N.N. Blokhin Russian Cancer Research Center Ministry of Health of Russia has been reproduced generic - “Epirubi-cin-RONC®”, which is fully conform to the imported drug.

The Elderly Project By the Fondazione Italiana Linfomi (FIL): A Prospective Multidimensional Assessment of Elderly Patients with Diffuse Large B-Cell Lymphoma

Introduction:The initial approach to elderly patients with Diffuse Large B-cell lymphoma (DLBCL) is usually based on the subjective judgment of the physician on the individual patient's ability to tolerate treatment with curative intent. "Comprehensive Geriatric Assessment" (CGA) is based on the use of the ADL (Activity of Daily Living), IADL (Instrumental ADL) and CIRS-G (Comorbidity Index Rating Scale for Geriatrics) scales and represents a tool to standardize initial patients fitness assessment and for planning systemic therapy. So far CGA has been rarely used in prospective studies and lacks a formal validation in patients with lymphoma.Objectives:FIL is conducting a prospective study with the aim of validating the use of CGA on a large series of elderly patients with DLBCL and to test a CGA based approach to the patient. CGA results will be used to define treatment goals that are the cure for the FIT subjects, and palliation for the FRAILs. Treatment goal for the UNFIT is cure with less toxic regimens.Methods:This study is conducted using a web based platform, accessible from the reserved area of the FIL website, to perform a quick and objective CGA evaluation of consecutive patients ≥ 65 years with untreated DLBCL. Patients younger than 80 years, without impairment of ADL and IADL and without severe comorbidities were considered FIT; those with intermediate fragility or those older than 80 years with FIT profile were classified as UNFIT (UN); those with severe impairment of ADL, IADL and CIRS and those older than 80 years with an UN profile were classified as FRAIL (FR). Informed consent was required to enrol patients in this study; the planned sample size was 1000 patients.Results:The study started in December 2013. At time of current analysis 792 patients have been registered by 45 centres: 328 (41%), 207 (26%), and 257 (33%) were classified as FIT, UN and FR, respectively.Median age was 77 years (yrs) (65-95); 73 (65-79), 80 (65-95) and 81 (65-95) yrs for FIT, UN and FR patients respectively; overall 65% were in stage III-IV. By univariate analysis, the three categories differed in terms of median age (p<0.001), B-symptoms (p=0.035), ECOG PS>1 (p<0.001), elevated LDH (p=0.035) and IPI score (p=0.004).Fourty-nine percent of cases were defined as UN only because of age (≥80 yrs); other reasons for UN were impairment of IADL, ADL in 30% and 18%, respectively. Only 3% of cases were UN due to CIRS (5-8 comorbidities of grade 2). Regarding FRAIL patients 27% of patients were classified in this group due to CIRS impairment, 24% and 18% due to IADL and ADL impairment, respectively. In remaining 31%, patients were FRAIL due to age ≥80 yrs (Figure 1). The most frequent altered ADL items among UN and FR patients were continence (15%) and bathing (30%), respectively; regarding IADL the most frequent altered items were buying and food preparation for either UN (19% and 12%) and FR (53% and 41%). Most frequent grade 3 comorbidities among the 257 FR patients were those referred to heart (16%), vascular system (9%), muscoloskelatal (7%), and genitourinary (5%).Data on planned treatment were available in 643 patients. Rituximab was used in all but 6 (2%), 18 (12%), and 35 (17%) FIT, UN, and FR cases.Treatment with curative intent (full doses R-CHOP-like regimens) was used in 94% and 65% of FIT and UNFIT cases; surprisingly curative intent was declared also in 38% of FRAIL cases. Six percent, 25% and 26% of FIT, UN and FR patients were treated with an attenuated R-CHOP-like immuno-chemotherapy regimens.Palliative regimens were used in 36% and 10% of FR and UN patients respectively.Conclusion:The preliminary data of Elderly Project showed that, with the CGA criteria as adopted in this study, the 59% of elderly patients with DLBCL at diagnosis were not FIT.Rituximab and doxorubicin containing regimen seems to be the reference treatment for FIT, UN and also for a significant proportion of FR patients but the actual value of using this approach for non-FIT patients is not clear and will be assessed with this project. [Display omitted] DisclosuresMerli:Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Luminari:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Other: Travel, Accomodations, Expenses; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Cavallo:JANSSEN: Honoraria; CELGENE: Honoraria; ONYX: Honoraria. Chiappella:Roche: Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Speakers Bureau; Teva: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Celgene: Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee.

Improved Survival for MDS/CMML Patients Treated with the Combination of Decitabine (DAC) and Arsenic Trioxide (ATO) in a Phase II Adaptive Three Arm Randomization Study: DAC Alone Vs. DAC +/- Carboplatin or ATO

▪Introduction: DAC is a hypomethylating agent FDA approved for the treatment of advanced myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).Despite its clinical activity, the duration of response is limited and prognosis at relapse is poor. In pre-clinical studies, we identified potent epigenetic effects of ATO alone and in combination with DAC, and also found that carboplatin (Carbo) can enhance gene reactivation in combination with DAC. We therefore initiated a randomized phase 2 clinical trial (NCT02188706) to compare the safety and efficacy of DAC in combination with either Carbo or ATO as compared to single agent DAC in patients with MDS/CMML and Acute Myeloid Leukemia. Here we present updated results for the MDS/CMML cohort.Methods: Patients with MDS/CMML INT-1 were randomized to one of three regimens: DAC 20 mg/m2 days 1-5, (DAC), DAC as above and Carbo AUC 5 on day 8 (DAC/Carbo), or DAC as above and ATO 0.15 mg/kg days 1-5 (DAC/ATO). We used adaptive randomization based on response rate which started after 10 patients were equally randomized to each arm. Cycles were scheduled every 28 days for a minimum of 4 cycles. Dose reductions/delays were allowed based on response and tolerability. Patients remained on treatment as long as they continued to benefit without toxicity. The primary endpoint was the composite response rate: the complete response (CR: complete response, mCR: marrow complete response and CRi: complete response with incomplete blood count recovery) and partial response (PR) rates using the modified IWG 2006 criteria. Secondary endpoints included median overall survival (OS) and safety. DNA methylation changes were measured using LINE1 bisulfite/pyrosequencing.Results: As of July 2016, 42 patients (MDS = 40, CMML=2) have been enrolled on study. Median age was 71 years (range, 35 to 84 years). There was no statistically significant difference in patients’ characteristics between the three arms. Median number of cycles for the treatment arms was 4 (range, 1-15). Response data was evaluable for 36 patients (8 on DAC alone, 5 on DAC/Carbo and 23 on DAC/ATO). Composite responses were seen in 3/8 patients on DAC (37.5%), 0/5 patients on DAC/Carbo (0%, p=0.23 compared to DAC alone) and 12/23 patients on DAC/ATO (52.2%, p=0.69 compared to DAC alone). Median OS among MDS/CMML patients receiving DAC/ATO (17.8 months) was improved compared to the DAC/Carbo (3.9 months) and DAC (9.8 months) arms (p=0.01) [Figure 1]. There was not a significant difference in high-grade (≥ grade 3) toxicity between the three arms, with grade 3 neutropenia and thrombocytopenia as the most common side effects. DNA methylation analysis showed equivalent demethylation in all the arms, suggesting that the epigenetic effects of ATO were independent of DNA methylation, which was consistent with pre-clinical studies.Conclusion: Our results demonstrate higher response rates and a significant survival benefit with the combination of DAC and ATO in comparison to DAC alone in patients with MDS/CMML. [Display omitted] DisclosuresKropf:Celgene: Consultancy; Takeda: Consultancy. Fung:Amgen: Consultancy; Genzyme: Consultancy. Kantarjian:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Issa:Astex Pharmaceuticals: Consultancy; Teva Pharmaceutical Industries: Consultancy.

Italian Real Life Experience with Brentuximab Vedotin: Results of a National Observational Study on Relapsed/Refractory Anaplastic Large Cell Lymphoma

From November 2012 to July 2014, brentuximab vedotin (BV) was available in Italy for patients with relapsed systemic anaplastic large cell lymphoma (ALCL) outside a clinical trial context based on a local disposition of the Italian Drug Agency (AIFA) issued according to a national law (Law 648/96: "medicinal products that are provided free of charge on the national health service"). A large Italian observational retrospective study was conducted on the use of BV in the everyday clinical practice to check if clinical trial results are confirmed even in a real life context. Primary endpoint was the best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and the safety profile. BV was infused intravenously at the dose of 1.8 mg/kg every 3 weeks for a maximum of 16 cycles. A total of 40 ALCL (18 anaplastic lymphoma kinase [ALK] negative and 22 ALK-positive status) patients were treated with BV in 40 Hematology Centers. All patients had histologically documented CD30+ ALCL; 16 (40%) had relapsed and 24 (60%) had refractory disease. Patients were heavily pretreated with a median of 2 previous therapies (including autologous transplant in the 32.5% of cases). Best response was observed after a median of 4 cycles in 31 patients (77.5%): 19 (47.5%) patients obtained a complete response (CR) and 12 (30%) achieved a partial response (PR); overall response rate at the end of the treatment was 62.5% (18 CR and 7 PR). The best response rate was higher in the elderly subset (>60 years): 9 (64.2%) CR and 3 (21.4%) PR, achieving a total of 85.6%. At the latest follow up 15/18 patients are still in CR (3 with consolidative procedure). Global progression free survival was 39.1% at 29 months and disease free survival 54% at 23.9 months (median not reached). Median duration of response was 12 months (range 9-24 months). We identified 5 long term responders (patients with a response ≥ 12 months), all were still in CR at the latest follow up (1 underwent allogeneic transplant). Particularly, all the long term responders were aged <30 years at first BV infusion.All patients were included in the safety profile for the analysis; in general, the treatment was well tolerated even in this real life context and the toxicity profile was closely similar to the previously published data; no death has been linked to BV toxicity. Toxicity was primarily neurological and rarely so serious as to require treatment reduction or interruption; furthermore, neurological toxicity always reversed completely after end of treatment. No long-term toxicity was assessed during the follow-up period, even in patients later subjected to transplant consolidation.BV induces clinical responses quite rapidly, i.e. within the first 4 cycles in most responders, thus permitting the timely application of the transplantation phase. Furthermore, BV displays a favorable toxicity profile, without overlapping toxicities with most of the agents employed in high-dose conditioning regimens. For patients ineligible for transplant or for who transplant failed, BV may represent a feasible effective therapeutic option in everyday clinical practice. DisclosuresRusconi:Takeda: Consultancy; Teva: Consultancy, Other: Congress attendance; Janssen: Consultancy, Other: Congress attendance. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

Novel Long Non Coding RNA Blackmamba Is Associated to ALK- anaplastic Large Cell Lymphoma

Systemic Anaplastic Large Cell Lymphomas (ALCLs) is among the common subtypes of T-cell lymphomas. The prognosis of ALCLs patients has been proven to be associated with translocations of the anaplastic lymphoma kinase (ALK) gene, having ALK negative patients (ALK-ALCL) a poorer 5-years survival rate (30-40%). We now recognize that ALK- ALCL includes multiple subsets some of which are bear unique genetic defects and unique clinical outcomes. Long non coding RNAs (lncRNAs) are regulators of gene expression controlling critical processes (epigenetic regulation, imprinting, cell cycle, apoptosis) frequently deregulated in cancer. In T-cells, more than 500 lncRNAs are associated with lymphocyte signatures, control cell differentiation and cell identity. While lncRNAs are found to be differentially expressed in solid cancer and directly linked to the different stages of carcinogenesis, their role in lymphoid neoplasms is largely unknown.To identify novel lncRNAs maintaining the neoplastic phenotype of ALCL, we prepared cDNA libraries representative of coding and non-coding RNA. High coverage and directional RNA-sequencing was performed in 30 purified human T lymphocytes from multiple healthy donors, corresponding to different stages of differentiation, 22ALK+ ALCL and 20 ALK-ALCL patients' samples. Seven bona fide ALCL cell lines were included.By de novo transcriptome reconstruction and using a new bioinformatic pipeline, we identified 83lncRNAs exclusively expressed in ALCL patient's samples. Among them, 82 lncRNAs were coshared between ALK+ and ALK- ALCL and only one was exclusively expressed in ALK-ALCL samples. We named this new lncRNA BlackMamba.We selected the 10 top-scoring ALCL-associated lncRNAs and BlackMamba and determined their expression by RT-PCR, in a validation set of ALCL (ALK+: n=3, ALK-: n=3), T-ALL (n=8), PTCL (n=9), and AITL (n=9) samples. Resting and activated PBMCs from two additional donors were included.Our data confirmed that the 10 top-scoring ALCL-associated lncRNAs were expressed exclusively in ALCLs without differences in the expression among ALCL subtypes. Moreover, BlackMamba was detected only in ALCL samples with a preferential expression in ALK-ALCL samples. All lncRNAs were not expressed in normal T-lymphocytes.We next determine the BlackMamba expression in ALCL (n=6), T-ALL (n=3), cutaneous T-lymphomas (n=3) cell lines by RT-PCR. FedP, MAC1 and MAC2a (ALK-ALCL) cell lines showed the highest expression.Because the cellular localization of lncRNAs affects their function, we assessed the sub-cellular localization of BlackMamba by nucleo/cytoplasm cell fractionation and RT-PCR in FedP and MAC2A cell lines. BlackMamba displayed a preferential nuclear/chromatin-associated localization. Having proven that JAK/STAT signaling pathway plays a key role in both ALK+ and ALK-ALCL, we test whether the expression of BlackMamba could be modulated after treatment with JAK1/2 (ruxolitinib) TKi. Our data showed that, in FedP and MAC2A cell lines, BlackMamba expression was 50% down-regulated relative to control.Next, to identify whether BlackMamba may have a unique associated to specific chromatin remodel proteins, we verified its association with several candidates and found the physical interaction with the histone-lysine N-methyltransferase enzyme EZH2 by RIP in the FedP cells.Notably, after BlackMamba knock down, the proliferation of FedP cells was reproducibly reduced (25% at 84hrs using multiple RNAi oligonucleotides).Collective, our data indicate that ALCL aberrantly express novel and uncharacterized lncRNAs and that BlackMamba is a novel lncRNA associated with ALK-ALCL. Moreover, BlackMamba may contributes to the maintenance of ALK-ALCL neoplastic phenotype. DisclosuresMerli:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Lenalidomide Plus R-CHOP (R2CHOP) in Patients with DLBCL Is Associated with a Lower Risk of CNS Relapse: Combined Analysis from Two Phase 2 Studies

BackgroundCentral nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a devastating event occurring in approximately 5% of patients treated with standard R-CHOP (Thanarajasingam et al, ASH 2015, abs 1456). Isolated CNS relapse is associated with significant morbidity and mortality. New treatment regimens with agents that cross the blood-brain barrier (BBB) are needed. The combination of lenalidomide with R-CHOP (R2CHOP) has shown promising results in activated B-cell (ABC) type DLBCL in phase 2 studies and is currently being evaluated in randomized trials. Lenalidomide crosses the BBB and has been demonstrated to have single-agent activity in relapsed CNS lymphoma. Accordingly, the addition of lenalidomide to R-CHOP may decrease the risk of CNS relapse. Here we characterize the combined incidence of isolated CNS relapse in a population of DLBCL patients who received R2CHOP for induction therapy in two independent phase 2 studies.MethodsWe analyzed the incidence of isolated CNS relapse in patients with histologically-confirmed DLBCL enrolled in two R2CHOP phase 2 trials - one conducted by Mayo Clinic (MC) and the other by Italian Lymphoma Foundation (FIL) - in the context of clinical variables that included age, gender, disease stage, cell of origin, and administration of CNS prophylaxis. We assessed CNS-International Prognostic Index (CNS-IPI) factors (age, stage, lactate dehydrogenase level, ECOG performance status, extranodal sites, adrenal/kidney involvement) and classified patients into groups of low, intermediate, and high risk of CNS relapse. The risk of CNS relapse in R2CHOP-treated patients was then estimated and compared against published rates in RCHOP-treated patients based on CNS-IPI score.ResultsOne hundred thirty-six patients with DLBCL from both cohorts (87 MC patients, 49 FIL patients) were included in this analysis. Mean age was 65 and median follow-up in 104 patients still alive was 48.2 months (range: 2.1-88.5). 61.8% of patients were male; 86.0% had stage III disease or higher; 44.1% had ECOG performance status of 0; cell of origin phenotype by immunohistochemistry according to Hans algorithm was germinal center B-cell (GCB), non-GCB (ABC), and not available in 43.4%, 36.8%, and 19.8%, respectively; 14.7% received intrathecal (IT) methotrexate for CNS prophylaxis per local practice. No patients received intravenous methotrexate. 10.3%, 71.3%, and 18.4% of patients were classified into low, intermediate, and high-risk CNS-IPI groups, respectively. Only one of 136 patients developed isolated CNS relapse, corresponding to an estimated incidence of CNS relapse of 0.007 (0.7%).ConclusionsDespite a large proportion of patients with intermediate and high risk of CNS relapse treated in both phase 2 studies, induction therapy with R2CHOP in patients with DLBCL is associated with a lower-than-expected rate of isolated CNS relapse. The latter is unlikely to be explained by use of IT chemotherapy, which is considered to be marginally effective in this setting and was implemented only in a small proportion of patients. This suggests that addition of CNS-penetrating small molecules, such as lenalidomide, to R-CHOP may decrease the risk of CNS relapse. DisclosuresChiappella:Celgene: Speakers Bureau; Teva: Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Amgen: Speakers Bureau. Nowakowski:Morphosys: Research Funding; Celgene: Research Funding; Bayer: Consultancy, Research Funding. Cavallo:Janssen-Cilag: Honoraria; Onyx: Honoraria; Celgene: Honoraria. Gaidano:Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Vitolo:Takeda: Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures.

Frequency and Prognostic Significance of Cytogenetic Abnormalities in 1269 Patients with Therapy-Related Myelodysplastic Syndrome - a Study of the International Working Group (IWG-PM) for Myelodysplastic Syndromes (MDS)

Frequency and Prognostic Significance of Cytogenetic Abnormalities in 1269 Patients with Therapy-Related Myelodysplastic Syndrome - a Study of the International Working Group (IWG-PM) for Myelodysplastic Syndromes (MDS)

Rituximab, Bendamustine and Cytarabine (RBAC500) As Induction Therapy in Elderly Patients with Mantle Cell Lymphoma: Final Results of a Phase 2 Study from the Fondazione Italiana Linfomi

▪Background: The combination of rituximab (R, 375 mg/m2 intravenously [IV], day 1), bendamustine (B, 70 mg/m2IV, days 2 and 3), and cytarabine (800 mg/m2, IV on days 2 to 4) was highly active in patients with mantle-cell lymphoma (MCL) in a phase 2 study [R-BAC; Visco et al, JCO 2013]. This regimen was well tolerated, but hematologic toxicity was quite relevant, especially in terms of transient grade 3 to 4 thrombocytopenia (76% of cycles). Aiming at reducing hematologic toxicity, the Fondazione Italiana Linfomi (FIL) designed a phase 2 trial adopting the R-BAC schedule, but lowering cytarabine dose to 500 mg/m2 (RBAC500).Materials and Methods: Patients with newly diagnosed MCL, aged 61 to 80 years, not eligible for autologous transplant and fit according to the comprehensive geriatric assessment, were enrolled. Patients presenting with non-nodal leukemic disease were excluded. The primary endpoints were complete remission rate (CR) measured by FDG-PET according to Cheson criteria 2007, and safety. Secondary endpoints included rate of molecular response (MR) by nested-PCR using patient specific IGH or BCL1 based targets, progression-free (PFS) and overall survival (OS). The study was conducted according to the Bryant and Day two-stage design.Results: From May 2012 to February 2014, 57 patients with MCL from 29 centers were recruited and treated. Central pathology revision was performed in 87% of cases. Median age was 71 years (range 61-79), 75% were males, and 91% had Ann Arbor stage III/IV disease. Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, high in 45%, Ki-67 was ≥30% in 31%, and 9% had the blastoid cytological variant. Overall, 53 patients (91%) received at least 4 cycles, while 36 (63%) had 6 cycles (median 5.3 cycles per patient). Fifteen patients (26%) discontinued treatment before reaching cycle 6 because of toxicity/adverse events, that mainly consisted of prolonged hemato-toxicity between cycles. Only one patient discontinued due to progressive disease. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 49% and 52% of administered cycles, respectively. Febrile neutropenia occurred in 6% of cycles. Extra-hematologic toxicity was mainly cardiac (5%). Overall response rate was 96%, and CR was 93%. The MR rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow (BM) samples. With a median follow-up of 34 months (28-52), the 2-years PFS (± confidence interval) was 81%±5% and the OS 85%±4%. Elevated Ki-67 (≥30%), and the blastoid variant were the strongest independent predictors of adverse PFS. Patients with either of these two features (33%), had a significantly inferior PFS (41% vs 97% after 34 months) compared to patients with classical/pleomorphic variants and low proliferative index (p<0.0001, Figure 1).Conclusions: The R-BAC500 regimen can be safely administered as first line therapy to elderly patients with MCL. Hematologic toxicity is substantially reduced compared to our previous experience. With 93% of FDG-PET negative CR, and a 2-years PFS of 81% without maintenance therapy, the R-BAC500 regimen is a highly effective treatment for patients with MCL, and compares favourably with previously reported regimens in this patient population, including R-bendamustine. [Display omitted] DisclosuresVisco:Gilead: Speakers Bureau; Lundbeck: Consultancy; Mundipharma: Research Funding; Celgene: Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Di Rocco:Celgene: Honoraria. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria.

Differences Between CEBPA bZIP and TAD Mutations and Their Effect on Outcome-an Analysis in 4578 Patients with Acute Myeloid Leukemia

Mutations of the key myeloid transcription factor CCAAT/enhancer binding protein alpha (C/EBPa) are found in 5-10% of patients with acute myeloid leukemia (AML). Two mutational clusters exist, in the aminoterminal transcription activation domains (TAD1 or 2) and in the basic leucine zipper domain (bZIP) located at the carboxyterminal-part of the protein. Biallelic mutations (biCEBPA) have been found to be associated with improved outcome and are now included as an independent entity in the WHO-classification. In contrast, monoallelic CEBPA-mutations (moCEBPA) do not appear to provide prognostic information. We characterized a large cohort of AML patients for CEBPA mutations and further analyzed the mutational spectrum of mono- and biallelic CEBPA-mutant AML patients to better understand potential differences in the biology of these groups. Patients and Methods: Patients (including all age groups) analyzed had a newly diagnosed AML and were registered in clinical protocols of the Study Alliance Leukemia (SAL)(AML96, AML2003 or AML60+, SORAML) or the SAL-register. Screening for CEBPA mutations was done using PCR and capillary electrophoresis. All identified CEBPA mutations were confirmed using conventional Sanger sequencing and the samples were further analyzed using next generation sequencing (Trusight Myeloid Panel, Illumina) for the presence of associated alterations. Results: In the 4578 patients analyzed, 228 (5%) with CEBPA-mutations were identified. An initial analysis revealed substantial clinical differences between the different mutation subtypes. Patients with biCEBPA (n=111) were significantly younger (median age 46 yrs) than wt-CEBPA patients (median 57 yrs; p<.001). Interestingly, single bZIP mutant patients (n=64) had a similar median age (50 yrs.) as biCEBPA, whereas single TAD mutant patients (n=53) were significantly older (median 63 yrs.). In addition, WBC counts, CD34 positivity as well as the history of prior MDS differed between the subgroups (single TAD mutant had significantly lower WBC counts, lower rate of CD34 positivity and had a higher rate of prior MDS than biCEBPA and single bZIP mutant patients). Along with this, the distribution of co-mutations differed significantly between the subgroups, especially GATA2 mutations were more common in biCEBPA and single bZIP mutant patients (37% and 34%, respectively) compared to only 3% (single TAD)(p=.001). A similar pattern was seen for mutations in DNMT3A (8% biCEBPA, 20% single bZIP vs. 36% single TAD; p=.001), and NPM1 (3% biCEBPA, 8% single bZIP, 32% single TAD; p<.001). In 2897 patients, the different CEBPA mutations were correlated with outcome. This analysis indicated a differential effect of the individual mutations on outcome, with an improved rate of complete remission (CR), overall survival (OS) and event free survival (EFS) for biCEBPA and single bZIP mutations in univariate and multivariate analyses (shown for OS in Figure 1a). Given the similarity of single bZIP and biCEBPA mutations, it appears reasonable to speculate on a common mechanistical background, since most of the biCEBPA mutants include a bZIP alteration. Recent experimental evidence generated by several groups indeed supports a specific role of these bZIP missense mutations. To address this in the clinical context, we regrouped patients with mutant CEBPA into patients with (n=157) or without bZIP mutations (n=71), irrespective of the biallelic status. As illustrated in Figure 1b, the bZIP mutant group had a significantly better OS, similar results were obtained for EFS and CR. In multivariate analysis, the presence of a bZIP mutation was the strongest indicator for achievement of CR (HR 7.5, 95% CI: 3-19; p<.001), and together with favorable cytogenetics the factor associated with best OS (HR: .48; 95% CI .36-.64; p<.001). In conclusion, our results obtained in one of the largest cohorts of AML patients analyzed for CEBPA mutations indicate that especially the presence of a missense bZIP mutation is associated with a favorable outcome in AML patients. These data point to substantial differences in prognostic implications of individual CEBPA mutations and support the major functional divergence of these alterations. If confirmed, these results might necessitate further refinement of their use in AML-classification. [Display omitted] DisclosuresMiddeke:Sanofi: Honoraria. Platzbecker:Janssen-Cilag: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Thiede:AgenDix: Employment, Other: Ownership.

Inclusion of Patient's Self-Reported Fatigue into a Standard Laboratory Risk Classification Enhances Survival Prediction in Patients with Advanced Myelodysplastic Syndromes

BACKGROUND: Patients with higher risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS) have poor life expectancy making accurate prediction of overall survival (OS) a critical issue for optimal and personalized patients' management.PURPOSE: The primary objective of this study was to develop a patient-based prognostic index for higher risk-disease, that would include self-reported fatigue into the widely used IPSS classification. A secondary objective was to examine whether this patient-based index would provide more accurate OS prediction than the standard IPSS classification.PATIENTS AND METHODS: Analysis is based on 280 newly diagnosed patients with MDS classified with an intermediate-2 or high-risk score (i.e., higher-risk) according to the IPSS. Patients were recruited in an international prospective cohort observational study involving 37 centers. OS was defined as the date of diagnosis of IPSS intermediate-2 or high risk MDS up to death for any cause. Patients were censored at the date of last follow up if not dead at the time of analysis. Before treatment start, all patients completed the EORTC QLQ-C30 questionnaire and the fatigue scale was a priori selected for possible inclusion into the IPSS. Among all observed values of the fatigue score (range: 0-100) we looked for a threshold defining four risk groups, formed by patients reporting either low or high fatigue respectively in intermediate-2 and high risk IPSS groups. The final prognostic index was developed based on univariate and multivariate Cox models. Differences among Kaplan-Meier OS estimation of new risk categories were assessed by log-rank test. Sensitivity analyses were performed, 1) assessing differences in patients’ baseline characteristics among risk groups, by Kruskal-Wallis and Fisher’s exact tests 2) accounting for several potential confounding factors (baseline and time-dependent) in a multivariate extended Cox model, including treatment received after baseline assessment and further evolution into acute myeloid leukemia, 3) performing a bootstrap resampling procedure to internally validate the final prognostic index. Discrimination and calibration of the new index were evaluated. For all analyses, α=0.05.RESULTS: With a median follow- up of 15 months (IQR 8-27) we observed 113 deaths. The median OS of the overall population was 17 months (95% CI, 15-19). The majority of patients (N=165, 59%) received treatment with hypomethylating agents. The final cut-off value selected for the EORTC QLQ-C30 fatigue scale was 45 points discriminating between patients with low (<45 points) or high fatigue (≥45 points). A new risk score classification was then developed, namely, the Fatigue(FA)-IPSS(h), enabling to distinguish three risk group categories (i.e., risk-1, risk-2 and risk-3) in contrast to the two categories of the IPSS (intemediate-2 and high-risk). Patients with the most favorable prognosis according to the FA-IPSS(h) (i.e., risk-1) had a median OS of 23 months (95% CI, 19-29), those with risk-2 had a median survival of 16 months (95% CI, 12-17) and those with the least favorable prognosis (risk-3) had median OS of 10 months (95% CI, 4-13). In contrast, median OS was 20 months (95% CI, 17-24 months) and 13 months (95% CI, 9-16 months) for patients with an IPSS intermediate-2 and high risk scores, respectively. Survival rates at 6 months, one and two years were markedly different amongst the three groups of the FA-IPSS(h). For example, one-year OS for patients with the most favorable prognosis (risk-1) was 80.2% (95% CI, 73.4-87.8) and only 37.5% (95% CI, 23.8-59.1) for those with the poorest prognosis (risk-3). Sensitivity analyses supported our findings. The FA-IPSS(h) index showed very good predictive performance (bootstrap-corrected c-index=0.911).CONCLUSION: The FA-IPSS(h) is a new prognostic index that integrates patient's self-reported fatigue into the well established IPSS index. Its use might enhance physicians' ability to more accurately predict OS in higher-risk MDS. Also, implementation of this index into standard practice might have important implications to elicit a more active patient participation during initial consultations. DisclosuresEfficace:Seattle Genetics: Consultancy; Bristol Myers Squibb: Consultancy; TEVA: Consultancy, Research Funding; Lundbeck: Research Funding. Gaidano:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria. Bonnetain:Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgène: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria; Integragen: Consultancy, Honoraria; Nestle: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; Merck Serono: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Fianchi:Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Breccia:Novartis: Consultancy, Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Platzbecker:Celgene Corporation: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding.