Abstract: Human herpesvirus‐6 (HHV‐6) and human cytomegalovirus (HCMV) DNAs were quantified by real‐time PCR assays in blood and saliva obtained from 50 patients with acute leukemia at the time of diagnosis (50 of each matrix), aplasia (65 of each matrix), remission (55 of each matrix), and relapse (20 of each matrix) to evaluate which biological matrix was more suitable to identify a viral reactivation, search for a possible link between HHV‐6 and HCMV reactivations, and evaluate the relations between viral loads and count of different leukocyte types in blood. The median HHV‐6 loads were 136; 219; 226, and 75 copies/million cells in blood at diagnosis, aplasia, remission and relapse, respectively. The HCMV loads were 193 and 317 copies/million cells in blood at diagnosis and remission. In the saliva samples, the HHV‐6 loads were 22,165; 15,238; 30,214, and 17,454 copies/million cells at diagnosis, aplasia, remission, and relapse, respectively. The HCMV loads were 8,991; 1,461; 2,980, and 4,283 copies/million cells at diagnosis, aplasia, remission, and relapse, respectively. The HHV‐6 load in the blood was correlated to the counts of polymorphonuclear leukocytes (R 2  = 0.5; P  〈  0.0001) and lymphocytes (R 2  = 0.4; P  = 0.001) and was not correlated to the monocyte counts (R 2  = 0.07; P  = 0.7). Saliva appears to be a more sensitive biological matrix than whole blood in the detection of HHV‐6 or HCMV reactivations. The HHV‐6 and HCMV reactivations were linked only in saliva. J. Med. Virol. 87:451–460, 2015 . © 2014 Wiley Periodicals, Inc.

Abstract: Patients with persistent/chronic immune thrombocytopenia (cITP) have low platelet counts, increased risk of bleeding and bruising, and often suffer from reduced health‐related quality of life (HRQoL). cITP treatments may either improve HRQoL by increasing platelet counts or decrease it because of side effects. The open‐label EXTEND study (June 2006 to July 2015) evaluated long‐term safety, tolerability, and efficacy of eltrombopag (an oral thrombopoietin‐receptor‐agonist) in adults with cITP who completed a previous eltrombopag ITP trial. The final results of EXTEND were published and used to assess changes in patient‐reported HRQoL over time and association between HRQoL and platelet response. Four validated HRQoL instruments were administered: SF‐36v2 including physical component summary (PCS) and Mental Component Summary; Motivation and Energy Inventory Short Form (MEI‐SF); Fatigue Subscale of FACIT (FACIT‐Fatigue); and FACT‐Thrombocytopenia Subscale Six‐Item Extract (FACT‐Th6). For the 302 patients enrolled, median duration of eltrombopag treatment was 2.37 years. All 4 HRQoL instruments demonstrated positive mean changes from baseline over time adjusted for patient baseline characteristics and rescue therapy use, and had positive association with platelet response (platelet count ≥30 × 10 9 /L; ≥50 × 10 9 /L; and ≥50 × 10 9 /L and 〉 2 times baseline). Improvements from baseline started within 3 months and persisted through 5 years of treatment for FACIT‐Fatigue and FACT‐Th6 ( P 〈 .05 for nearly all time points); through 2.5 years for SF‐36v2 PCS and less consistently for the MEI‐SF. In conclusion, in addition to eltrombopag increasing platelet counts and reducing bleeding/bruising, it also alleviated fatigue, concerns about bleeding and bruising, and improved physical function in many patients, especially responders.

Abstract: Human herpesviruses (HHVs) remain latent after primary infection and can be reactivated in response to immunosuppression and chemotherapy. Little is known about their incidence, potential relationships, risk factors and clinical impact in non-transplant leukemia patients. This study investigated prospectively incidence, risk factors, clinical impact and possible association of HHVs-(1–7) infections in patients with newly diagnosed acute leukemia. Methods Study design involved longitudinal sampling before chemotherapy and in different phases of chemotherapy: post-induction, post-remission, and post-salvage during 2016–2018. A total of 734 plasma samples from 95 patients were analyzed by a qualitative, multiplex PCR for HHVs detection and a quantitative real-time PCR was used for cytomegalovirus (CMV) quantification. HHVs-(1–6) IgG and IgM antibodies were tested using immunoassays. Risk factors were analyzed by binary logistic regression and relationships between viruses were analyzed using the Chi-square or Fisher’s exact test as appropriate. Results The overall seroprevalences of HHV-(1–6) IgG were high ( 〉  80%). At least one herpes viral agent was detected in 60 patients (63.3%). CMV was the most commonly detected virus in the different phases of chemotherapy (19.4%), followed by HHV-6 (9.7%), HHV-7 (5.2%) and EBV (2.7%). HSV-1/2 and VZV DNA were not detected. Twenty-seven patients (28.4%) had more than one virus detected in the follow-up, with 23 who were co-infected. CMV/HHV-6 was the most frequent co-infection (69.5%, 16/23). HHV-6 infection ( p  = 0.008) was identified as a risk factor for CMV infection while salvage treatment ( p  = 0.04) and CMV infection ( p  = 0.007) were found to be independent risk factors for HHV-6 infection. CMV co-infection was associated with severe lymphopenia with an absolute lymphocyte count (ALC) ( 〈  500/μL) (p = 0.009), rash ( p  = 0.011), pneumonia ( p  = 0.016) and opportunistic infections [bacteremia, p   〈  0.001 and invasive fungal infection, ( p  = 0.024)] more frequently than CMV mono-viral infections. Conclusions Our data suggest that co-infection with HHVs, especially CMV and HHV-6, may contribute to the development of serious clinical manifestations with profound lymphopenia, pneumonia rash and increased risk for bacterial and fungal co-infections. These findings may suggest the synergistic effect of HHVs associated infection.

Abstract: Background: EXTEND (June 2006 to July 2015) was an open-label, dose-adjustment extension study to evaluate the safety and efficacy of eltrombopag for the treatment of patients with chronic immune thrombocytopenia (cITP) who had previously been enrolled in an eltrombopag trial. CITP may lead to fatigue and interference with daily activities, and ultimately affect health-related quality of life (HRQoL). Objective: To assess patient-reported HRQoL changes over time during long-term treatment with eltrombopag in patients with cITP using the final EXTEND data. Methods: Four standard validated HRQoL instruments for chronic disease were used in this study: SF-36v2 including the Physical Component Summary (PCS) and Mental Component Summary (MCS) to measure general physical and mental health status; Motivation and Energy Inventory Short Form (MEI-SF) to measure motivation and energy; Fatigue Subscale of FACIT (FACIT-F) to measure symptoms of fatigue; and FACT-Thrombocytopenia Subscale Six-Item Extract (FACT-Th6) to measure concerns related to bleeding and bruising and their impact on usual activities. The instruments were used at baseline (BL) and at a frequency of every 3 months until last on-treatment assessment. Patients were blinded to their current platelet count results before completing the questionnaires. Generalized estimating equations were used to estimate mean changes in HRQoL from BL to different time periods for each instrument, accounting for within-patient correlation. The models adjusted for time period from BL, demographic characteristics, BL clinical characteristics (BMI, BL use of cITP medication, prior splenectomy, prior eltrombopag use, and BL platelet count), and time-varying covariates for rescue therapy use (defined as the composite of new cITP medication, increased dose of cITP medication from BL, platelet transfusion, and splenectomy). Adjusted mean best changes in HRQoL from BL were also estimated using a similar method. Proportions of responders based on minimally important difference (MID) from BL were identified for each of the instruments. Response was defined as a change from BL score of at least one-half the standard deviation (SD) of the normalized scores (5 points) for SF-36v2 PCS and SF-36v2 MCS, at least one-half the SD of BL scores observed across all patients for MEI-SF and FACT-Th6, and at least 3 or 5 points for FACIT-F. Proportions of patients achieving any improvement and time to best improvement from BL were also reported. Results: 302 patients were enrolled in EXTEND. By instrument, 289 to 293 patients had a BL and at least one on-treatment HRQoL assessment for analysis. Median treatment duration was 2.4 years. All HRQoL instruments had positive mean changes from BL over time; noticeably improvements from BL persisted through 5 years of treatment for FACIT-F and FACT-Th6 (nearly all p 〈 0.05) (Table 1) and through the median duration of eltrombopag treatment for SF-36v2 PCS. All HRQoL instruments had a statistically positive and clinically meaningful (greater than MID threshold) mean best change from BL (p 〈 0.01) (Table 2). About half of patients had a response at least once during treatment based on MIDs in changes from BL: 45.4% (SF-36v2 PCS); 44.7% (SF-36v2 MCS); 42.3% (MEI-SF); 57.5% (3 points) and 47.3% (5 points) for FACIT-F; and 49.5% (FACT-Th6). Most patients experienced an improvement from BL (a higher post-baseline score at least once): 84.9% (SF-36v2 PCS); 82.8% (SF-36v2 MCS); 79.9% (MEI-SF); 77.1% (FACIT-F); and 80.6% (FACT-Th6). Best improvement occurred at a median of 6-10 months post BL. Conclusion: About 80% of patients with cITP treated with eltrombopag experienced an improvement from BL in HRQoL, often within a year of BL. About half of patients achieved a clinically meaningful response from BL. This study found positive and meaningful mean best changes from BL in all HRQoL scores, including those measurements more closely related to clinical outcomes such as fatigue, bleeding, and bruising as well as more general measures such as motivation, energy, physical and mental health status. Improvements from BL persisted over time in particular for fatigue, bleeding, bruising, and physical health status. Disclosures Saleh: GSK: Consultancy, Research Funding, Speakers Bureau. Burgess:Novartis: Employment. Portella:Novartis: Employment. Roy:Novartis: Employment. Barghout:Novartis: Consultancy. Ivanova:Novartis: Research Funding; GSK: Research Funding; Teva: Research Funding; Lilly: Research Funding. Bussel:GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Boehringer Ingelheim: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; BiologicTx: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Symphogen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Abstract 2410 Poster Board II-388 BACKGROUND: Eltrombopag (PROMACTA®; GlaxoSmithKline, Collegeville, PA, USA) is an oral, small molecule, thrombopoietin receptor agonist that is approved in the US for the treatment of chronic immune thrombocytopenic purpura (ITP) and is being evaluated for the treatment of thrombocytopenia of various etiologies (eg, chronic liver disease, hepatitis C, MDS, chemotherapy). The prevalence of hepatobiliary laboratory abnormalities (HBLAs) in the overall population of chronic ITP patients, specifically ALT 〉 3× ULN (4.6%), has been shown to be relatively high compared with other disease populations (Bennett Haematologica 2009). OBJECTIVE: To evaluate the effects of eltrombopag on the liver by analyzing HBLAs across the ITP clinical program. METHODS: Data were collected and analyzed from patients in 3 randomized, placebo-controlled (TRA100773A, TRA100773B, RAISE) and 2 open-label (REPEAT, EXTEND) eltrombopag studies. The analysis followed an FDA draft guidance on Drug-Induced Liver Injury (DILI), taking into consideration ALT or AST ≥3× ULN, total bilirubin or alkaline phosphatase (AP) 〉 1.5× ULN, and potential combinations of these HBLAs. RESULTS: In the 3 placebo-controlled studies, 7% (9/128) of placebo patients and 11% (33/299) of eltrombopag patients met at least 1 of the DILI screening criteria (Table 1). In these studies, a similar incidence of abnormalities was observed in both treatment groups with the exception of ALT ≥3× ULN (placebo 2%; eltrombopag 5%). Total bilirubin elevations were observed in 3% and 4% of patients in the placebo and eltrombopag groups, respectively. 3 patients (2%) on placebo and 4 patients (2%) on eltrombopag were withdrawn due to elevations of ALT and/or total bilirubin. In REPEAT, 5% (3/66) of patients met at least 1 of the DILI screening criteria. Results in EXTEND were similar with 24 patients (8%) meeting at least 1 of the DILI screening criteria and 5 patients (2%) being withdrawn due to an HBLA. 18 EXTEND patients met at least 1 of the DILI screening criteria in a previous eltrombopag study. Of these, 7 patients (39%) met at least 1 of the DILI screening criteria during EXTEND; 5/7 experienced the same HBLAs as in the previous study. The recurrent HBLAs were generally of a lesser magnitude than the initial ones. In studies in which fractionation was required, 17 of the 18 patients with total bilirubin 〉 1.5× ULN had hyperbilirubinemia due to indirect bilirubin. Bilirubin was not fractionated in 1 patient. Of the 60 eltrombopag-treated patients with HBLAs across the program, 25 patients (42%) had their elevations resolve despite continued eltrombopag treatment. Across the program, 5 patients had ALT 〉 3× ULN and bilirubin 〉 1.5× ULN (Table 1). Of these 5 patients, 3 provisionally met Hy's Law criteria (ALT 3× ULN and bilirubin 〉 2× ULN). Ultimately, however, none of these patients met Hy's Law criteria as 1 patient had an increase in indirect bilirubin and 2 patients had confounding factors: 1 with acute cholangitis and 1 with septicemia and right-sided congestive heart failure. None of the patients experiencing HBLAs was reported to present with clinical symptoms indicative of liver function impairment. CONCLUSION: Eltrombopag treatment can lead to an elevation of ALT or indirect bilirubin. In clinical trials, these elevations have been typically mild, reversible and not accompanied by clinical symptoms indicative of impaired liver function. Disclosures: Maddrey: GlaxoSmithKline: Consultancy. Cheng:GlaxoSmithKline: Research Funding. Wroblewski:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.