Topic: 10. Myelodysplastic syndromes - Clinical Background: Hyperchromic anemia is one of the most common anemias in the emergency department. While the diagnosis of anemia itself is not difficult, the elucidation of its causes is a difficult clinical task. This is largely due to the lack of a clear understanding of the variety of causes that lead to similar red blood cell color characteristics. In this regard, the differential diagnosis of hyperchromic anemia, which is associated only with cyancobalamin/folic acid deficiency, seems relevant. Aims: to study the nosology of patients diagnosed with hyperchromic macrocytic anemia (HMA). To evaluate clinical, laboratory blood and bone marrow parameters in patients with HMA. Methods: From 01/2021 to 11.2021, 2358 therapeutic patients were admitted to the V.M. Buyanova Hospital, of whom 377 (16%) were patients diagnosed with anemia, of whom 57 (15%) were patients with hyperchromic anemia. Fifty-seven(15%) HMA patients were included in the study. 24 males and 33 females. The age of the patients ranged from 21 to 93 years (Me 70). B12 and folic acid levels were below normal in all patients. All 57 patients underwent bone marrow examination. According to the results of myelogram data the patients were divided into 3 groups: Group 1 38 patients with true B12 folate deficiency anemia, Group 2 11 patients appeared with myelodysplastic syndrome/acute myeloid leukemia (MDS/OML), Group 3 10 patients appeared with secondary HMA (toxic, nephrotic, after chemotherapy). Results: We compared the data of the 1st and 2nd groups of patients. The sex composition of both groups did not differ. The age of patients in Group 1 ranged from 32 to 93 years (Me 70), in Group 2 the age was 50-90 years (Me 79). The hemoglobin level in group 1 ranged from 33 to 90 g/dl (Me 60), and in group 2 it was 36-86 g/dl (Me 57). Erythrocyte count in group 1 ranged from 0.85 to 2.35 x 1012/l (Me-1.57), in group 2 from 0.87 to 2.57 (Me-1.53). Platelet count in group 1 ranged from 24 to 253 x 109/l (Me- 114), in group 2 was 8- 225 x 109/l was from (Me- 54) the differences were statistically significant - p=0.029. Leukocyte levels in group 1 were 1.6 to 8.0 x 109/l (Me- 4.1), in group 2 were 0.8 to 11.8 x 109/l. LDH levels in group 1 ranged from 344 to 13130 units/l (Me - 4400), in group 2 - 306 to 3022 units/l (Me - 672) differences were statistically significant p=0.004. Hypercellular bone marrow in group 1 was in 26 patients (68%), in group 2 - in 1 patient (11%). The difference is statistically significant p=0.008 The number of blast cells in myelogram in the 1st group did not exceed 2% (Me-1.6%), in the 2nd group ranged from 7 to 82% (Me - 21%), the difference is statistically reliable p=0.001 The level of megaloblasts in group 1 ranged from 2 to 57(Me 33), in group 2 from 10 to 21(Me-15). The overall 2-year survival rate in group 1 was 73%, while in group 2 only 43% p=0.001 Summary/Conclusion: Despite the availability of vitamin B12 and folic acid testing, patients with HMA require in-depth examination. Thus, 16% of patients with HMA were found to have myeloproliferative diseases - MDS/OML. The overall 2-year survival rate of patients with MDS/OML against GMA background is extremely low. Anemia of extremely severe degree, thrombocytopenia, LDH level not exceeding 2 norms should be an indication for bone marrow hematopoiesis investigation Keywords: Anemia, MDS

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: HCV is involved in the oncogenesis of a number of malignant non-Hodgkin’s lymphomas. HCV+ MZL associated with chronic hepatitis C infection. There are a number of unresolved issues in the treatment of pts with HCV+ MZL: 1 start with antiviral therapy(AT) or immunochemotherapy; 2 If with AT, what to start in the first line of AT: interferon ribaverin or direct-acting antiviral drugs (DAAs)? Or a combination of DAAs and interferon. Data on the effectiveness of DAAs and long-term results of treatment of pts with HCV+ MZL are limited. Aims: The aim of our work was to conduct a prospective study to evaluate the efficacy of DAAs on both virus elimination and antitumor response. To evaluate the possibility of enhancing the antitumor effect of DAAs. Methods: Twenty-three HCV+ MZL pts were included in our study. The median age was 54 years (31-75 years), 47% male, stage III-IV were in 19(82%) pts, B-symptoms were in 8 (35%). Spleen and bone marrow lesions were 14(61%)pts, liver lesions were 13(56%). Elevated ALT levels were in 21(91%) pts, AST in 16(69%), GGTP in 8(35%) LDH in 21(91%). Reduced platelet (PT)count was in 16(69%) pts, red blood cell count was reduced in 9(39%) pts. Liver cirrhosis was in 4(17%)pts. Genotype 1 was in 17(74%), genotype 2 + 3 in 6(26%) pts. Previously published results Blood. 2022 Feb 3;139(5):732-747. indicate that the HCV+ MZL group was significantly younger, had more advanced stages, and bone marrow and liver lesions were more common. Elevations of ALT, AST, GGTP, LDH were also significantly higher in the HCV+ MZL pts. Reduced erythrocyte and PT levels were significantly more common in the HCV+ MZL pts. All pts started treatment with DAAs (sofosbuvir + lidipasvir or sofosbuvir + valpatosvir). The duration of therapy was 6 to 8 mths. Results: Complete elimination of the virus was observed in all 23 (100%) pts. The maximum time to achieve virologic remission was 2 mths. The overall rate of antitumor response (complete + partial remissions of CR + PR) on DAA therapy was obtained in 14(62%) pts. The median achievement of remission was 4.5 mths. In 9 pts with splenomegaly (more than 18 cm) only tumor stabilization was achieved. INF was combined to DAA therapy in these 9 pts. CR+PR was achieved in 7 of 9 pts. The overall 4-year survival rate was 92%. The 4-year PFS was 62%. Summary/Conclusion: AT is the preferred first-line therapy in pts with HCV+MZL. Because of its safety, the rate of complete virologic response, DAAs should be considered first-line therapy. If there is no antitumor effect from DAAs, IFNs may be combined. Keywords: Low-grade NHL, Hepatitis C virus

BACKGROUND: Coronavirus disease 2019 (COVID-19) causes a hypercoagulable state with a high incidence of thrombotic complications. Patients with a history of myocardial revascularization have more severe complications due to COVID-19. Coronary stent thrombosis has become significantly more common during the COVID-19 pandemic. AIM: The aim of our study is to analyze scientific information on the risks of stent thrombosis in patients who underwent COVID-19. METHODS: A search was made for scientific publications in evidence-based medicine databases and web resources: PubMed, MEDLINE, UpToDate, TripDatabase, ResearchGate, and Google Scholar. Inclusion criteria were: (1) Observational studies or case series involving patients with a confirmed diagnosis of COVID-19 and myocardial infarction requiring myocardial revascularization; (2) the division of the population into survivors and non-survivors; and (3) data on the presence of the previous myocardial revascularization. Exclusion criteria: Case description and editorials/bulletins. In all articles selected for further analysis, 49 sources were considered that met the inclusion criteria and excluded duplication or repetition of information. RESULTS: Coronavirus infection has contributed to the change in the course of myocardial infarction in patients undergoing myocardial revascularization. The incidence of stent thrombosis has a positive correlation with the severity of the coronavirus infection. The previous myocardial revascularization procedures significantly increase the risk of mortality in patients with coronavirus infection. This is especially actual for elderly patients. CONCLUSION: One of the most vulnerable groups is elderly patients who have undergone myocardial revascularization after myocardial infarction in the past and have concomitant diseases. An analysis of scientific publications has shown that further larger-scale clinical studies are needed to confirm the hypothesis about the negative impact of coronavirus infection on stent thrombosis in patients who have undergone COVID-19.

This Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon α-2a (PegIFNα-2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients.

AIM:To evaluate addition of boceprevir to peginterferon/ribavirin (PR) in Russian patients with chronic hepatitis C virus (HCV).METHODS:Treatment-naive (TN) and treatment-experienced (TE) patients (who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebo-controlled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. TN patients randomized to triple therapy received boceprevir (800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8 (TW8) HCV RNA levels. TE patients received boceprevir plus PR for 32 wk and then further therapy according to TW8 HCV RNA levels. Treatment was discontinued for TN patients with detectable HCV RNA at TW24 and TE patients with detectable HCV RNA at TW12 because of futility. The primary efficacy end point was sustained virologic response (SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy.RESULTS:SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2% (95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both TN and TE patient groups (TN 78.4% vs 56.3%; TE 69.4% vs 30.0%). Within TE patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type (null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both TN (86%) and TE (71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone (47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia (< 10 g/dL) and those without anemia (71.2% vs 77.4%).CONCLUSION:Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study.

BACKGROUND:A randomized, double-blind, multinational, phase 3 study was conducted comparing the efficacy and safety of peginterferon lambda-1a (Lambda)/ribavirin (RBV)/telaprevir (TVR) vs. peginterferon alfa-2a (Alfa)/RBV/TVR in patients with chronic hepatitis C virus (HCV) genotype-1 (GT-1) infection.METHODS:Patients (treatment-naïve or relapsers on prior Alfa/RBV treatment) were randomly assigned in a 2:1 ratio to receive Lambda/RBV/TVR or Alfa/RBV/TVR. Total duration of treatment was either 24 or 48 weeks (response-guided treatment), with TVR administered for the first 12 weeks. The primary endpoint was the proportion of patients who achieved a sustained virologic response at post treatment week 12 (SVR12), which was tested for noninferiority of Lambda/RBV/TVR.RESULTS:A total of 838 patients were enrolled, and 617 were treated; 411 and 206 patients received Lambda/RBV/TVR and Alfa/RBV/TVR, respectively. The majority of patients were treatment-naïve, with HCV GT-1b and a high baseline viral load (≥800,000 IU/mL). Less than 10% of patients had cirrhosis (Lambda, 7.5%; Alfa, 6.8%). Lambda/RBV/TVR did not meet the criterion for noninferiority (lower bound of the treatment difference interval was -12.3%); the SVR12 in all patients (modified intent-to-treat) was 76.2% in the Lambda arm and 82.0% in the Alfa arm. Overall, the frequency of adverse events in each arm was comparable (Lambda, 91.7%; Alfa, 97.1%). As expected based on the safety profile of the 2 interferons, there were more hepatobiliary events observed in the Lambda arm and more hematologic events in the Alfa arm.CONCLUSIONS:In this comparison of Lambda/RBV/TVR and Alfa/RBV/TVR in patients who were treatment-naïve or had relapsed on prior Alfa/RBV treatment, Lambda failed to demonstrate noninferiority based on SVR12 results. Treatment with Lambda/RBV/TVR was associated with a higher incidence of relapse. More patients discontinued Lambda/RBV/TVR treatment during the first 4 weeks of study treatment, mainly due to hepatobiliary-related events, and more Lambda patients were lost to follow-up.

В статье рассматриваются замкнутые классы полиномов первой степени над кольцами A=Z,Q,R, сохраняющих разбиения множества A, в которых ровно одно подмножество бесконечно, а число конечных подмножеств конечно. Устанавливается состав классов. Также доказывается алгоритмическая неразрешимoсть распознавания сохранения полиномом произвольной степени таких разбиений над кольцом Z.

В статье рассматриваются замкнутые классы полиномов первой степени над кольцами A=Z,Q,R, сохраняющих разбиения множества A, в которых ровно одно подмножество бесконечно, а число конечных подмножеств конечно. Устанавливается состав классов. Также доказывается алгоритмическая неразрешимoсть распознавания сохранения полиномом произвольной степени таких разбиений над кольцом Z.

BACKGROUND & AIMS: Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in phase III trials for chronic hepatitis C virus (HCV) infection. We performed a phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-alpha 2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV. METHODS: We analyzed data from patients who did not respond (null response), had a partial response, or relapsed after treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n = 396), or placebo plus PegIFN and RBV for 48 weeks (n = 66). All patients were followed for 24 weeks after planned end of treatment; the primary end point was the proportion of patients with sustained virologic response (SVR; undetectable HCV RNA) at that time point. RESULTS: Overall, rates of SVR at 24 weeks were significantly higher in the groups given simeprevir than those given placebo (61%-80% vs 23%; P < .001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%-59% vs 19%; prior partial response, 48%-86% vs 9%; prior relapse, 77%-89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo. CONCLUSIONS: In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, and RBV and was generally well tolerated. ClinicalTrials.gov number: NCT00980330.

Hepatitis C virus (HCV) infected patients often take multiple co-medications to treat adverse events related to HCV therapy, or to manage other co-morbidities. Drug–drug interactions associated with this polypharmacy are relatively new to the field of HCV pharmacotherapy. With the advent of the direct-acting antivirals telaprevir and boceprevir, which are both substrates and inhibitors of the cytochrome P450 (CYP) 3A iso-enzyme, knowledge and awareness of drug–drug interactions have become a cornerstone in the evaluation of patients starting and continuing HCV combination therapy. In our opinion, an overview of conducted drug–drug interaction studies and a list of contraindicated medications is not enough for the clinical management of these drug–drug interactions. Knowledge of pharmacokinetic profiles and concentration–effect relationships is key for the interpretation of these data, and insight into how to manage these interactions (e.g., dose adjustments, safe alternatives and therapeutic drug monitoring) is of equal importance. This review provides a practical overview of the safe and effective management of these clinical challenges.

The phase IIb, double-blind, placebo-controlled PILLAR trial investigated the efficacy and safety of two different simeprevir (SMV) doses administered once-daily (QD) with pegylated interferon (Peg-IFN)--2a and ribavirin (RBV) in treatment-naive patients with HCV genotype 1 infection. Patients were randomized to one of five treatments: SMV (75 or 150 mg QD) for 12 or 24 weeks or placebo, plus Peg-IFN and RBV. Patients in the SMV arms stopped all treatment at week 24 if response-guided therapy (RGT) criteria were met; patients not meeting RGT continued with Peg-IFN and RBV until week 48, as did patients in the placebo control group. Sustained virologic response (SVR) rates measured 24 weeks after the planned end of treatment (SVR24) were 74.7%-86.1% in the SMV groups versus 64.9% in the control group (P < 0.05 for all comparisons [SMV versus placebo], except SMV 75 mg for 24 weeks). Rapid virologic response (HCV RNA <25 IU/mL undetectable at week 4) was achieved by 68.0%-75.6% of SMV-treated and 5.2% of placebo control patients. According to RGT criteria, 79.2%-86.1% of SMV-treated patients completed treatment by week 24; 85.2%-95.6% of these subsequently achieved SVR24. The adverse event profile was generally similar across the SMV and placebo control groups, with the exception of mild reversible hyperbilirubinemia, without serum aminotransferase abnormalities, associated with higher doses of SMV. Conclusion: SMV QD in combination with Peg-IFN and RBV significantly improves SVR rates, compared with Peg-IFN and RBV alone, and allows the majority of patients to shorten their therapy duration to 24 weeks. (Hepatology 2013; 58:1918-1929)

1376 THE ASPIRE TRIAL: TMC435 IN TREATMENT-EXPERIENCED PATIENTS WITH GENOTYPE-1 HCV INFECTION WHO HAVE FAILED PREVIOUS PEGIFN/RBV TREATMENT S. Zeuzem, G.R. Foster, M.W. Fried, C. Hezode, G.M. Hirschfield, I. Nikitin, F. Poordad, O. Lenz, M. Peeters, V. Sekar, G. De Smedt. J.W. Goethe University Hospital, Frankfurt, Germany; Queen Mary, University of London, London, UK; University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Hopital Henri-Mondor, Universite Paris-Est Creteil, Creteil, France; Toronto Western Hospital Liver Centre, Toronto, ON, Canada; Russian State Medical University, Moscow, Russia; Cedars-Sinai Medical Center, Los Angeles, CA, USA; Tibotec BVBA, Mechelen, Belgium; Tibotec Inc, Yardley, PA, USA E-mail: zeuzem@em.uni-frankfurt.de

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