National Specialized Hospital for Active Treatment of Hematologic Diseases

The WIL-31 study demonstrated efficacy and safety of prophylaxis with the plasma-derived von Willebrand factor/factor VIII concentrate wilate in von Willebrand disease (VWD) of all types and was the only prospective study with an on-demand run-in study as an intra-individual comparator. This subgroup analysis examines the efficacy of wilate prophylaxis in patients with type 3 VWD in WIL-31. Patients received 20-40 IU/kg wilate prophylaxis 2-3 times weekly for 12 months. Twenty-two patients in WIL-31 had type 3 VWD. Mean total annualized bleeding rate (ABRs) during on-demand versus prophylaxis was 37.1 versus 5.2 (86% reduction). During prophylaxis, 115 bleeds occurred, most (95%) of which were minor; the most common bleeding site was the nose (40% of bleeds). Mean overall spontaneous ABRs during on-demand versus prophylaxis were 26.5 versus 2.8 (89% reduction); mean treated spontaneous ABRs were 20.3 versus 1.4, respectively (93% reduction). ABRs were reduced further during the second 6 months of prophylaxis versus the first 6 months. Results were consistent in subgroups by age. No serious adverse events related to study treatment and no thrombotic events were observed. Prophylaxis with wilate was effective and well tolerated in patients with type 3 VWD, in all age groups. NCT04052698; https://clinicaltrials.gov/study/NCT04052698.

Background. Type 2 diabetes mellitus (T2D) and moderate-to-severe obstructive sleep apnea (OSA) commonly coexist and exacerbate poor glycemic control, systemic inflammation, and diminished quality of life (QoL). Although continuous positive airway pressure (CPAP) therapy has demonstrated metabolic and anti-inflammatory benefits, its real-world impact in Bulgarian outpatient settings—where CPAP costs are borne entirely by patients—has not been characterized. Objectives. To evaluate the effects of six months of CPAP therapy on glycemic control (hemoglobin A1c [HbA1c]), systemic inflammation (high-sensitivity C-reactive protein [hsCRP]), body mass index (BMI), lipid profile (low-density lipoprotein [LDL]), QoL (Short Form 36 Physical Component Summary [SF-36 PCS] and Mental Component Summary [SF-36 MCS]), and survival among Bulgarian outpatients with T2D and moderate-to-severe OSA. Methods. In this prospective, multicenter cohort study conducted from January 2022 to July 2023, 142 adults with established T2D and OSA (apnea–hypopnea index [AHI] ≥ 15) were enrolled at three outpatient centers in Bulgaria. Fifty-five patients elected to purchase and use home-based CPAP (intervention group), while 87 declined CPAP—either because of cost or personal preference—and continued standard medical care without CPAP (control group). All participants underwent thorough outpatient evaluations at baseline (month 0) and at six months, including measurement of HbA1c, hsCRP, BMI, fasting lipid profile (LDL), and patient-reported QoL, via the SF-36 Health Survey. Survival was tracked throughout follow-up. Results. After six months, the CPAP group experienced a significant reduction in HbA1c from a median of 8.2% (IQR 7.5–9.5%) to 7.7% (6.7–8.7%), p < 0.001, whereas the control group’s HbA1c decreased modestly from a median of 8.6% (IQR 7.9–9.4%) to 8.3% (7.6–9.1%); p < 0.001), with a significant between-group difference at follow-up (p = 0.005). High-sensitivity CRP in the CPAP arm fell from a median of 2.34 mg/L (IQR 1.81–3.41) to 1.45 mg/L (IQR 1.25–2.20), p < 0.001, while remaining unchanged in controls (p = 0.847). BMI in the CPAP group declined significantly from 28.6 kg/m2, IQR 26.6–30.6 to 28 kg/m2, IQR 25.6–29.2 (p < 0.001), compared to no significant change in controls (median 28.9 kg/m2), p = 0.599. LDL decreased in the CPAP group from a median of 3.60 mmol/L (IQR 3.03–3.89) to 3.22 mmol/L (IQR 2.68–3.48), p < 0.001, with no significant reduction in controls (p = 0.843). Within the CPAP arm, both SF-36 PCS and SF-36 MCS scores improved significantly from baseline (p < 0.001 for each), although between-group differences at six months did not reach statistical significance (PCS: 48 ± 10 vs. 46 ± 9, p = 0.098; MCS: 46, IQR 40–54 vs. 46, IQR 39–53, p = 0.291). All-cause mortality during follow-up included 2 events in the CPAP group and 11 events in the control group (log-rank p = 0.071). Conclusions. In Bulgarian outpatients with T2D and moderate-to-severe OSA, six months of CPAP therapy significantly improved glycemic control, reduced systemic inflammation, lowered BMI and LDL, and enhanced QoL, with a non-significant trend toward reduced mortality. These findings underscore the importance of integrating CPAP into multidisciplinary management despite financial barriers.

MGTA-145 or GROβT, a CXCR2 agonist, has shown promising activity for hematopoietic stem cell (HSC) mobilization with plerixafor in pre-clinical studies and healthy volunteers. Twenty-five patients with multiple myeloma enrolled in a phase 2 trial evaluating MGTA-145 and plerixafor for HSC mobilization (NCT04552743). Plerixafor was given subcutaneously followed 2 h later by MGTA-145 (0.03 mg/kg) intravenously with same day apheresis. Mobilization/apheresis could be repeated for a second day in patients who collected <6 ×106 CD34+ cells/kg. Lenalidomide and anti-CD38 antibody were part of induction therapy in 92% (n = 23) and 24% (n = 6) of patients, respectively. Median total HSC cell yield (CD34+ cells/kg × 106) was 5.0 (range: 1.1–16.2) and day 1 yield was 3.4 (range: 0.3–16.2). 88% (n = 22) of patients met the primary endpoint of collecting 2 ×106 CD34+ cells/kg in ≤ two days, 68% (n = 17) in one day. Secondary endpoints of collecting 4 and 6 × 106 CD34+ cells/kg in ≤ two days were met in 68% (n = 17) and 40% (n = 10) patients. Grade 1 or 2 adverse events (AE) were seen in 60% of patients, the most common AE being grade 1 pain, usually self-limited. All 19 patients who underwent transplant with MGTA-145 and plerixafor mobilized HSCs engrafted successfully, with durable engraftment at day 100. 74% (17 of 23) of grafts with this regimen were minimal residual disease negative by next generation flow cytometry. Graft composition for HSCs and immune cells were similar to a contemporaneous cohort mobilized with G-CSF and plerixafor.

Psoriasis is a common, life-long skin disease with a significant negative health and societal impact. Data on rates of disease control and treatment strategies are lacking in Central and Eastern European countries. We aimed to describe the real-world disease severity, control, and treatment strategies for psoriasis in patients from Central and Eastern European countries. CRYSTAL (EUPAS36459) was a cross-sectional, retrospective study in adults (18-75 years) from Bulgaria, Estonia, Hungary, Latvia, Lithuania, Romania, and Russia. We enrolled patients with moderate-to-severe psoriasis receiving continuous systemic treatment for ≥24 weeks. We used the Psoriasis Area and Severity Index (PASI) to describe disease severity and the Dermatology Life Quality Index (DLQI) to assess quality of life (QoL) and collected other outcomes [psoriasis work productivity and activity impairment (WPAI-PSO), patient satisfaction] at enrollment. Analyses were descriptive. A total of 690 patients were included in the analyses. Median disease duration was 11.8 years. Current treatment was monotherapy for most patients (95.8%) with either biological (BIO group; 88.4%) or conventional (NON-BIO group; 7.4%) agents. Mean (± standard deviation) absolute PASI scores were 3.5 ± 5.7, 3.1 ± 5.3, and 6.6 ± 7.4 in the overall population, the BIO group, and the NON-BIO group, respectively. Among patients treated with monotherapy, absolute PASI scores ≤1, ≤3, and ≤5 were observed for 44.1%, 72.0%, and 82.6% of BIO patients and 21.6%, 33.3%, and 49.0% of NON-BIO patients. Mean DLQI total score was 3.3 ± 5.1; higher scores were noted for higher absolute PASI. The most impacted WPAI-PSO domain was presenteeism; for all domains, impact increased with increased absolute PASI. A total of 91.8% of BIO patients and 74.5% of NON-BIO patients were satisfied with the current treatment. We observed a better disease control in BIO than NON-BIO patients. However, around half of BIO patients did not reach clear skin status and reported an impact on QoL. An improvement in treatment strategies is still needed in Central and Eastern European countries to optimize outcomes of moderate-to-severe psoriasis.

We aimed to investigate the expression of pro-inflammatory cytokine genes TNFA, IL6, IL12B, IL23, IL18 and immunoregulatory genes FOXP3, TGFB1, and IL10 in the peripheral blood of patients with rheumatoid arthritis (RA) at messenger ribonucleic acid (mRNA) level. The total RNA was isolated from peripheral blood samples. Real-time quantitative PCR was used to perform TaqMan-based assays to quantify mRNAs from 8 target genes. IL23A was upregulated (1.7-fold), whereas IL6 (5-fold), FOXP3 (4-fold), and IL12B (2.56-fold) were downregulated in patients compared to controls. In addition, we found a strong positive correlation between the expression of FOXP3 and TNFA and a moderate correlation between FOXP3 and TGFB1. These data showed the imbalance of the T helper (Th) 1/Th17/ T regulatory (Treg) axis at a systemic level in RA. In cases with active disease, the IL10 gene expression was approximately 2-fold higher; in contrast, the expression of FOXP3 was significantly decreased (3.38-fold). The main part of patients with higher disease activity expressed upregulation of IL10 and downregulation of TNFA. Different disease activity cohorts could be separated based on IL10, TNFA and IL12B expression combinations. In conclusion, our results showed that active disease is associated with an elevated IL10 and lower TNFA mRNA level in peripheral blood cells of RA patients.

IntroductionSurging HIV prevalence across countries of Central and Eastern Europe (CEE) is largely a result of poor HIV care engagement and a lack of comprehensive support for key populations. This is fostered by widespread stigma across healthcare, community, and legislative settings.DiscussionThroughout CEE, HIV stigma and intersectional stigma are serious obstacles to providing adequate medical care to people living with HIV. Anticipated and enacted (experienced) stigma from healthcare professionals, and fears of breaches in confidentiality, deter individuals from having an HIV test and engaging in HIV care. Furthermore, negative connotations surrounding HIV infection can lead to discrimination from family, friends, colleagues, and the public, leading to internalized stigma and depression. Key populations that have higher HIV prevalence, such as men who have sex with men, people who inject drugs, transgender individuals, and sex workers, experience additional stigma and discrimination based on their behaviour and identities. This contributes to the concentrated HIV epidemics seen in these populations in many CEE countries. The stigma is exacerbated by punitive legislation that criminalizes HIV transmission and penalizes sexual orientation, drug use, gender identities, and sex work. Despite high levels of HIV stigma and intersectional stigma, there are many evidence-based interventions that have reduced stigma in other parts of the world. Here, we discuss the interventions that are currently being enacted in various countries of CEE, and we suggest additional effective, evidence-based interventions that will tackle stigma and lead to increased HIV care engagement and higher rates of viral suppression. We cover the promotion of the undetectable = untransmittable (U = U) message, stigma-reduction education and training for healthcare professionals, patient-centric approaches for testing and treatment, and advocacy for non-discriminatory legislation, policies, and practices. We also consider targeted stigma-reduction interventions that acknowledge the wider challenges faced by marginalized populations.ConclusionsHIV stigma and intersectional stigma in CEE drive poor engagement with HIV testing services and care. Widespread adoption of evidence-based interventions to tackle stigma highlighted in this review will improve the quality of life of people living with HIV, improve HIV care engagement, and ultimately slow the surging HIV prevalence and concentrated epidemics occurring throughout CEE.

Цел: Миелопролиферативните неоплазии (МПН) са хетерогенна група клонални заболявания на хемопоетичните стволови клетки, характеризиращи се с повишена пролиферация на клетки от миелоидния ред в костния мозък (КM). Ph-негативните MПН са най-честият рисков фактор за тромбоза на вена лиеналис (ТВЛ), включваща синдром на Бъд-Киари (БКС) и тромбоза на порталната вена (ТПВ). Редица проучвания разглеждат ролята на различните етиологични и рискови фактори за ТВЛ, включващи придобити протромботични състояния, наследствена тромбофилия и локални заболявания. Настоящото съобщение описва рядко срещан клиничен случай на пациентка с 3 рискови фактора за БКС: Ph-нег. МПН, причинена от придобита мутация JAK2V617F, наследствено нарушение на кръвосъсирването, фактор V Leiden мутация, и употреба на хормонална контрацепция.&#x0D; Материал и методи: Диагностично-терапевтичният алгоритъм при конкретната пациентка прецизно следва актуалните препоръки за поведение при това състояние, включващо и оценка на всички възможни протромботични рискови фактори.&#x0D; Резултати: Пациентката продължава своето регулярно проследяване от гастроентеролог и хематолог, поддържайки добро качество на живот без нови тромботични инциденти и нормални хематологични показатели.&#x0D; Заключение: Представеният клиничен случай потвърждава ролята на рутинния скрининг за МПН при ТВЛ. Откроява необходимост от извършване на скрининг за вродена тромбофилия, независимо от JAK2 статуса на пациента, поради вероятността за мултифакторна генеза на тромбообразуване при тези състояния, които от своя страна налагат прилагането на различни по механизъм на действие антитромботични терапии.

There are currently three thrombopoietin receptor agonists (TPO-RAs) approved in Europe for treating patients with immune thrombocytopenia (ITP): romiplostim (Nplate®), eltrombopag (Revolade®), and avatrombopag (Doptelet®). However, comparative clinical data between these TPO-RAs are limited. Therefore, the purpose of this study was to perform a literature review and seek expert opinion on the relevance and strength of the evidence concerning the use of TPO-RAs in adults with ITP. A systematic search was conducted in PubMed and Embase within the last 10 years and until June 20, 2022. A total of 478 unique articles were retrieved and reviewed for relevance. The expert consensus panel comprised ITP senior hematologists from eight countries across Central Europe. The modified Delphi method, consisting of two survey rounds, a teleconference and email correspondence, was used to reach consensus. Forty articles met the relevancy criteria and are included as supporting evidence, including five meta-analyses analyzing all three European-licensed TPO-RAs and comprising a total of 31 unique randomized controlled trials (RCTs). Consensus was reached on seven statements for the second-line use of TPO-RAs in the management of adult ITP patients. In addition, the expert panel discussed TPO-RA treatment in chronic ITP patients with mild/moderate COVID-19 and ITP patients in the first-line setting but failed to reach consensus. This work will facilitate informed decision-making for healthcare providers treating adult ITP patients with TPO-RAs. However, further studies are needed on the use of TPO-RAs in the first-line setting and specific patient populations.

Background: Patients with multiple myeloma are poor mobilizers and often require multiple cytapheresis procedures. Most popular mobilization regimens are with G-CSF given as a sole treatment or in combination with cyclophosphamide. Recently, several reports indicated that higher yields could be obtained following chemomobilization with cytarabine and G-CSF. Aims: Our aim was to compate the effectiveness of chemomobilization with cytarabine and G-CSF with the other regimens which we have used. Methods: Patients received 2x400mg/m2 cytarabine for two days, followed by 5mcg/kg G-CSF two days after for at least nine days. Cytapheresis was initiated with WBC count above 5x109/L, PLT count above 30x109/L and CD34+ cell count above 20/µl. Results of this group of patients were compared with results from a historic group of myeloma patients harvested between 2018 and 2020. Results: The new regimen showed markedly higher initial counts of CD34+ cells resulting in significantly better average yields (12.6x10^6/kg for the cytarabine + G-CSF group; 3.98 x10^6/kg for the G-CSF group and 4.998 x10^6/kg for the Cyclophosphamide+ G-CSF group). Summary/Conclusion: Compared with other hematological malignancies, patients with multiple myeloma are hard to mobilize for collection of sufficient CD34+ cells. Possible explanations are advanced age and bone marrow involvement. Chemomobilization with cytarabine and G-CSF seem to overcome poor mobilization and collection yields for this patient group.

Introduction: The COVID-19 pandemic has been challenging time for medical care, especially in the field of infectious diseases (ID), but it has also provided an opportunity to introduce new solutions in HIV management. Here, we investigated the changes in HIV service provision across Central and Eastern European (CEE) countries before and after the COVID-19 outbreak. Methods: The Euroguidelines in Central and Eastern Europe Network Group consists of experts in the field of ID from 24 countries within the CEE region. Between 11 September and 29 September 2021, the group produced an on-line survey, consisting of 32 questions on models of care among HIV clinics before and after the SARS-CoV-2 outbreak. Results: Twenty-three HIV centers from 19 countries (79.2% of all countries invited) participated in the survey. In 69.5% of the countries, there were more than four HIV centers, in three countries there were four centers (21%), and in four countries there was only one HIV center in each country. HIV care was based in ID hospitals plus out-patient clinics (52%), was centralized in big cities (52%), and was publicly financed (96%). Integrated services were available in 21 clinics (91%) with access to specialists other than ID, including psychologists in 71.5% of the centers, psychiatrists in 43%, gynecologists in 47.5%, dermatologists in 52.5%, and social workers in 62% of all clinics. Patient-centered care was provided in 17 centers (74%), allowing consultations and tests to be planned for the same day. Telehealth tools were used in 11 centers (47%) before the COVID-19 pandemic outbreak, and in 18 (78%) after (p = 0.36), but were represented mostly by consultations over the telephone or via e-mail. After the COVID-19 outbreak, telehealth was introduced as a new medical tool in nine centers (39%). In five centers (28%), no new services or tools were introduced. Conclusions: As a consequence of the COVID-19 pandemic, tools such as telehealth have become popularized in CEE countries, challenging the traditional approach to HIV care. These implications need to be further evaluated in order to ascertain the best adaptations, especially for HIV medicine.