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Objectives Acute myeloid leukemia (AML) is a highly heterogeneous disease. Although patients can be classified into risk groups based on their genetic changes, the prognosis of disease within these categories varies widely. This situation raises the need to search for new molecular markers related to AML. Serine peptidase inhibitor Kazal type 2 (SPINK2) has recently been reported to be upregulated in AML and associated with poor outcomes by meta-analysis and in a limited number of AML patients. Methods We analyzed SPINK2 mRNA expression in 62 patients (45 adult and 17 pediatric) with AML and 11 cell lines using quantitative Real-Time PCR (qRT-PCR). SPINK2 protein level was determined using ELISA in cell lines. Results We found that the expression of SPINK2 mRNA and protein levels in AML cell lines (HL60 and NB4) have increased compared to other cell lines (K562, Jurkat and NALM6, MCF7, HeLa, HUVEC, hFOB, 293T, U87). SPINK2 mRNA expression was upregulated in patients with AML compared to controls (p=0.004) and significantly lower in t(8;21)-positive patients compared to negative patients (p=0.0006). Conclusions Our results suggest that SPINK2 serves an important role in AML development. Further studies are needed to evaluate SPINK2 expression in AML patients with t(8.21) and investigate to clarify its prognostic value in various subgroups of AML.

Resumen Objectivos La leucemia mieloide aguda (AML, por sus siglas en inglés) es una enfermedad muy heterogénea. Aunque se puede clasificar a los pacientes en grupos de riesgo según sus mutaciones genéticas, el pronóstico dentro de cada categoría varía sustancialmente. Es perentorio identificar nuevos marcadores moleculares de la AML. Recientemente, se ha descrito la elevación del inhibidor de la serina peptidasa Kazal tipo 2 (SPINK2) en la AML, habiendo sido relacionada con peores resultados clínicos en metaanálisis, así como en un número limitado de pacientes con AML. Métodos Analizamos la expresión de SPINK2 en 62 pacientes (45 adultos y 17 niños) con AML y en 11 líneas celulares mediante PCR cuantitativa (qRT-PCR). Los niveles de la proteína SPINK2 se determinaron en líneas celulares mediante ELISA. Resultados Observamos un aumento de expresión del ARNm de SPINK2 y de los niveles de la proteína en las líneas celulares de AML (HL60 y NB4), frente a otras líneas celulares (K562, Jurkat y NALM6, MCF7, HeLa, HUVEC, hFOB, 293T, U87). Los pacientes con AML mostraron una expresión elevada de ARNm de SPINK2 frente a los controles (p=0,004) y esta fue significativamente menor en los pacientes t(8;21) positivos, frente a los pacientes negativos (p=0,0006). Conclusions Estos resultados sugieren que el gen SPINK2 tiene un papel relevante en el desarrollo de la AML. Son necesarios más estudios para evaluar la expresión de SPINK2 en los pacientes con AML con la mutación t(8.21) e investigar su valor pronóstico en varios subgrupos de pacientes con AML.

Hyper immunoglobulin M (HIGM) syndrome is a rare disorder of the immune system with impaired antibody functions. The clinical picture of the patients varies according to the underlying genetic variation. In this study, we identified two novel variants in AID and UNG genes, which are associated with autosomal recessive type HIGM, by targeted next-generation sequencing (NGS) panel. A biallelic 11 base pair deletion (c.278_288delATGTGGCCGAC) in the coding sequence of activation-induced cytidine deaminase (AID) gene was identified in a 36-year-old patient. Biallelic two base pair insertion in exon 7 of uracil nucleoside glycosylase (UNG) gene (c.924_925insGG) was identified in a 40-year-old patient. Both variants were confirmed by Sanger sequencing. HIGM, like many of the other primary immunodeficiencies, is a rare and difficult-to-diagnose entity with heterogeneous clinical phenotypes. It should be suspected in patients with a history of early-onset recurrent respiratory infections, enlarged lymph nodes, and autoimmune disorders. There might be a delay in diagnosis until adulthood especially in subtle cases or if HIGM is not included in the differential diagnosis due lacking of awareness. In this regard, genetic testing with NGS-based diagnostic panels provide a rapid and reasonable tool for the molecular diagnosis of patients with immunodeficiencies and hence, decrease the time to diagnose and prevent infection-related complications associated with increased morbidity and mortality.

Introduction: Inherited factor VII (FVII) deficiency (FVIID) is the most common of inherited rare bleeding disorders. Other determinants of clinical severity apart from FVII level (FVIIL) include genetic and environmental factors. We aimed to identify the cut-off FVIILs for general and severe bleedings in patients with FVIID by using an online national registry system including clinical, laboratory, and demographic characteristics of patients. Methods: Demographic, clinical, and laboratory data of patients with FVIID extracted from the national database, constituted by the Turkish Society of Hematology, were examined. Bleeding phenotypes, general characteristics, and laboratory features were assessed in terms of FVIILs. Bleeding rates and prophylaxis during special procedures/interventions were also recorded. Results: Data from 197 patients showed that 46.2% of patients had FVIIL< 10%. Most bleeds were of mucosal origin (67.7%), and severe bleeds tended to occur in younger patients (median age: 15 (IQR:6-29)). Cut-off FVIILs for all and severe bleeds were 16.5% and 7.5%, respectively. The major reason for long-term prophylaxis was observed as central nervous system bleeding (80%). Conclusion: Our data are consistent with most of the published literature in terms of cut-off FVIIL for bleeding, as well as reasons for prophylaxis, showing both an increased severity of bleeding and younger age at diagnosis with decreasing FVIIL. However, in order to offer a classification similar to that in Hemophilia A or B, data of a larger cohort with information about environmental and genetic factors are required.

Acute haemolytic transfusion reactions (AHTR) are feared complications of packed red blood cell (PRBC) transfusions. This study aims to investigate the clinical consequences of the isolated enzyme-phase crossmatch incompatible PRBC transfusions by clinically observing all events during the study period at a single institution, with the primary aim of detecting AHTR. Ninety-four transfusions of interest were administered during the study period. Laboratory investigations were adequate in 73 episodes, where no AHTR developed and 1.1g/dl mean increment in haemoglobin concentration was documented. Three transfusions terminated prematurely; however, further investigations ruled out AHTR. The remaining 21 transfusions were also completed uneventfully without noteworthy clinical deterioration. This study's results provide clinical validation to omit pre-transfusion screening with the enzyme-phase crossmatch, document the safety and short-term efficacy of isolated enzyme-phase incompatible transfusions. The findings encourage future clinical research on understanding the long-term efficacy of such transfusions, which may be valuable for transfusion-dependant patients.

Background: TNF receptor superfamily member 13B ( TNFSRF13B ) is a member of the TNF superfamily which is crucial for B cell maturation, plasma cell differentiation and antibody response. Impaired expression of TNFRSF13B gene was associated with common variable immune deficiency (CVID), selective IgA deficiency, autoimmunity and/or lymphoproliferation disorders. Beside disease-causing variants of this gene, the polymorphisms can be associated with strong or weak TNFRSF13B expression that leads to unbalanced B cell response and increased autoreactive antibody production. Materials and Methods: Within the scope of this paper, we detect 26 variants (three synonymous, five missense, eleven UTR, seven intronic variants) in the TNFRSF13B gene by screening 80 pediatric and adult CVID patients. Results: Beyond categorization of these detected variants as likely benign, benign, or variant of uncertain significance, we perform an integrative bioinformatics approach to provide a plausible explanation for CVID associations of these detected variants from different perspectives, e.g. missense variants from a thermodynamical point of view, UTR variants from regulatory issues, synonymous variants in RNA binding perspectives and so on. 58% of (15/26) detected variants were altered regulatory elements, such as transcription factor binding or miRNA binding sites and splice site regions or thermodynamic impact on protein. Thirteen variants were found to have at least tenfold increased allele frequencies compared to global databases indicating TNFRSF13B variants which have a potential regulatory effect, more common in CVID patients. Conclusions: All findings have suggested that the presence of these variants may not be the causative variant for CVID phenotype but might be associated with minimal or moderate regulatory impacts on CVID patients. This study also emphasizes the importance of using the integrative bioinformatic approach to identify promising variants.

Hematopoietic stem cell transplantation (HSCT) is a risk factor for viral hepatitis reactivations because it affects lymphocyte number and functions. Latent hepatitis B virus (HBV) may stay in dormant form in hepatocytes and may be reactivated in prolonged immunosuppression. This study analyzes the incidence of reactivation of HBV infections in HSCT patients in a middle endemic country like Turkey. Five hundred and sixty-one HSCT patients from 1994 to 2015 were retrospectively evaluated. Sixty-six patients had a serologic feature of HBV infection. Fifteen patients were hepatitis B surface antigen (HBsAg)-positive patients (3 allogeneic and 12 autologous) while 51 of them were anti-hepatitis B core IgG (anti-HBc IgG)-positive patients (22 allogeneic and 29 autologous). Although under lamivudine prophylaxis, reactivation was seen in three of 12 (25%) chronic HBV (HBsAg positive) patients who received autologous HSCT and in two of the three HBsAg-positive patients who received allogeneic HSCT. Rate of reactivation in the whole HBsAg-positive group was 33%. Reactivation occurred on median 270th day (range: 60-730). Reverse seroconversion incidence was 10% on 133th day for HBsAg negative, but anti-HBc IgG-positive patients, which increased to 17% on 360th and to 23% on 1500th day. Cumulative incidence increased to 41% on 2280th day for isolated anti-HBc IgG-positive patients. Hepatitis B surface antibodies (anti-HBs) were found to be protective as reactivation did not exceed 11% on 5050th day when anti-HBs was positive. When anti-HBc IgG-positive cases were analyzed according to their transplantation types, allogeneic HSCT was found to have higher cumulative incidence (45% on 3258th day) for HBV reactivation than autologous HSCT (7% on 5050th day). Besides, HBV reactivation in anti-HBc IgG-positive patients who received allogeneic transplantation was related to mortality. Findings of this study suggest that HBV prophylaxis extending over 1 year should be prescribed for HBsAg-positive patients independent of the transplantation type. Prophylaxis should also be given to anti-HBc IgG-positive patients if an allogeneic HSCT is to be performed.

Simay Çokgezer,1 Tu&gbreve;rul Elverdi,2 Ay&scedil;e Saliho&gbreve;lu,2 Muhlis Cem Ar,2 &Scedil;eniz Öngören,2 Zafer Ba&scedil;lar,2 Ahmet Emre E&scedil;kazan2 1Department of Internal Medicine, Istanbul University-Cerrahpa&scedil;a, Cerrahpa&scedil;a Faculty of Medicine, Istanbul, Turkey; 2Division of Hematology, Department of Internal Medicine, Istanbul University-Cerrahpa&scedil;a, Cerrahpa&scedil;a Faculty of Medicine, Istanbul, TurkeyCorrespondence: Ahmet Emre E&scedil;kazan, Istanbul University-Cerrahpa&scedil;a, Cerrahpa&scedil;a Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Fatih, Istanbul, Turkey, Tel +90 533 722 73 76, Fax +90 212 589 79 34, Email emre.eskazan@iuc.edu.trIntroduction: The aim of this study was to evaluate treatment responses, toxicity, and survival among cHL patients aged ≥ 50 years.Methods: We retrospectively identified all newly diagnosed cHL patients and only included cases who were ≥ 50 years old at the time of diagnosis and with data available between 1999 and 2020.Results: There were 101 patients, of which 52 were between 50 and 59 years of age, and 49 patients were ≥ 60 years old. Sixty-two patients were male, and the most common histopathological subtype was mixed cellularity cHL (58.4%). ECOG PS, CCI, CIRS, and ACE-27 scores were significantly higher in patients aged ≥ 60 years than those of 50– 59 age group. While all patients aged 50– 59 years received ABVD as first-line therapy, 79% (n=39) of cases aged ≥ 60 years had ABVD. In patients receiving ABVD, 95% and 92.7% of the cases aged 50– 59 and ≥ 60 years had CR, respectively (p=0.999). Age groups were comparable in terms of hematological and non-hematological toxicities (p=0.369, p=0.127, respectively). Although not statistically significant, median survival was longer in patients receiving a transplant than in those without transplantation (108 months vs 52 months, p=0.069). In multivariate analysis, the risk of progression was higher in patients with lymphocyte ≤ 600/mm3 and in those who were unresponsive to first-line therapy (p=0.002 and p< 0.001, respectively). Patients with B symptoms, age ≥ 60 years, and CIRS > 3 had higher risk of mortality (p=0.001, p=0.012, p=0.038, respectively). By using these 3 parameters, we defined a new risk score, which divided our patient cohort into two as low- and high-risk groups. Low-risk patients had significantly higher survival rates than the high-risk group (83.9% vs 40.5%, p< 0.001).Discussion: This new prognostic score should be further tested and validated in other patient populations. Although our study has some limitations including the limited number of patients and its retrospective nature, there are not so many studies in elderly cHL patients and elderly and/or frail patients are generally excluded in most of the clinical trials. Thus, this real-life single-center experience would contribute to the literature.Keywords: classical Hodgkin lymphoma, cHL, elderly patients, survival, toxicity

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

Severe acute kidney injury (AKI) requiring urgent hemodialysis (uHD) is associated with considerable morbidity and mortality in patients with multiple myeloma (MM).To evaluate the renal function, outcome, and survival status of patients with MM who received uHD and to compare their overall survival with MM patients who did not receive uHD.A total of 70 eligible MM patients who received uHD were included together with 70 control patients with MM.In the study group, 11 patients (15.7%) were known to have pre-existing chronic kidney disease. Thirty-four percent of the study group had AKI requiring uHD at MM diagnosis. Seventy-eight percent of the study group had severe AKI due to myeloma kidney. Renal function recovered in 36 patients (51.4%). Patients with MM who became hemodialysis dependent had significantly higher serum creatinine (sCr) levels at the time of AKI compared to patients with renal recovery (p 0.05). Logistic regression analysis showed that high sCr on admission was significantly associated with hemodialysis dependence (odds ratio 0.78; 95% CI: 0.63-0.96; p = 0.018). The median overall survival was 30 months [IQR: 26] in the study group and 84 months [IQR: 96.25] in the control group (p 0.05). Cox regression analysis showed that the need for uHD at initial MM diagnosis was associated with reduced survival (hazard ratio (HR) 1.9; 95% CI: 1.1-3.2; p = 0.017). Renal recovery did not provide a survival benefit.The need for uHD was associated with poor survival. Recovery of renal function was not associated with improved survival.

T cell receptor excision circles (TRECs) and kappa-deleting excision circles (KRECs) are DNA fragments potentially indicative of T and B cell development, respectively. Recent thymic emigrants (RTEs) are a subset of peripheral cells that may also represent thymic function. Here, we investigated TREC/KREC copy numbers by quantitative real-time PCR in the peripheral blood of patients with primary immunodeficiencies (PIDs, n = 145) and that of healthy controls (HCs, n = 86) and assessed the correlation between RTEs and TREC copy numbers. We found that TREC copy numbers were significantly lower in children and adults with PIDs (P < .0001 and P < .002, respectively) as compared with their respective age-matched HCs. A moderate correlation was observed between TREC copies and RTE numbers among children with PID (r = .5114, P < .01), whereas no significant correlation was detected between RTE values and TREC content in the HCs (r = .0205, P = .9208). Additionally, we determined TREC and KREC copy numbers in DNA isolated from the Guthrie cards of 200 newborns and showed that this method is applicable to DNA isolated from both peripheral blood samples and dried blood spots, with the two sample types showing comparable TREC and KREC values. We further showed that RTE values are not always reliable markers of T cell output. Although additional confirmatory studies with larger cohorts are needed, our results provide thresholds for TREC/KREC copy numbers for different age groups. 34951041

Patients with solid malignancies are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection than the healthy population. The outcome of SARS-CoV-2 infection in highly immunosuppressed populations, such as in patients with hematological malignancies, is a point of interest. We aimed to analyze the symptoms, complications, intensive care unit admissions, and mortality rates of patients with hematological malignancies infected with SARS-CoV-2 in Turkey.In this multicenter study, we included 340 adult and pediatric patients diagnosed with SARS-CoV-2 from March to November 2020. Diagnosis and status of primary disease, treatment schedules for hematological malignancies, time from last treatment, life expectancy related to the hematological disease, and comorbidities were recorded, together with data regarding symptoms, treatment, and outcome of SARS-CoV-2 infection.Forty four patients were asymptomatic at diagnosis of SARS-CoV- 2 infection. Among symptomatic patients, fever, cough, and dyspnea were observed in 62.6%, 48.8%, and 41.8%, respectively. Sixty-nine (20%) patients had mild SARS-CoV-2 disease, whereas moderate, severe, and critical disease was reported in 101 (29%), 71 (20%), and 55 (16%) patients, respectively. Of the entire cohort, 251 (73.8%) patients were hospitalized for SARS-CoV-2. Mortality related to SARS-CoV-2 infection was 26.5% in the entire cohort; this comprised 4.4% of those patients with mild disease, 12.4% of those with moderate disease, and 83% of those with severe or critical disease. Active hematological disease, lower life expectancy related to primary hematological disease, neutropenia at diagnosis of SARS-CoV-2, ICU admission, and first-line therapy used for coronavirus disease-2019 treatment were found to be related to higher mortality rates. Treatments with hydroxychloroquine alone or in combination with azithromycin were associated with a higher rate of mortality in comparison to favipiravir use.Patients with hematological malignancy infected with SARS-CoV-2 have an increased risk of severe disease and mortality.Solid malignite hastalarının şiddetli akut solunum yolu enfeksiyonu-koronavirüs-2 (SARS-CoV-2) enfeksiyonuna sağlıklı bireylerden daha yatkın oldukları gösterilmiştir. Bu verilerin ardından oldukça yoğun immünosupresif olan hematolojik malignite hastalarında SARS-CoV-2 infeksiyonu sonuçları ilgi konusu olmuştur. Biz de bu makalede Türkiye’de hematolojik malignite tanısı ile takip ve tedavi edilirken SARS-CoV-2 enfeksiyonu saptanan hastaların semptom, komplikasyon, yoğun bakım ünitesine yatış ve mortalite oranlarını değerlendirmeyi amaçladık.Çok merkezli çalışmamıza Mart-Kasım 2020 tarihleri arasında SARS-CoV-2 enfeksiyonu tanısı alan erişkin ve pediatrik 340 hastayı dahil ettik. Hastaların hematolojik malignite tanıları, hastalık statusları, tedavileri, son tedaviden enfeksiyona kadar geçen süre, komorbiditeleri, yaşam beklentileri değerlendirildi. Semptomları, oluşan komplikasyonlar ve sonuçlar analiz edildi.Kırk-dört hasta semptomsuz olarak enfeksiyonu geçirirken, semptomatik hastaların ateş, öksürük, ve dispne oranları sırasıyla %62,6, %48,8 ve %41,8 idi. Altmış altı hasta (%20) hastalığı hafif geçirirken, orta, ciddi ve kritik hastalık tanısı alanların oranı sırasıyla %29, %20 ve %16 idi. Tüm kohortta ölüm oranı %26,6 idi; ölüm hafif hastalığı olanlarda %4,4 , orta derece hastalık geçirenlerde %12 ve ciddi/kritik hastalık geçirenlerde ise %83 olarak saptandı. Aktif hematolojik hastalık olması, primer hematolojik hastalığa bağlı düşük hayat beklentisi, SARS-CoV-2 tanısı aldığında nötropenik olmak, yoğun bakıma alınmış olmak ve ilk sıra koronavirüs hastalığı-2019 tedavisi yüksek ölüm riski ile ilişkilendirilen faktörlerdendi. Tek başına veya azitromisin ile kombine olarak hidroksiklorokin kullanan hastaların sadece favipiravir kullananlara göre ölüm riskleri daha yüksek saptandı.SARS-CoV-2 infeksiyonu geçiren hematolojik malignite hastalarında daha yüksek oranda ciddi hastalık ve ölüm riski gözlenmektedir.

Acquired hemophilia A (AHA) is a rare disease caused by autoantibodies inhibiting factor VIII (FVIII) activity. Although the conditionis usually idiopathic, there may be other underlying diseases. Treatment consists of two steps: treatment of acute bleeding and immunosuppression. In this multicenter study, we aimed to demonstrate the clinical characteristics, management details, and survival of AHA patients in Turkey. Data was collected from eleven centers in Turkey. aPTT, FVIII, FVIII inhibitor, and hemoglobin (HB) levels, mixing test results, and demographics at diagnosis, treatment information, adverse events, bleeding episodes during follow-up, relapses, and outcome were analyzed. Twenty-nine patients were analyzed (58.6% female). No underlying disorder could be detected in 14 patients. The most prevalent etiologies were pregnancy, malignancy and infections. The median FVIII activity and FVIII inhibitor titer at diagnosis were 0.7% (0.0-29.4%) and 32.6 BU (0.6-135.6 BU) respectively. Bleeding was severe in 44.8% of patients. The HB value was significantly lower in patients with severe bleeding. Most of the patients (n = 25, 86.2%) had only one bleeding episode without relapse, three patients (10.3%) had two bleeding episodes, and one patient had more than three bleedings. 21 (75%) patients received hemostatic therapy. The use of recombinant FVIIa was slightly higher than activated prothrombin complex concentrate (15 versus 10 patients). Immunosuppressive treatment was initiated in 26 (93%) patients. Regimens containing steroid, cyclophosphamide, and rituximab in different combinations were the most preferred. The median follow-up period was 13 months (2-156 months). Median overall survival was 154.97 months. Four and six-year survival were 90.9 +/- 0.8% and 77.9 +/- 14.1% respectively. This is a unique study that investigated the demographic characteristics, treatment approaches, and patient survival of AHA in Turkey.

Hyper immunoglobulin M (HIGM) syndrome is a rare disorder of the immune system with impaired antibody functions. The clinical picture of the patients varies according to the underlying genetic variation. In this study, we identified two novel variants in AID and UNG genes, which are associated with autosomal recessive type HIGM, by targeted next generation sequencing (NGS) panel. A biallelic 11 base pair deletion (c.278_288delATGTGGCCGAC) in the coding sequence of activation-induced cytidine deaminase (AID) gene was identified in a 36-years-old patient. Biallelic two base pair insertion in exon 7 of Uracil nucleoside glycosylase (UNG) gene (c.924_925insGG) was identified in 40-years-old patient. Both variants were confirmed by Sanger sequencing. HIGM, like many of the other primary immunodeficiencies, is a rare and difficult-to-diagnose entity with heterogeneous clinical phenotypes. It should be suspected in patients with a history of early-onset recurrent respiratory infections, enlarged lymph nodes and autoimmune disorders. There might be a delay in diagnosis until adulthood especially in subtle cases or if HIGM is not included in the differential diagnosis due lacking of awareness. In this regard, genetic testing with NGS-based diagnostic panels provide a rapid and reasonable tool for the molecular diagnosis of patients with immunodeficiencies and hence, decrease the time to diagnose and prevent infection-related complications associated with increased morbidity and mortality.

Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment >20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

The association between myelodysplastic syndrome (MDS) and Behçet syndrome (BS) is recognized for over 25 years. High frequency of trisomy 8 and intestinal ulcers are striking features of this association. There are no recommendations for how these patients should be treated. A systematic literature review was performed in PubMed using the keyword combination "(((((intestinal) OR gastrointestinal) OR ulcer) OR Behcet*)) AND ((myelodysplastic syndrome) OR MDS)" in March 2019. Our aim was to gain insight regarding clinical responses to individual treatment modalities. A recent case was also presented and included in the analysis. Data from 41 articles reporting on a total of 53 patients carried adequate information to assess treatment responses. Glucocorticoids provided benefit in 23 of 43 patients. Azacitidine, decitabine, thalidomide, and cyclosporine contributed to a clinical improvement in 4/6, 2/3, 3/4, and 5/8 patients respectively. Hematopoietic stem cell transplantation was successful in 9 of 13 patients. With the use of TNF inhibitors, azathioprine, and mesalamine derivatives, clinical improvement was observed in 3/11, 0/4, and 6/18 patients respectively. Patients with MDS and BS-like features who are resistant to glucocorticoids have so far benefited more from treatment approaches directed at MDS, rather than the immunosuppressive agents used for BS.

Despite effective factor replacement and various treatment schedules, there remain several challenges and unmet needs in the prophylactic treatment of hemophilia limiting its adoption and thereby posing an increased risk of spontaneous bleeding. In this regard, extended half-life (EHL) recombinant factor VIII (rFVIII) and factor IX (rFIX) products promise optimal prophylaxis by decreasing the dose frequency, increasing the compliance, and improving the quality of life without compromising safety and efficacy. EHL products might lead to higher trough levels without increasing infusion frequency, or could facilitate the ability to maintain trough levels while reducing infusion frequency. This paper aims to provide a comprehensive review of the rationale for developing EHL coagulation factors and their utility in the management of hemophilia, with special emphasis on optimal techniques for half-life extension and criteria for defining EHL coagulation factors, as well as indications, efficacy, and safety issues of the currently available EHL-rFVIII and EHL-rFIX products. Potential impacts of these factors on quality of life, health economics, and immune tolerance treatment will also be discussed alongside the challenges in pharmacokinetic-driven prophylaxis and difficulties in monitoring the EHL products with laboratory assays.Etkin faktör yerine koyma tedavisi ve değişik tedavi programlarına rağmen günümüzde hemofilinin profilaktik tedavisinde hala çözülmemiş sorunlar ve karşılanmamış gereksinimler vardır. Bu nedenle kanama riski ve kanamaya bağlı komplikasyonlar önemini korumaktadır. Bu bağlamda profilakside kullanılacak uzatılmış yarı ömürlü rekombinant faktör VIII ve faktör IX ürünleri tedavinin güvenlilik ve etkililiğinden ödün vermeksizin doz sıklığının azaltılması, hasta uyumunun artması ve yaşam kalitesinin düzelmesini sağlayarak optimal tedavi koşullarının oluşmasına yardımcı olabilir. Uzatılmış yarı ömürlü faktörler infüzyon sıklığını artırmadan daha yüksek çukur değerler ulaşılması veya mevcut çukur değerin daha seyrek infüzyonla idamesi konusunda önemli bir açılım sağlayabilir. Bu derlemede uzatılmış yarı ömürlü faktör konsantrelerinin geliştirilmesine neden gerek duyulduğu, hemofili tedavisindeki olası yerleri, faktör yarı ömrünü uzatmak için kullanılan teknikler ve mevcut uzatılmış yarı ömürlü faktör konsantrelerinin etkililik, güvenlilik ve endikasyonları ile ilişkili kapsamlı bilgi sunulacaktır. Ayrıca bu ürünlerin yaşam kalitesi ve sağlık ekonomisi üzerine etkileri, immün tolerans tedavisindeki yerleri, farmakokinetik temelli profilaside kullanımları ile laboratuvar izleminde karşılaşılan güçlükler tartışılacaktır.

Background In the European LeukemiaNet (ELN) 2013 recommendations, chronic myeloid leukemia (CML) patients with warning response (WR) were suggested to be monitored closely continuing with the same tyrosine kinase inhibitor (TKI). Differently, the guidelines of the National Comprehensive Cancer Network considers switching to another TKI as an option. Patients and Methods We retrospectively evaluated 73 CML patients receiving first-line imatinib, who were followed and managed in accordance with ELN recommendations. We compared patients with molecular WR with patients with optimal response (OR) and failure regarding short- and long-term outcomes. Results The cumulative major molecular response (MMR) rates in patients with OR were significantly higher at any time point than those achieved by the WR group. Patients with WR at 3 months had significantly inferior failure-free survival (FFS) than optimal responders, but overall survival (OS) was similar. For 6 and 12 months, the WR and OR groups had similar FFS and OS. Twenty of 23 patients with WR at 12 months achieved MMR during imatinib treatment. Conclusion It takes longer to get to ELN time points with imatinib than second-generation TKIs (2GTKIs). Treatment might fail in a small proportion of the patients with WR during imatinib treatment, but close and careful monitoring and timely switching to 2GTKIs might translate into favorable outcomes. Avoiding early switch to 2GTKIs would prevent patients from experiencing potential toxicities. There is still a need for prospective comparative studies (ie, continuing imatinib treatment vs. switching to 2GTKIs) in patients with WR, to justify the validity of this response category and to explore the benefit of treatment change in these patients.

The coronavirus disease 2019 (COVID-19) pandemic has brought life to a standstill globally. Intermittent quarantines were applied to control the pandemic and reduce contamination. During the pandemic, patients with hematological malignancies were among the most vulnerable population. Our aim was to compare in terms of demographic data, disease-related factors, symptom-to-diagnosis interval, diagnosis-to-treatment interval , and interim and end-of-treatment response in classical Hodgkin lymphoma patients diagnosed during the pandemic and in the pre-pandemic periods. A total of 90 patients were included, of which 65 and 25 were diagnosed in the 2 years before the pandemic and the 12-month period during the pandemic, respectively. Demographic features were comparable in both groups. Although the percentage of patients with advanced-stage disease was higher during the pandemic (64% vs 53.8%), this difference did not reach statistical significance (P = 0.384). The median symptom-to-diagnosis interval was significantly longer during the pandemic than was observed within the pre-pandemic era (16 weeks vs 8 weeks, P = 0.042). The median diagnosis-to-treatment intervals was similar in both groups (13 days vs 15 days, P = 0.253). In the pre-pandemic and pandemic periods, 85.2% and 72.7% of the patients had complete response at end-of-treatment evaluation, respectively (P = 0.208). We found that symptom-to-diagnosis interval was significantly prolonged during the pandemic. Higher percentage of patients with advanced-stage disease during the pandemic might also be due to this delay, nevertheless, this difference did not reach to a significant difference regarding treatment response in both groups.

Background Cytokine release syndrome (CRS), characterized by overproduction of proinflammatory cytokines in the course of severe coronavirus disease 2019 (COVID-19), has been suggested as the major cause of mortality. Tocilizumab, a recombinant humanized monoclonal antibody against human IL-6 receptor, poses a therapeutic option for the treatment of CRS leading to severe acute respiratory syndrome in coronavirus-2 (SARS-CoV-2) infection. Methods We performed a single-center retrospective study to reveal the outcome of COVID-19 patients on tocilizumab and proposed “the Cerrahpasa-PREDICT score”, a new clinical scoring system using clinical and laboratory parameters that would help predicting the 28-day mortality of COVID-19 patients receiving tocilizumab. Results Eighty-seven patients (median age: 59 years) were included of whom 75.8% were male. Tocilizumab use significantly improved clinical and laboratory parameters. The 28-day mortality rate on tocilizumab was 16.1%. The Cerrahpasa-PREDICT score, consisting of platelet counts, procalcitonin, D-dimer levels, SO2R and the time from symptom onset to tocilizumab administration had a positive predictive value of 94.5% and negative predictive value of 92.9% for anticipating 28-day mortality. Conclusions Severe COVID-19 should closely be monitored for the signs of hyperinflammation. We showed that administration of tocilizumab early in the course of the disease (prior to ICU admission) resulted in a favorable outcome. Close monitoring usually aids identifying patients who would benefit from tocilizumab. In this regard, the Cerrahpasa-PREDICT score might serve as a practical tool for estimating the 28-day mortality in COVID-19 patients who received tocilizumab and would facilitate timely recognition of fatal cases to be evaluated for other therapeutic options.

Objective: Hemophilia A is the second most common bleeding disorder causing patients to have lifelong follow-up and treatment. Despite being a rare disease, hemophilia A has a high economic burden on individuals and the public. The purpose of this study was to estimate the total disease cost of hemophilia A in Turkey. Materials and Methods: Data used in this analysis were collected through literature review, including studies conducted in Turkey in December 2018. A disease burden analysis was performed by modeling hemophilia A-related costs among patients, their relatives, and the social security system. Two expert panels were held to evaluate real-world data sources and to provide further information. All direct medical and non-medical costs were calculated annually from the Social Security Institution of the Republic of Turkey perspective, while indirect costs were estimated from the patient and community perspective. Results: For the calendar year of 2018, the number of hemophilia A patients in Turkey were estimated to be 5,055, with an average weight of 64.7 kg. The average annual direct medical, direct non-medical, and indirect costs of hemophilia A were calculated as euro93,268 ($109,286; (sic)502,717), euro2,533 ($2,968; (sic)13,655), and euro7,957 ($9,323; (sic)42,888) per patient, respectively, with a total annual cost of euro103,759 ($121,578; (sic)559,259). For the management of patients with inhibitors (4.9%), the average annual total cost was calculated to be euro325,439 ($381,330; (sic)1,754,117) per patient. The total annual disease burden of hemophilia A in 2018 was estimated to be about euro524 million ($614 million; (sic)2.82 billion), which corresponded to 1.6% of the total health expenditure in Turkey. Conclusion: The most important reason hemophilia A has a significant economic burden in Turkey is that replacement therapy is expensive. The major cost contributor was identified as factor replacement therapy. With inhibitor development, the average annual cost increased more than 3-fold., Roche Mustahzarlari Sanayi A.S., Roche Mustahzarlari Sanayi A.S. provided a study grant for medical writing support, which was provided by Pleksus Clinical Research, Istanbul, Turkey. Roche or Pleksus has not influenced the content of this study.

Background/aim: A proliferation-inducing ligand (APRIL) has been investigated as a prognostic marker in chronic lymphocytic leukemia (CLL) patients. However, there is no cut-off level for serum APRIL (sAPRIL) levels that predict time to treatment in CLL patients. Materials and methods: Between May and December 2012, 94 consecutive CLL patients and 25 healthy controls were assessed. sAPRIL levels were measured by ELISA. Demographic data and prognostic markers were obtained from the patients' files. Treatment-naive patients were followed up for 6.5 years for any treatment need. Results: Patients were divided into 3 groups: Treatment-naive (n = 47), chemotherapy receiving (n = 25), and those who had received chemotherapy previously (n = 22). There was no difference in median sAPRIL levels of patients who were receiving chemotherapy at the sampling time and the healthy controls, which indicates that sAPRIL levels might be influenced by treatment. For treatment-naive patients, the best cut-off in predicting time to treatment was found at the sAPRIL level of 2.04 ng/mL, with 78% sensitivity and 63% specificity. Time to treatment was significantly earlier in the APRIL high group (n = 27) than in the APRIL low group (n = 20) (P = 0.010, log-rank test). Conclusion: sAPRIL, a simple, promising blood test which can be measured by ELISA, will likely obtain a place in the wide range of prognostic markers in CLL. Prospective large-scale studies are required to validate and confirm the feasibility of the proposed cut-off level of 2.04 ng/mL as a predictor of time to treatment in treatment-naive CLL patients. Scientific Research Projects Coordination Unit of stanbul University [19694] Acknowledgments/Disclaimers/Conflict of interest The study was supported by an unrestricted grant by Scientific Research Projects Coordination Unit of stanbul University (Project No.: 19694) .