Germline genetic variants in Turkish familial multiple myeloma/monoclonal gammopathy of undetermined significance cases.

Multiple myeloma (MM) is a haematological malignancy primarily affecting the elderly, with a striking male predilection and ethnic disparities in incidence. Familial predisposition to MM has long been recognized, but the genetic underpinnings remain elusive. This study aimed to investigate germline variants in Turkish families with recurrent MM cases. A total of 37 MM-affected families, comprising 77 individuals, were included. Targeted next-generation sequencing analysis yielded no previously reported rare variants. Whole exome sequencing analysis in 11 families identified rare disease-causing variants in various genes, some previously linked to familial MM and others not previously associated. Notably, genes involved in ubiquitination, V(D)J recombination and the PI3K/AKT/mTOR pathway were among those identified. Furthermore, a specific variant in BNIP1 (rs28199) was found in 13 patients across nine families, indicating its potential significance in MM pathogenesis. While this study sheds light on genetic variations in familial MM in Turkey, its limitations include sample size and the absence of in vivo investigations. In conclusion, familial MM likely involves a polygenic inheritance pattern with rare, disease-causing variants in various genes, emphasizing the need for international collaborative efforts to unravel the intricate genetic basis of MM and develop targeted therapies.

Baseline inflammation indexes and neutrophil-to-LDH ratio for prediction of the first mobilization failure without plerixafor-based regimens in multiple myeloma and lymphoma patients: A single-center retrospective study.

BACKGROUND: Many factors were identified for mobilization failure (MF) in autologous hematopoietic stem-cell transplantation. To our knowledge, this is the first study to investigate the efficacy of baseline inflammation indexes and neutrophil-to-lactate dehydrogenase (LDH) ratio to predict MF in multiple myeloma (MM) and lymphoma. METHODS: A total of 240 patients with lymphoma or MM hospitalized between January 2014 and June 2022 for the first stem cell mobilization were included in this retrospective single-center study. We evaluated the impact of baseline demographic, clinical, and laboratory data (before granulocyte colony-stimulating factor and chemotherapy implementation), including neutrophil, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), neutrophil-to-C-reactive protein, and neutrophil-to-LDH ratios on MF. RESULTS: A total of 240 patients were divided into successful (214 patients, 89.16%) and poor mobilizers (26 patients, 10.84%). Poor mobilizers had lower neutrophil, NLR, SII, and neutrophil-to-LDH ratios (P values were .001, .022, .001, and .001, respectively). Among these markers, only the neutrophil-to-LDH ratio was statistically low in both poor mobilizer MM and lymphoma patients. Receiving operator characteristic curve analysis was performed to evaluate neutrophil, SII, and neutrophil-to-LDH ratios for MF. Neutrophil-to-LDH ratio had the highest specificity (93.93%, for ≤9.904 cut-off) compared to the other two variables. Multivariate logistic regression analysis showed that neutrophil-to-LDH ratio ≤ 9.904 (cut-off) (odds ratio: 7.116, P = .001), neutrophil counts ≤3300/mm3 (cut-off) (odds ratio: 3.248, P = .021), and lymphoma diagnosis (odds ratio: 2.674, P = .039) were independent risks for MF. CONCLUSION: The neutrophil-to-LDH ratio could be a novel marker in lymphoma and MM patients to predict the first MF. New studies should be conducted for the optimization of this index.

An atypical case of refractory passenger lymphocyte syndrome after renal transplantation.

BACKGROUND: Passenger lymphocyte syndrome (PLS) causes immune-mediated hemolysis in solid and bone marrow transplant recipients. Donor-derived antibodies against the recipient erythrocyte drive the pathogenesis. It is a rare entity in kidney transplantation, and most of the cases are self-limited. CASE PRESENTATION: A 36-year-old woman presented with fatigue 13 days after living donor renal transplantation. The operation was uneventful, and she was discharged with normal graft functions on the 11th day of transplantation Findings were consistent with cold agglutinin disease at her admission. However, the cold agglutinin test was negative. Eventually, she was diagnosed with PLS. Refractory intravascular hemolysis and frank hemoglobinuria were also present in the patient. Hemolysis was resistant to steroids, intravenous immunoglobulin (IVIG), and Rituximab. Because of life-threatening anemia related to refractory PLS, mycophenolate and tacrolimus were interrupted. However, hemolysis persisted. Following that, immunoadsorption (IA) treatment was obtained. Unfortunately, graft loss occurred due to rejection despite the resolution of PLS after IA. CONCLUSION: PLS is a rare and usually self-limited entity. Our case was an atypical refractory PLS that resembled cold agglutinin disease. Also, frank hemoglobinuria was observed related to severe intravascular hemolysis. These features have not been described before in PLS, to the best of our knowledge. Additionally, IA treatment had never been reported in the literature for PLS, as far as we know. Treatment and management could be a challenge in refractory PLS. Rituximab, IVIG, and extracorporeal treatments could be beneficial. It should be borne in mind that refractory PLS can cause graft and patient loss.

Salvage Intrapartum Splenectomy for the Treatment of Transfusion-refractory Anaemia in a ß-thalassemia Intermedia Patient.

Thalassemia intermedia (TI) patients may need a transfusion during physiological stress conditions, such as pregnancy. We present a case of a female TI patient with emerging transfusion-refractory anaemia during pregnancy, which resolved after splenectomy performed simultaneously with cesarean delivery. A 26-year pregnant woman at 29th gestational weeks was referred with a diagnosis of TI due to emerging anaemia which was refractory to transfusion. Splenectomy at term was decided to improve anaemia, and transfusion response. A preterm infant was delivered by cesarean section due to threatened preterm labour. Once the uterine incision was closed, an open splenectomy was performed. Postoperative follow-up was uneventful. To the best of our knowledge, the present case is the first open splenectomy performed during cesarean delivery as a salvage option for the management of transfusion-refractory anaemia. Key Words: Thalassemia intermedia, Splenectomy, Pregnancy, Hemolytic anaemia.

Salvage for Postpartum Massive Haemorrhage in a Jehovah's Witness with Intravenous Iron Therapy and Cell Saver System.

Intraoperative cell salvage (ICS) system performs autologous transfusion by filtering and reinfusing the shed blood into corporeal circulation during the surgery. Especially for pregnant Jehovah's Witnesses, the ICS system could be a life-saving intervention. This report describes the successful use of intravenous iron therapy and ICS during the cesarean delivery of a Jehovah's Witness diagnosed with placenta previa totalis who refused to receive any type of blood or blood product transfusion. Intravenous iron treatment initiated in the preoperative period can reduce the need for blood and blood product transfusion. The ICS system provides recognised advantages; however, its utilisation requires high technology equipment and skilled health staff. Key Words: Jehovah's witness, pregnancy, Iron therapy, Intraoperative cell salvage.

Extracorporeal photopheresis in steroid-refractory chronic graft-versus-host disease: A retrospective multicenter study.

BACKGROUND AND OBJECTIVES: Extracorporeal photopheresis (ECP) is a treatment strategy in steroid-refractory chronic graft-versus-host disease (cGvHD). In this study, we aimed to share our multicenter experience using ECP in our steroid-refractory cGvHD patients. MATERIALS AND METHODS: In this multicenter observational retrospective study with the participation of four Turkish transplant centers, 100 patients with the diagnosis of steroid-refractory cGvHD who underwent ECP were analyzed. All ECP procedures were performed with the off-line system. RESULTS: Severe cGvHD was observed in 77 % of the patients. 50 % of the patients had more than 1 organ involvement. The overall response rate in cGvHD was 58 %, and the complete response (CR) rate was 35 %. The skin was the most involved organ, with a response rate of 61.2 % (CR rate 30.6 %) in cGvHD. At a median 13 months (1-261) follow-up, overall survival (OS) was 41 % (n = 41) and the mortality rate was 59 % (n = 59). Median overall survival (OS) was 2 months for non-responders and 91 months for responders (p < 0.001). Significant OS differences were observed for patients responding to ECP in cGvHD (HR = 4.1, p = 0.001) patients. CONCLUSIONS: ECP is a good therapeutic alternative and could be used earlier in patients with steroid-resistant cGvHD.

Recombination frequencies of human leukocyte antigen loci in hematological malignancies among Turkish population.

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option with growing performance for leukaemia, aplastic anaemia and genetic disorders. The frequency of MHC (Major Histocompatibility Complex) gene locus recombination is increased at loci close to the telomeres and in the female gender. The aim of the present study is to document the recombination events by pedigree diagrams with the primary goal to determine the frequency of recombination in a different ethnic population from mostly reported studies. METHODS: Altogether 9545 allogeneic HSCT recipients and their family-based potential donors (n:36231) were included in this retrospective study. RESULTS: Recombinations were determined in 118 (F/M:50/68) out of 9545 families enrolled on the study. These were present in 40 of the patients and 78 of healthy donors. The frequency of recombinations was 0.42% and 0.22%, in patients and donors, respectively. Of the 118 recombinations, 60 were detected in A locus (13 inpatients), 14 in B locus (3 inpatients) and 42 in DR locus (22 inpatients). In our study, due to recombinations in HLA (Human Leukocyte Antigen)-A,-B,-DR loci, we found that some patient-donor pairs became 6/5 matched instead of 6/6 (n:45), eliminating the allogeneic HSCT possibility for the patients from the full-matched siblings. CONCLUSION: To our knowledge, this is the first study reporting the recombination frequencies in HLA loci among Turkish population and thus, providing informative data to the clinicians regarding the cross-over possibilities in Turkish patients with haematological malignancies.

Frequency of RHD variants in serologically weak D Turkish blood donors.

BACKGROUND: RhD typing has remained of primary importance, as being the leading cause of hemolytic disease of the newborn. Among Rh system's 55 blood group antigens, RhD is the most immunogenic. We aimed with this study to determine weak D/partial D variant frequency in blood donors who were admitted to our blood center and have serologically designated blood group weak D. MATERIALS AND METHODS: We screened blood donors who admitted between 2011 and 2017 to our blood center. Sixty-seven serologically weak D phenotyped donors have participated in the study. These donors' samples were studied further by Polymerase Chain Reaction Sequence- Specific Primers (PCR-SSP) for determining D variants. RESULTS: Weak D phenotype was detected in 228(0.12 %) out of 177,554 donors. Sixty-seven of them agreed to take part in the study. The frequency of weak D and partial D was 68.7 % (n = 46), and 22.4 % (n = 15), in order. The most encountered weak D and partial D variant was type 15 and DFR type, respectively. CONCLUSIONS: The prevalence of serologically weak D phenotypes varies by race and ethnicity. Turkey is a country covering a mixture of European and Asian DNA with different ethnic groups. Thus, our research as giving the overall distribution of RHD variants from the largest city of Turkey, which may reflect the general ethnic background of the country, would help to the establishment of a databank for blood banking. This paper is the first molecular study on RHD variants in Turkey. New molecular research would be more reliable and precise.

Early Access Program Results From Turkey and a Literature Review on Daratumumab Monotherapy Among Heavily Pretreated Patients With Relapsed/Refractory Myeloma.

BACKGROUND: In countries where frontline drug approval is limited to first-generation proteasome inhibitors or immunomodulatory drugs, relapses have been both more frequent and less durable. We investigated real world data on the efficacy and safety of daratumumab monotherapy among patients with relapsed refractory multiple myeloma (RRMM) from Turkey using a prospective early access program. PATIENTS AND METHODS: A total of 42 patients with RRMM after a minimum of 3 previous lines of proteasome inhibitor/immunomodulatory drug-based treatments were included from 25 centers across Turkey. Daratumumab monotherapy was administered intravenously at a dose of 16 mg/kg weekly (cycles 1-2), on alternate weeks (cycles 3-6), and monthly thereafter. RESULTS: The median daratumumab monotherapy duration was 5.5 months (range, 0.2-28.7 months). The overall response rate was 45.2%, including 14 (33.3%) partial responses, 4 (9.5%) very good partial responses, and 1 (2.4%) complete response. The median duration of response was 4.9 months. The median progression-free survival (PFS) was 5.5 (95% confidence interval, 2.6-8.4 months) with 12- and 18-month PFS rates of 35.7% and 31.0%, respectively. The median overall survival was not reached; the 12- and 18-month overall survival rates were 64.3% and 59.5%, respectively. The depth of response had a significant effect on PFS (log-rank test, P = .026). Overall, of the 76 adverse events reported, 33 (43.4%) were grade ≥ 3; only 4 (9.52%) were grade 3 infusion-related reactions. No infusion-related reactions or adverse events led to treatment discontinuation. CONCLUSION: The present findings from our daratumumab early access program have confirmed the efficacy and safety profile of daratumumab monotherapy in heavily pretreated Turkish patients with RRMM.

Incidence and risk factors for hepatic sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: A retrospective multicenter study of Turkish hematology research and education group (ThREG).

Hepatic sinusoidal obstruction syndrome (HSOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively evaluated the incidence, risk factors, treatment and survival for HSOS after allo-HSCT in Turkey. We also reported our experience of defibrotide (DF) for HSOS prophylaxis in high-risk (HR) patients. Across Turkey, 1153 patients from 10 centers were enrolled in the study. We evaluated the medical records of patients who were treated with allo-SCT between January 2012 and December 2015. The study included 1153 patients (687 males/466 females) with median age of 38 (15-71) years. The incidence of HSOS was 7.5 % (n = 86). The incidences of HSOS in the HR/DF+, HR/DF- and standard risk (SR) group were 8%, 66.7 % and 6.2 %, respectively. The rate of HSOS development was not statistically different between HR/DF + and SR group (p = 0.237). HSOS prophylaxis (defibrotide) was significantly decreased HSOS-related mortality (p = 0.004). The incidence of HSOS was found similar to literature in this large Turkish cohort. Defibrotide prophylaxis appears to be associated with low incidence of HSOS development and reduced HSOS-related mortality. Although these results are promising, future studies are needed to support the efficacy of defibrotide prophylaxis in patients with risk of HSOS.

Severe thrombocytopenia and alveolar hemorrhage represent two types of bleeding tendency during tirofiban treatment: case report and literature review.

Tirofiban is a glycoprotein (GP) IIb/IIIa receptor antagonist used in the treatment of acute coronary syndrome (ACS). Thrombocytopenia is a well-known complication of GPIIb/IIIa inhibitors. Life-threatening complications such as alveolar and gastrointestinal system hemorrhages may occur in the course of thrombocytopenia. Platelet count should be monitored closely, including during the first few hours of the infusion. Adverse events may be prevented by prompt discontinuation of the therapy. Herein we present two cases of profound and sudden thrombocytopenia associated with tirofiban use in the treatment of ACS together with a review of the literature.

Complete resolution of transplantation-associated thrombotic microangiopathy and hepatic veno-occlusive disease by defibrotide and plasma exchange.

Transplantation-associated thrombotic microangiopathy has been associated with significantly reduced survival following allogeneic bone marrow transplantation. We describe here the course of Transplantation-associated thrombotic microangiopathy and hepatic veno-occlusive disease, and response to plasma exchange therapy. A 19-year-old male patient underwent hematopoietic stem cell transplantation (HSCT) from his HLA-matched brother for lymphoblastic lymphoma in the first complete remission. Transplantation-associated thrombotic microangiopathy was diagnosed 17 days after transplantation. At that time, neurological abnormalities were not present. Cyclosporin A (CsA) was discontinued. Hematological stabilization was recorded. On day +20, abdominal distention, painful hepatomegaly and ascites complicated the clinical picture. With a high hepatic venous pressure gradient (18mmH20), veno-occlusive disease of the liver was diagnosed and defibrotide was started, which resulted in a dramatic cessation of pain and increase in urinary output. However, transplantation-associated thrombotic microangiopathy-related symptoms progressed and plasma exchange was instituted, which resulted in worsening of veno-occlusive disease symptoms. He was referred to the Intensive Care Unit due to respiratory compromise and was intubated. Plasma exchange was continued in order after hemofiltration. In three days, fever resolved, hemofiltration could be stopped, and ventilator dependence ended. After 19 aphereses, serum LDH level returned to normal and schistocytes were minimal on microscopic examination of the blood film. Platelet count increase was more gradual. Plasma exchange was discontinued. On the 40th day of defibrotide, all symptoms related with veno-occlusive disease were resolved and defibrotide was stopped. We think that our case is important to establish the relation and management strategy of these two small vessel complications of HSCT.

Soluble transferrin receptor and soluble transferrin receptor-ferritin index for evaluation of the iron status in elderly patients.

We aimed to evaluate the diagnostic values of soluble transferrin receptor (sTfR) concentration, transferrin-ferritin index (soluble transferrin receptor concentration/log ferritin), ferritin levels and other related parameters in geriatric patients with anemia of chronic disease (ACD) and iron deficiency (IDA). Forty-four elderly subjects (median age 73 [63-94]) and twenty healthy subjects (median age 49 [44-56]) were enrolled into this study, divided into four groups: twenty middle aged healthy subjects (group A), fifteen elderly patients with IDA (group B), fourteen elderly patients with ACD (group C) and fifteen nonanemic geriatric subjects (group D). Hemoglobin, mean corpuscular volume, serum iron concentration and transferrin saturation levels of the patients in IDA group were found significantly lower than those in both non-anemic group and healthy subjects. Serum sTfR concentrations of the patients in IDA group were significantly higher than those in non-anemic geriatric group, ACD group and healthy subjects. Transferrin-ferritin index of the patients with IDA was significantly higher than that in non-anemic geriatric and ACD group. Serum ferritin levels of the patients in IDA group did not show any differences when compared with the other groups. Serum ferritin was highly specific for IDA (95%) when compared with ACD, although its sensitivity was low (38%). STfR values were negatively correlated with both transferrin and ferritin levels (p = 0.042 r = -0.40; and p = 0.034 r = -0.41, respectively). In conclusion, serum soluble transferrin receptor and transferrin-ferritin index may be used together with serum ferritin to distinguish the iron deficiency state in the elderly.