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.

The relationship of the endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) gene polymorphism in Turkish type 2 diabetic patients with and without diabetic foot ulcers.

OBJECTIVE: This study aims to evaluate the influence of eNOS G894T and VEGF C936T gene polymorphism in diabetic foot ulcers. METHOD: We studied 50 patients with diabetic foot ulcers and 57 diabetic patients without diabetic foot ulcer and a control group of 75 healthy individuals. RESULTS: The genotype eNOS distribution did not differ between Type 2 Diabetic Patients group and Diabetic Foot Ulcer group (P>0.05). The frequency of the polymorphic T allele in Type 2 Diabetic Patients were significantly higher than the control group (42.3% and 24.5%, respectively)(p<0.01). The frequency of the polymorphic T allele between the Type 2 Diabetic Patients and Diabetic Foot Ulcer group was similar (p>0.05). The genotype VEGF distribution did not differ between Type 2 Diabetic Patients group and Diabetic Foot Ulcer group (P>0.05). The frequency of the polymorphic T allele between the Type 2 Diabetic Patients and Diabetic Foot Ulcer group was similar for both groups (p>0.05). CONCLUSION: Polymorphism of eNOS G894T is not a risk factor for diabetic foot ulcer formation. T allele is a risk factor for diabetes, but T allele is not a risk factor for diabetic foot ulcer formation. Polymorphism of VEGF C936T and T allele are not risk factors for diabetes occurence and diabetic foot formation.

Frequency of Finding Family Donors: A Single Center Experience.

OBJECTIVES: Allogeneic hematopoietic stem cell transplant is a curative treatment option for many hematologic diseases. The existence of a fully compatible donor for recipients is the first condition for minimized transplant-related mortality and morbidity. The best donor for hematopoietic stem cell transplant is an HLA-matched sibling donor. The possibility of finding an HLA-matched sibling is less than 30% worldwide. Hematopoietic stem cell transplant is needed for an increasing number of patients every year, but the ability to find a fully compatible donor has limited its use. MATERIALS AND METHODS: From August 2012 to May 2017, we screened 412 adult patients who required AHSCT and their families for HLA tissue groups who were seen at our center (Baskent University Adana Dr. Turgut Noyan Research and Medical Center Hematology Unit). To screen tissue groups at our center, we perform lowresolution typing for HLA-A, -B, -C, -DRB1, and -DQB. If an HLA genotype cannot be identified, verification typing is done using highresolution testing. RESULTS: We found matched family donors in 227 (55%) of 412 patients screened at our center. The ratio of HLAmatched related donors was 83% for 279 patients who received allogeneic stem cell transplant. CONCLUSIONS: The likelihood of finding eligible unrelated donors has been gradually increasing, in part due to the development of the National Bone Marrow Bank. However, a careful screening for related donors is still important. Our findings indicate the importance of careful examination of family genealogy and of careful family screening in our region.

Organ damage mitigation with the Baskent Sickle Cell Medical Care Development Program (BASCARE).

The Eastern Mediterranean is among the regions where sickle cell disease (SCD) is common. The morbidity and mortality of this disease can be postponed to adulthood through therapies implemented in childhood. The present study focuses on the organ damage-reducing effects of the Baskent Sickle Cell Medical Care Development Program (BASCARE), which was developed by a team who lives in this region and has approximately 25 years of experience. The deliverables of the program included the development of an electronic health recording system (PRANA) and electronic vaccination system; the use of low citrate infusion in routine prophylactic automatic erythrocyte exchange (ARCE) programs including pregnant women; the use of leukocyte-filtered and irradiated blood for transfusion; the use of magnetic resonance imaging methods (T2) for the management of transfusion-related hemosiderosis; and the implementation of an allogeneic hematopoietic stem cell transplantation protocol for adult patients. The sample was composed of 376 study subjects and 249 control subjects. The hospital's Data Management System and the central population operating system were used for data collection. BASCARE enabled better analysis and interpretation of complication and mortality data. Vaccination rates against influenza and pneumococcal disease improved (21.5% vs 50.8% and 21.5% vs 49.2%, respectively). Effective and safe ARCE with low citrate infusion were maintained in 352 subjects (1003 procedures). Maternal and fetal mortality was prevented in 35 consecutive pregnant patients with ARCE. Chelating therapy rates reduced from 6.7% to 5%. Successful outcomes could be obtained in all 13 adult patients who underwent allogeneic peripheral stem cell transplantation from a fully matched, related donor. No patients died by day 100 or after the first year. Cure could be achieved without graft loss, grades III to IV acute graft versus host disease, extensive chronic graft versus host disease, or other major complications. The BASCARE program significantly improved patient care and thereby prolonged the life span of SCD patients (42 ± 13 years vs 29 ±â€Š7 years, P < .001). We may recommend using such individualized programs in centers that provide health care for patients with SCD, in accordance with holistic approach due to the benign nature but malignant course of the disease.

The relationship of Interleukin-6 -174 G>C gene polymorphism in type 2 diabetic patients with and without diabetic foot ulcers in Turkish population.

OBJECTIVE: We aims investigate Turkish type 2 diabetic patients with/without diabetic foot ulcers and healthy group and examined the contribution of Interleukin (IL)-6 -174 G>C gene polymorphism to the development of diabetic foot ulcers. DESIGN AND PATIENTS: The Interleukin (IL)-6 -174 G>C genotypes were determined prospectively in 50 patients with diabetic foot ulcers and 35 without diabetic foot ulcers and a control group of 119 healthy individuals. Genotyping of the Interleukin (IL)-6 -174 G>C gene polymorphisms for all individuals was performed by PCR-RFLP method. RESULTS: The genotype IL6 distribution did differ between the control group (CC 13.3%, GC 66.7%, GG 20%) and type 2 diabetic patients (CC 2.4%, GC 47.1%, GG 50.6%) (P<0.001). The genotype IL6 distribution did not differ between type 2 diabetic patients group (CC 0%, GC 45.7%, GG 54.3%) and diabetic foot ulcers (CC 4%, GC 48%, 48%) (P>0.05). The frequency of the polymorphic G allele in between the control group and type 2 diabetic patients was no similar for the groups (58.4% and 74.1%, respectively) (p<0.05). The frequency of the polymorphic G allele in between the type 2 diabetic patients and diabetic foot ulcers was similar for the groups (77.1% and 72%, respectively) (p>0.05). CONCLUSION: The gene polymorphism of Interleukin-6 -174 G>C and G allele are an risk factor for diabetes, but gene polymorphism of Interleukin-6 -174 G>C is not an independent risk factor for diabetic foot. Genetic factors in the pathogenesis of diabetic foot may also show any changes in different populations.

Tacrolimus-Induced Diabetic Ketoacidosis After Allogeneic Bone Marrow Transplant.

New-onset diabetes mellitus after solid-organ transplant makes for complicated tacrolimus immunosuppression. However, tacrolimus-associated diabetic ketoacidosis has not been reported in bone marrow transplant. We report 24-year-old women, hospitalized with diabetic ketoacidosis, 70 days after undergoing a bone marrow transplant with tacrolimus immunosuppression. Clinicians should be wary about tacrolimus levels and the risk of hyperglycemic states after bone marrow transplant as with other solid-organ transplants.

QTc prolongation during peripheral stem cell apheresis in healthy volunteers.

BACKGROUND AND AIM: Today, voluntary donation of peripheral blood stem cells by healthy donors for allogeneic hemopoietic cell transplantation is common worldwide. Such donations are associated with small but measurable risks of morbidity and mortality. Most complications are associated with citrate infusion during cell collection. We studied the effects of citrate infusion on the QTc and other vital parameters during and after peripheral stem cell apheresis in volunteers. METHOD: To ensure that donors were healthy, screening included taking a detailed medical history, physical examination, and laboratory measurements of plasma calcium and magnesium. Corrected QT (QTc) values were assessed using a 12-lead electrocardiographic platform that derived QTc values automatically. RESULTS: In all, 141 apheresis procedures were performed. The mean QTc values at baseline, at 2 and 4 h during the procedure, and at 30 min after the procedure, were 347.6 ± 59.5, 349.9 ± 52.8, 391.8 ± 54.0, and 404.8 ± 59.2 ms, respectively. The baseline and 2 h QTcs did not differ significantly, but the baseline QTc did differ significantly from the 4 h and 30 min after the procedure values. The plasma levels of calcium and magnesium did not significantly differ before and after the procedure. CONCLUSION: QTc prolongation may develop during leukopheresis, particularly if the procedure takes more than 2 h. Thus, to enhance donor safety, QTc measurement should be standard for all donors. In addition, any family history of sudden death should be noted, to prevent the development of possible fatal arrhythmia in susceptible donors.

Effectiveness of Visual Methods in Information Procedures for Stem Cell Recipients and Donors.

OBJECTIVE: Obtaining informed consent from hematopoietic stem cell recipients and donors is a critical step in the transplantation process. Anxiety may affect their understanding of the provided information. However, use of audiovisual methods may facilitate understanding. In this prospective randomized study, we investigated the effectiveness of using an audiovisual method of providing information to patients and donors in combination with the standard model. MATERIALS AND METHODS: A 10-min informational animation was prepared for this purpose. In total, 82 participants were randomly assigned to two groups: group 1 received the additional audiovisual information and group 2 received standard information. A 20-item questionnaire was administered to participants at the end of the informational session. RESULTS: A reliability test and factor analysis showed that the questionnaire was reliable and valid. For all participants, the mean overall satisfaction score was 184.8±19.8 (maximum possible score of 200). However, for satisfaction with information about written informed consent, group 1 scored significantly higher than group 2 (p=0.039). Satisfaction level was not affected by age, education level, or differences between the physicians conducting the informative session. CONCLUSION: This study shows that using audiovisual tools may contribute to a better understanding of the informed consent procedure and potential risks of stem cell transplantation.

Active Invasive Fungal Infection in a Patient With Severe Aplastic Anemia.

Severe aplastic anemia is almost always fatal unless treated. Invasive fungal infections, particularly those caused by Aspergillus species, have long been recognized as a major cause of death in severe aplastic anemia. However, there are few specific reports about infections and their therapy in patients with aplastic anemia. Despite improvements in the last few years, the response rate of new antifungal drugs, such as voriconazole and liposomal amphotericin B, has only about a 30% recovery rate in patients with severe neutropenia and persistent fever. There is a paucity of data available about hematopoietic stem cell transplant under active invasive fungal infection in the literature. Therefore, we aimed to discuss the treatment scenarios for 2 severe aplastic anemia patients who have invasive fungal infections.

Anorectal Complications During Neutropenic Period in Patients with Hematologic Diseases.

BACKGROUND: Neutropenic patients are susceptible to any anorectal disease, and symptomatic anorectal disease afflicts 2-32% of oncology patients. Perianal infections are the most feared complication, considering the lack of natural defense against infectious microorganisms. When septic complications develop, the anorectal disease is potentially fatal, especially in neutropenic patients in whom mortality rates range between 11-57%. Although anorectal diseases are a frequent complication with potentially fatal outcomes among patients with hematologic diseases, sufficient data are not available in the literature. In this study, we aimed to investigate the anorectal complications developing during the neutropenic period in patients with hematologic diseases. METHODS: A total of 79 patients whose neutropenic period (absolute neutrophil count <500/mcL) continued for 7 days, or longer were included in the study. RESULTS: A total of 34 patients out of 79 (43%) were detected to develop anorectal complications, of them 6 (7.6%) developed an anorectal infection. The patients were characterized according to the hematological disease and its status (active or not), the type of treatment and the presence of a history of an anorectal pathology before the onset of the hematologic disease. Nineteen (24.1%) patients had the history of anorectal disturbances before diagnosis of the hematologic disease, and recurrence of an anorectal pathology was found in 14 out of 19 patients(73.7%). In addition, the overall mortality rate was higher among the patients who developed anorectal complications compared to another group (41.2% vs. 22.2%, p=0.059). CONCLUSION: Anorectal pathology is a common complication with high recurrence rate in neutropenic patients. Perianal infections are important as they can cause life-threatening outcomes although they are relatively rare among all anorectal complications. Therefore perianal signs and symptoms should be meticulously evaluated concerning early diagnosis and treatment.

Cobalamin deficiency can mask depleted body iron reserves.

Vitamin B12 deficiency impairs DNA synthesis and causes erythroblast apoptosis, resulting in anaemia from ineffective erythropoiesis. Iron and cobalamin deficiency are found together in patients for various reasons. We have observed that cobalamin deficiency masks iron deficiency in some patients. We hypothesised that iron is not used by erythroblasts because of ineffective erythropoiesis due to cobalamin deficiency. Therefore, we aimed to demonstrate that depleted iron body reserves are masked by cobalamin deficiency. Seventy-five patients who were diagnosed with cobalamin deficiency were enrolled in this study. Complete blood counts and serum levels of iron, unsaturated iron binding capacity (UIBC), ferritin, vitamin B12, and thyroid stimulant hormone were determined at diagnosis and after cobalamin therapy. Patients who had a combined deficiency at diagnosis and after cobalamin therapy were recorded. Before cobalamin therapy, we found increased serum iron levels (126.4 ± 63.4 µg/dL), decreased serum UIBC levels (143.7 ± 70.8 µg/dL), increased serum ferritin levels (192.5 ± 116.4 ng/mL), and increased transferrin saturation values (47.2 ± 23.5 %). After cobalamin therapy, serum iron levels (59.1 ± 30 µg/dL), serum ferritin levels (44.9 ± 38.9 ng/mL) and transferrin saturation values (17.5 ± 9.6 %) decreased, and serum UIBC levels (295.9 ± 80.6 µg/dL) increased. Significant differences were observed in all values (p < 0.0001). Seven patients (9.3 %) had iron deficiency before cobalamin therapy, 37 (49.3 %) had iron deficiency after cobalamin therapy, and a significant difference was detected between the proportions of patients who had iron deficiency (p < 0.0001). This study is important because insufficient data are available on this condition. Our results indicate that iron deficiency is common in patients with cobalamin deficiency, and that cobalamin deficiency can mask iron deficiency. Therefore, we suggest that all patients diagnosed with cobalamin deficiency should be screened for iron deficiency, particularly after cobalamin therapy.

A Rare Complication Developing After Hematopoietic Stem Cell Transplantation: Wernicke's Encephalopathy.

Thiamine is a water-soluble vitamin. Thiamine deficiency can present as a central nervous system disorder known as Wernicke's encephalopathy, which classically manifests as confusion, ataxia, and ophthalmoplegia. Wernicke's encephalopathy has rarely been reported following hematopoietic stem cell transplantation. Herein, we report Wernicke's encephalopathy in a patient with acute myeloid leukemia who had been receiving prolonged total parenteral nutrition after haploidentical allogeneic hematopoietic stem cell transplantation. To the best of our knowledge, this is the first case reported from Turkey in the literature.

[An unusual cause of febrile neutropenia: brucellosis]. / Nötropenik atesin ender bir nedeni: Bruselloz.

Febrile neutropenia which is a common complication of cancer treatment, is one of the major causes of morbidity and mortality. Several gram-negative and gram-positive bacteria are responsible for infections in neutropenic patients, however the most common microorganisms are Escherichia coli and coagulase-negative staphylococci, in decreasing order. Although Brucella spp. infections are endemic in Turkey, brucellosis-related febrile neutropenia has only rarely been reported. In this report, a case of brucellosis-related febrile neutropenia in a patient with acute myeloblastic leukemia (AML) was presented. A 56-year-old male patient presenting with fever, petechiae/purpura, leukocytosis, thrombocytopenia, and anemia was admitted to our hospital. Laboratory studies revealed a hemoglobin level of 8.27 g/dl, leukocyte count of 77.100 k/ml, absolute neutrophil count of 200 k/ml, and platelets at 94.200 k/ml. The patient was diagnosed as AML-M1 and piperacillin/tazobactam was started as the first-line antibiotic therapy due to the febrile neutropenia. On admission, blood and urine cultures were negative. Once the fever was controlled, remission/induction chemotherapy was initiated. However, fever developed again on the eight day, and vancomycin was added to the therapy. Since the fever persisted, the antibiotic therapy was gradually replaced with meropenem and linezolid. However, fever continued and the patient's general condition deteriorated. Subsequently performed Brucella tube agglutination test revealed positivity at 1/320 titer and the microorganism grown in blood culture (Bactec 9050; BD, USA) was identified as B.melitensis by conventional methods. Rifampicin and doxycycline therapy was started immediately, however, the patient died due to septic shock. If the tests for brucellosis were performed earlier when response to second step antibiotic therapy lacked in this patient, it was assumed that mortality could be prevented by the prompt initiation of the appropriate treatment. Thus, since brucellosis is endemic in Turkey, it should be considered as a possible agent of febrile neutropenia especially in patients unresponsive to empiric antibiotherapy and appropriate diagnostic tests should be performed.

Therapeutic potential of apigenin, a plant flavonoid, for imatinib-sensitive and resistant chronic myeloid leukemia cells.

Despite the presence of many therapeutic regimens like imatinib and other tyrosine kinase inhibitors, the development of resistance, intolerance, and side effects makes chronic myeloid leukemia (CML) therapy challenging. Thus, there is a need to discover novel drugs for CML patients. In this study, we attempted to assess apigenin, a common plant dietary flavonoid, in terms of its cytotoxic, apoptotic, and cytostatic effects on imatinib-sensitive and resistant Philadelphia-positive CML cells. We analyzed apigenin's effects on cell proliferation, apoptosis, caspase-3 activity, loss of mitochondrial membrane potential, and cell cycle progression in K562 and K562/IMA3 cells. Furthermore, we described genes and gene networks that are modulated in CML in response to apigenin. Results of our study revealed that apigenin has cytotoxic and apoptotic effects on both cell types. We also displayed that apigenin induced G2/M arrest in K562 cells while arresting K562/IMA3 cells in S phase especially at the highest apigenin concentration. The expression analysis identified a set of genes that were regulated by apigenin in K652 and K562/IMA3 cells. Association of modulated genes with biological functional groups identified several networks affected by apigenin including cell survival, proliferation, cell death, cell cycle, and cell signalling pathways.

[Evaluation of fourteen adult cases with visceral leishmaniasis]. / On dört eriskin viseral leyismanyoz olgusunun degerlendirilmesi.

Visceral leishmaniasis is a life threatening systemic infectious disease caused by Leishmania protozoon, which is transmitted by phlebotomine sandflies, and is widespread in Mediterranean countries including Turkey. The aim of this study was to retrospectively evaluate the visceral leishmaniasis cases followed in our clinic between January 2005 to April 2012, under the light of the current literature. A total of 14 cases (7 female, 7 male; age range: 19-64 years, mean age: 41.6 ± 12.9 years) diagnosed as visceral leishmaniasis and followed for one year after their treatment were included in the study. Data of the cases were obtained from the patient files. Ten of the cases were immunocompetent and four were immunosuppressive. While six of the cases were residents in Adana, eight were from different cities of south and southeastern Anatolia, Turkey. The median period between the development of symptoms and diagnosis was 75 (range: 2-272) days and 79% (11/14) of them were admitted to a health center and used antimicrobial agents. The leading presenting complaint was fever (100%) followed by chills and shiver (93%), weakness (71%) and weight loss (57%). Physical examination revealed fever in 8 (57%), splenomegaly in 11 (79%) and hepatosplenomegaly in 7 (50%) cases. Based on laboratory findings, pancytopenia was detected in 10 (71.4%) and hypoalbuminemia was detected in all (100%) of the cases. The diagnosis of visceral leishmaniasis was made by the detection of amastigote form of the parasite in the smears of bone marrow aspiration for 12 (86%) cases and of tissue (liver/spleen) biopsies for two cases. Bone marrow samples obtained from all of the patients were inoculated into NNN (Novy-MacNeal-Nicole) media and only 4 (29%) of them yielded the growth of Leishmania promastigots. Parenteral lipozomal amphotericin B was initiated to 10 immunocompetent patients at a dose of 3 mg/kg/day and to three immunosuppressive patients at a dose of 4 mg/kg/day. One immunosuppressive patient lost his life before initiation of treatment. With regard to disease progression, it was detected that two cases (of whom one was renal and one was bone marrow transplant patient) lost their lives (mortality rate: 14%), however all the other cases were cured completely. The present study comprised the highest number of visceral leishmaniasis adult cases reported in Turkey and enabled the review of disease characteristics. In conclusion, cases presenting with fever, hepatosplenomegaly, pancytopenia and hypoalbuminemia and living in endemic regions should be precisely evaluated in terms of visceral leishmaniasis.

Gastroscopic removal of a migrated adjustable gastric band: a case report.

Laparoscopic gastric banding is a popular method for treating morbid obesity. Band migration is a well-known late complication and the treatment is usually reoperation. In this case report, we show that a band penetrating the gastric wall can be treated by gastroscopic operation with the Gastric Band Cutter device without complication. It seems that this technique is simpler than reoperation and is beneficial even when the intraluminal migration is partial.

Delayed and overlooked diagnosis of an unusual opportunistic infection in a renal transplant recipient: visceral leishmaniasis.

Visceral leishmaniasis is a rare opportunistic infection in renal transplantation patients and its presentation may be associated with or masked by many other factors in immunosuppressed patients. So, if it is not searched for in particular, diagnosis may be easily overlooked or delayed in renal transplant patients. A 32-year-old renal transplant recipient devoleped splenomegaly, pyrexia and pancytopenia. Six months after the first bone marrow examination, the delayed diagnosis was made possible by a second bone marrow aspiration. Liposomal amphotericin B was effective in his treatment although he had a recurrence. Early diagnosis of visceral leishmaniasis is crucial for the renal transplant recipient's therapy; and even in treated patients, the mortality rate may be high. In our case, although the time up to diagnosis was as long as six months after the onset of symptoms, response to treatment was satisfactory with higher doses of liposomal amphotericin B in the second cycle. Also, in the short term, the rate of recurrence was comparable to other reported patients who were diagnosed and treated in a month.