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Item Haploidentical Versus Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia: A Study From the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation(2022) Nagler, Arnon; Labopin, Myriam; Swoboda, Ryszard; Pioltelli, Pietro; Arat, Mutlu; Yakoub-Agha, Ibrahim; Kulagin, Alexander; Maria Raiola, Anna; Ozdogu, Hakan; Risitano, Antonio; Nur Ozkurt, Zubeyde; Sanz, Jaime; Brissot, Eolia; Zina, Peric; Giebel, Sebastian; Ciceri, Fabio; Mohty, Mohamad; 000892089600008The results of haploidentical stem cell transplantation (haploHCT) for patients with acute lymphoblastic leukemia (ALL) transplanted in active disease remain largely unknown. We retrospectively analyzed adult patients with R/R ALL who underwent haploHCT or matched sibling donor (MSD-HCT) as a first transplantation between 2012 and 2020. The analysis comprised 274 patients, 94 had a haploHCT, and 180 had an MSD-HCT. The median follow-up was 32 months. The median age was 33 (range 18-76) and 37 (18-76) years in the haplo- and MSD-HCT groups, respectively. Post-transplant cyclophosphamide (PTCy) was used in 88% of haploHCT and in 4% of the MSD-HCT group. Graft-versus-host disease grade III-IV was higher in haploHCT than in the MSD-HCT group (18% versus 9%; P = 0.042). The 2-year chronic (c) graft-versus-host disease rates were 17% versus 33% (hazard ratio [HR] = 0.56; P = 0.14), respectively. By multivariate analysis, relapse incidence, and leukemia-free survival were not significatively different between the transplant groups, while nonrelapse mortality (NRM) was significantly higher (25% versus 18% at 2 years; HR = 2.03; P = 0.042) and overall survival (OS) lower (22% versus 38% at 2 years; HR = 1.72; P = 0.009) in the haploHCT group compared with the MSD-HCT group. We conclude that the 2-year OS of R/R ALL patients undergoing MSD transplants is significantly better than in haploHCT with a higher NRM in the latter.Item Improved Outcomes of Haploidentical Hematopoietic Cell Transplantation with Total Body Irradiation-Based Myeloablative Conditioning in Acute Lymphoblastic Leukemia(2021) Dholaria, Bhagirathbhai; Labopin, Myriam; Angelucci, Emanuele; Tischer, Johanna; Arat, Mutlu; Ciceri, Fabio; Guelbas, Zafer; Sica, Simona; Ozdogu, Hakan; Diez-Martin, Jose Luis; Koc, Yener; Pavlu, Jiri; Socie, Gerard; Giebel, Sebastian; Savani, Bipin N.; Nagler, Arnon; Mohty, Mohamad; 0000-0002-8902-1283; 33830029; AAD-5542-2021The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI)-based versus chemotherapy (CT)-based MAC regimens in patients with acute lymphoblastic leukemia (ALL). The study included 427 patients who underwent first haplo-HCT with post-transplantation cyclophosphamide (PTCy), following TBI-based (n = 188; 44%) or CT-based (n = 239; 56%) MAC. The median patient age was 32 years. Fludarabine-TBI (72%) and thiotepa-busulfan-fludarabine (65%) were the most frequently used TBI- and CT-based regimens, respectively. In the TBI and CT cohorts, 2-year leukemia-free survival (LFS) was 45% versus 37% (P = .05), overall survival (OS) was 51% versus 47% (P = .18), relapse incidence (RI) was 34% versus 32% (P = .44), and nonrelapse mortality (NRM) was 21% versus 31% (P < .01). In the multivariate analysis, TBI was associated with lower NRM (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.33 to 0.86; P = .01), better LFS (HR, 0.71; 95% CI, 0.52 to 0.98; P =.04), and increased risk for grade II-IV acute graft-versus-host disease (GVHD) (HR, 1.59; 95% CI, 1.08 to 2.34; P = .02) compared with CT-based MAC. The type of conditioning regimen did not impact RI, chronic GVHD, OS, or GVHD-free, relapse-free survival after adjusting for transplantation-related variables. TBI-based MAC was associated with lower NRM and better LFS compared with CT-based MAC in patients with ALL after haplo-HCT/PTCy. (C) 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.Item Comparison of the clinical course of COVID-19 infection in sickle cell disease patients with healthcare professionals(2021) Boga, Can; Asma, Suheyl; Leblebisatan, Goksel; Sen, Nazan; Tombak, Anil; Demiroglu, Yusuf Ziya; Yeral, Mahmut; Akin, Sule; Yesilagac, Hasan; Habesoglu, Mehmet Ali; Aribogan, Anis; Kasar, Mutlu; Korur, Asli; Ozdogu, Hakan; 0000-0002-9866-2197; 34032899; AAZ-9711-2021; AAY-2668-2021It is highly expected that COVID-19 infection will have devastating consequences in sickle cell disease (SCD) patients due to endothelial activation and decreased tissue and organ reserve as a result of microvascular ischemia and continuous inflammation. In this study, we aimed to compare the clinical course of COVID-19 in adult SCD patients under the organ injury mitigation and clinical care improvement program (BASCARE) with healthcare professionals without significant comorbid conditions. The study was planned as a retrospective, multicenter and cross-sectional study. Thirty-nine SCD patients, ages 18 to 64 years, and 121 healthcare professionals, ages 21 to 53, were included in the study. The data were collected from the Electronic Health Recording System of PRANA, where SCD patients under the BASCARE program had been registered. The data of other patients were collected from the Electronic Hospital Data Recording System and patient files. In the SCD group, the crude incidence of COVID-19 was 9%, while in healthcare professionals at the same period was 23%. Among the symptoms, besides fever, loss of smell and taste were more prominent in the SCD group than in healthcare professionals. There was a significant difference between the two groups in terms of development of pneumonia, hospitalization, and need for intubation (43 vs 5%, P < 0.00001; 26 vs 7%, P = 0.002; and 10 vs 1%, P = 0.002, respectively). Prophylactic low molecular weight heparin and salicylate were used more in the SCD group than in healthcare professionals group (41 vs 9% and 28 vs 1%; P < 0.0001 for both). The 3-month mortality rate was demonstrated as 5% in the SCD group, while 0 in the healthcare professionals group. One patient in the SCD group became continously dependent on respiratory support. The cause of death was acute chest syndrome in the first case, hepatic necrosis and multi-organ failure in the second case. In conclusion, these observations supported the expectation that the course of COVID-19 in SCD patients will get worse. The BASCARE program applied in SCD patients could not change the poor outcome.Item Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia(2021) Nagler, Arnon; Kanate, Abraham S.; Labopin, Myriam; Ciceri, Fabio; Angelucci, Emanuele; Koc, Yener; Gulbas, Zafer; Arcese, William; Tischer, Johanna; Pioltelli, Pietro; Ozdogu, Hakan; Afanasyev, Boris; Wu, Depei; Arat, Mutlu; Peric, Zinaida; Giebel, Sebastian; Savani, Bipin; Mohty, Mohamad; 32354866Graft-versus-host disease (GvHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation includes posttransplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing data in the European Society for Blood and Marrow Transplantation registry, we compared ATG- versus PTCy-based GvHD prophylaxis in 434 adults with acute lymphoblastic leukemia undergoing haploidentical hematopoietic cell transplantation. Of the 434 patients included in this study, ATG was used in 98 and PTCy in 336.. The median follow-up was approximately 2 years. The baseline characteristics of the patients were similar between the groups except that the ATG group was more likely to have had relapsed/refractory acute lymphoblastic leukemia (P=0.008), had conditioning not including total body irradiation (P<0.001), have had peripheral blood as the source of their grafts (P=0.001) and to have been transplanted in an earlier timeperiod (median year of transplantation: 2011 vs. 2015). The 100-day rates of grade II-IV and III-IV acute GvHD were similar in the ATG and PTCy groups, as were 2-year chronic GvHD rates. On multivariate analysis, leukemia-free survival and overall survival were better with PTCy than with ATG prophylaxis. Relapse incidence was lower in the PTCy group (P=0.03), while non-relapse mortality was not different. Advanced disease and lower performance score were associated with poorer leukemia-free survival and overall survival and advanced disease was associated with inferior GvHD-free/relapse-free survival. Compared to bone marrow grafts, peripheral grafts were associated with higher rates of GvHD. In patients with acute lymphoblastic leukemia undergoing unmanipulated haploidentical hematopoietic cell transplantation, PTCy for GvHD prevention resulted in a lower incidence of relapse and improved leukemia-free survival and overall survival, compared to ATG.Item Incidence and outcome of Kaposi sarcoma after hematopoietic stem cell transplantation: a retrospective analysis and a review of the literature, on behalf of infectious diseases working party of EBMT(2020) Cesaro, Simone; Tridello, Gloria; van der Werf, Steffie; Bader, Peter; Socie, Gerard; Ljungman, Per; McQuaker, Grant; Giardino, Stefano; ckan-Cetinkaya, Duygu; Anagnostopoulos, Achilles; Ozdogu, Hakan; Schots, Rik; Jindra, Pavel; Ladetto, Marco; Schroyens, Wilfried; Mikulska, Malgorzata; Styczynski, Jan; 0000-0002-8902-1283; 31435035; AAD-5542-2021The incidence, the clinical characteristics, and the outcome of Kaposi sarcoma (KS) in patients after hematopoietic stem cell transplantation (HSCT) were assessed. During the period 1987-2018, 13 cases of KS were diagnosed, 3 females and 10 males, median age of 50 years, median time from HSCT of 7 months. KS had an incidence of 0.17% in allogeneic and 0.05% in autologous HSCT. HHV-8 was documented in eight of nine tumor tissue samples assessed. The organ involvement was: skin in nine, lymph nodes in six, oral cavity in four, and visceral in three patients, respectively; seven patients had >1 organ involved. Five patients had immunosuppression withdrawn, whereas four and three patients received radiotherapy and chemotherapy, respectively. Eight patients are alive (median follow-up 48 months, range 5-128), whereas five patients died after a median time of 8 months from the diagnosis of KS. However, no death was caused by KS. We conclude that the incidence of KS after HSCT is very low. Although KS can be managed with the reduction of immunosuppression, visceral forms may require chemotherapy and/or radiotherapy. The low prevalence of KS indicates that screening for HHV-8 serology and surveillance for HHV-8 viremia are not indicated in HSCT patients.Item Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for T Cell Acute Lymphoblastic Leukemia: A Report from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party(2020) Ozdogu, Hakan; 0000-0002-8902-1283; 31926364; AAD-5542-2021Allogeneic hematopoietic cell transplantation (HCT) is recommended in high-risk patients with T cell acute lymphoblastic leukemia (T-ALL). For patients without an HLA-identical donor, haploidentical (haplo-) HCT is becoming the leading source of stem cell donation. However, data are scarce on predictive factors for outcome in that setting. We identified 122 adults (20% female; median age, 31 years; range, 18 to 68 years) with T-ALL who underwent haplo-HCT with post-transplantation cyclophosphamide (ptCy) between 2010 and 2017. The median duration of follow-up of living patients was 23 months. The 2-year incidences of relapse and nonrelapse mortality were 45% and 21%, respectively. The 2-year leukemia-free survival (LFS), overall survival (OS), and graft-versushost disease, relapse-free survival (GRFS) were 34%, 42%, and 27%, respectively. The 2-year LFS and OS were highly influenced by disease status at transplantation, being 49% and 55%, respectively, for patients in first complete remission (CR1); 34% and 50%, respectively, for those in second CR (CR2); and 8% and 12%, respectively, for patients with active disease. On multivariate analysis, only disease status was found to affect LFS and OS. Transplantation in CR2 negatively affected LFS, whereas active disease at the time of haplo-HCT negatively affected LFS and OS. In conclusion, haplo-HCT with ptCy produced encouraging results in this challenging disease, particularly when performed in patients in CR. Despite the limitation of the small sample size, our results were not affected by the type of conditioning, calling into question the need for total body irradiation-based myeloablative conditioning in that setting. (C) 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.Item The Clinicopathologic Features and the Factors Associated with the Survival in Light -Chain Amyloidosis Patients: A Single Center Descriptive Study(2020) Aytan, Pelin; Yeral, Mahmut; Gereklioglu, Cigdem; Kasar, Mutlu; Korur, Asli; Buyukkurt, Nurhilal; Asma, Suheyl; Kozanoglu, Ilknur; Ozdogu, Hakan; Boga, Can; 0000-0002-5086-5593; 0000-0003-3856-7005; 0000-0002-0895-4787; 0000-0002-8902-1283; 0000-0002-5268-1210; 0000-0002-9680-1958; AAD-6222-2021; AAD-5616-2021; AAL-3906-2021; AAE-1457-2021; AAD-5542-2021; AAE-1241-2021Objective: To present the clinicopathologic features and assess the factors related to the survival in light- chain amyloidosis (AL) patients. Method: All the patients with AL diagnosis being followed-up in the hematology department were recruited in the study. Clinicopathologic data were obtained. Factors related with overall survival (OS) including systemic inflammatory response markers were analyzed. Results: In 16 AL patients, the estimated OS was 58.6 +/- 10.8 months, with a-5-year- survival rate of 52.1%. While, 43.8% of the patients died during the study period. Gastrointestinal and respiratory complaints were the most frequent symptoms. Myocardial and renal biopsies were amyloid positive in 31.3% and 25% of the patients respectively. Myeloma was diagnosed in 18.8% and amyloid was positive in 31.3% of the bone marrow biopsies. There was no difference between surviving and deceased patients with respect to laboratory findings including systemic inflammatory markers. Only immunoglobulin M was significantly lower in the deceased patients and IgM was found to be the only factor independently associated with OS. Lower IgM levels were associated with decreased OS. An IgM value of 75.4 mg/dL was found as a cut-off value with a sensitivity and specificity of 71.4% and 66.7% respectively for the prediction of survival status. Conclusion: AL is a rare, progressive, systemic disease with a wide spectrum of clinical presentations. The disease most commonly presents with gastrointestinal and respiratory complaints. IgM level seems to be an independent predictor of survival and may be used as a prognostic marker.Item Non-Hematologic Malignancies Metastasing to the Bone Marrow: A Record-Based Descriptive Study From A Tertiary Center(2019) Aytan, Pelin; Kocer, Nazim Emrah; Yeral, Mahmut; Gereklioglu, Cigdem; Kasar, Mutlu; Buyukkurt, Nur Hilal; Asma, Suheyl; Ozdogu, Hakan; Boga, CanThe aim of this study is to assess the cases of nonhematologic maiignancies that had bone marrow (BM) metastasis with respect to hematologic abnormalities, radiologic findings and pathologic findings. All of the patients with BM investigation were retrospectively evaluated. The patients with BM metastasis by a non-hematologic malignancy were assessed. Data regarding patient characteristics including peripheral blood evaluation findings, imaging findings, BM evaluation results and survival were obtained from patient files and computer based electronic database. 30 cases were detected among 1831 BM aspirations and biopsies. The most common malignancies were breast (36.7%), prostate (13.3%), gastric(13.3%) and lung (13.3%) adenocarcinomas. 90.9% and 75% of the cases had positive radiologic findings with PET/CT and CT respectively. 43.3% of the patients died during the study period and the median time from BM assessment to death was 2 months. Anemia, thrombocytopenia and leukopenia were present in 90%, 73.3% and 20% respectively. Lactate dehydrogenase and alkaline phosphatase were elevated in 90% and 80% respectively. In 76.2% a leukoerythroblastic blood picture was present. All the cases were diagnosed with biopsy and aspiration detected infiltration in 40% and in 4 metastatic patients (13.3%) the aspiration was false negative. In 46.7% the aspiration resulted with dry tap. Grade 3 fibrosis was present in 76.7%. BM assessment is a minimally invasive technique and provides very beneficial clinical data, however, because the survival is very short after BM assessment and the PET/CT has a considerable sensitivity it is not necessary to confirm BM metastasis in patients whose tumor stage is already known.Item Therapeutic Potential of Apigenin, a Plant Flavonoid, for Imatinib-Sensitive and Resistant Chronic Myeloid Leukemia Cells(2014) Solmaz, Soner; Gokbulut, Aysun Adan; Cincin, Birsu; Ozdogu, Hakan; Boga, Can; Cakmakoglu, Bedia; Kozanoglu, Ilknur; Baran, YusufDespite 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.Item Use of Mesenchymal Cells to Modulate Immune Suppression and Immune Reconstruction in a Patient with Aplastic Anemia Complicated by Invasive Sino-Orbital Aspergillosis(2014) Ozdogu, Hakan; Yeral, Mahmut; Boga, Can; Kozanoglu, IlknurCultured human bone marrow mesenchymal cells (MSCs) have immunomodulatory and tissue regenerative properties. This report summarizes the result of post-transplant treatment with MSCs of a 26-year-old patient with aplastic anemia complicated by invasive sino-orbital aspergillosis. The patient was treated with MSCs to benefit from the dual effects of MSCs in immune reconstitution: suppression against alloreactive T cells and facilitation of the re-engraftment process. The patient did not develop acute or chronic graft-versus-host disease. The aspergillus infection healed completely. The engraftment failure was also ended without any complications. During his last visit in his fourth year after transplantation, the patient was in hematological remission. Human bone marrow-derived MSCs seem to have an important role in preventing or overcoming immunological complications in patients who undergo stem cell transplantation.
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