E-ISSN: 1308-5263
Turkish Journal of Hematology - Turk J Hematol: 38 (4)
Volume: 38  Issue: 4 - 2021
RESEARCH ARTICLE
1. Clinical Significance of TP53 Abnormalities in Newly Diagnosed Multiple Myeloma
Fang Ye, Tongtong Wang, Aijun Liu, Yanchen Li, Ningning Li, Huan Wang, Wenming Chen
doi: 10.4274/tjh.galenos.2021.2021.0064  Pages 246 - 253
Objective: This study aimed to identify the clinical significance of TP53 and common cytogenetic abnormalities.
Materials and Methods: A total of 114 patients with newly diagnosed multiple myeloma (MM) and TP53 abnormalities were selected from two large patient cohorts of collaborating hospitals from 2010 to 2017. The characteristics and outcomes of these patients were analyzed. TP53 and other common mutations in MM patients were quantified by fluorescence in situ hybridization. Kaplan-Meier curves and logrank tests were applied for survival analysis. A Cox proportional hazard model for covariate analysis was used to determine the prognostic factors.
Results: By extensive data analysis, we found that TP53 amplification is a strong positive predictor for complete response (CR) to therapy and positively correlated with patient survival. The number of simultaneous genomic abnormalities with TP53 mutation has a modest impact on patient survival. Among these mutations, 1q21 amplification is associated with decreased CR (odds ratio: 4.209) and FGFR3 levels are positively correlated with progression-free and overall survival.
Conclusion: TP53 abnormalities at the diagnosis of MM are of great clinical significance in predicting patient response to therapy and survival. Furthermore, 1q21 and FGFR3 mutations could potentially be used in combination with TP53 status to better predict patient survival and guide the selection of high-risk patients to advance patient treatment strategies.

2. Generation of Induced Pluripotent Stem Cells from Patients with Multiple Myeloma
İrem Yılmaz Başaran, Erdal Karaöz
doi: 10.4274/tjh.galenos.2021.2020.0682  Pages 254 - 263
Objective: Patient-specific induced pluripotent stem cells (iPSCs) have potential in human disease modeling and regenerative medicine. The in vitro phenotype of disease-specific iPSC-derived cells can be used to bridge the knowledge gap between clinical phenotype and molecular or cellular pathophysiology and to understand the pathology of diseases, along with further applications, such as creating new strategies for drug screening or developing novel therapeutic agents. The aim of our study was to generate iPSCs from multiple myeloma (MM) patients.
Materials and Methods: Mesenchymal stem cells (MSCs) isolated from MM patients were induced for pluripotency via the Sendai virus. Fibroblasts were used as a control. Microscopic analysis was performed daily. For colony selection, live staining was done using alkaline phosphatase staining. Reprogramming experiments were confirmed by flow cytometry, immunofluorescence (IF) staining, and gene expression analyses. To confirm the spontaneous differentiation potential, an in vitro embryonic body (EB) formation assay was performed.
Results: Fibroblasts and MSCs obtained from MM patients were reprogrammed using the Sendai virus, which contains reprogramming vectors with the four Yamanaka factors, Oct3/4, Sox2, Klf4, and c-Myc. Microscopic analysis revealed that the generated iPSCs possessed classical embryonic stem cell-like morphological characteristics. Reprogramming experiments further showed that both cell lines can be reprogrammed up to the pluripotent stage, which was confirmed by flow cytometry, IF staining, and gene expression analyses. Spontaneous differentiation potential was confirmed by in vitro EB formation assays.
Conclusion: iPSCs have been successfully obtained from MM patients for the first time. These cells could clarify the molecular mechanisms behind this disease.

3. LncRNA-DUXAP8 Regulation of the Wnt/β-Catenin Signaling Pathway to Inhibit Glycolysis and Induced Apoptosis in Acute Myeloid Leukemia
Hong Zhai, Junting Zhao, Juan Pu, Pan Zhao, Jin Wei
doi: 10.4274/tjh.galenos.2021.2020.0769  Pages 264 - 272
Objective: Acute myeloid leukemia (AML) is a malignancy of the hematopoietic system, accounting for approximately 70% of acute leukemias. Long noncoding RNA-DUXAP8 (lncRNA-DUXAP8) has been found to be abnormally expressed in a variety of tumors. However, its function and mechanism in AML have not been studied. We investigate the effect of lncRNA-DUXAP8 on AML and its mechanism so as to provide a new theoretical basis for the diagnosis and treatment of AML.
Materials and Methods: The expression of lncRNA-DUXAP8 in AML bone marrow tissues and the THP-1, HL-60, TF-1, AML193, and U937 cell lines was detected by qRT-PCR. It was then altered by transfecting plasmids overexpressing si-DUXAP8 and lncRNA-DUXAP8, respectively. CCK8 and cell colony assay were performed to evaluate the proliferation ability of AML cells. In addition, flow cytometry was used to observe the apoptosis process. Glucose and lactate kits were utilized to detect glucose consumption and lactate levels. Finally, western blotting was performed to detect the expression of proteins related to the Wnt/β-catenin signaling pathway in cells.
Results: LncRNA-DUXAP8 was downregulated in both AML bone marrow tissues and cell lines. Upon interfering with lncRNA-DUXAP8 in AML cell line THP-1, AML cell proliferation and glycolysis were promoted while cell apoptosis was inhibited. The opposite results were obtained after overexpressing lncRNA-DUXAP8. Meanwhile, western blotting confirmed that interference with lncRNA-DUXAP8 stimulated the expression of proteins Wnt5a, β-catenin, c-Myc, and cyclin-D1 in the Wnt/β-catenin pathway. Moreover, overexpression of lncRNA-DUXAP8 inhibited the expression of Wnt/β-catenin pathway proteins. Finally, LiCl, an activator of the Wnt/β-catenin pathway, reversed the regulation of AML cells by lncRNA-DUXAP8 upregulation compared with the DUXAP group.
Conclusion: This study showed that lncRNA-DUXAP8 regulated the Wnt/β-catenin signaling pathway to inhibit glycolysis and induce apoptosis in AML. This experiment has provided new angles and an experimental basis for treating patients with AML.

4. Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data
Anıl Tombak, Funda Pepedil Tanrıkulu, Salih Sertaç Durusoy, Hüseyin Derya Dinçyürek, Emin Kaya, Elif Gülsüm Ümit, İrfan Yavaşoğlu, Özgür Mehtap, Burak Deveci, Mehmet Ali Özcan, Hatice Terzi, Müfide Okay, Nilgün Sayınalp, Mehmet Yılmaz, Vahap Okan, Alperen Kızıklı, Ömer Özcan, Güven Çetin, Sinan Demircioğlu, İsmet Aydoğdu, Güray Saydam, Eren Arslan Davulcu, Gül İlhan, Mehmet Ali Uçar, Gülsüm Özet, Seval Akpınar, Burhan Turgut, İlhami Berber, Erdal Kurtoğlu, Mehmet Sönmez, Derya Selim Batur, Rahşan Yıldırım, Vildan Özkocaman, Ahmet Kürşad Güneş, Birsen Sahip, Şehmus Ertop, Olga Meltem Akay, Abdülkadir Baştürk, Mehmet Hilmi Doğu, Aydan Akdeniz, Ali Ünal, Ahmet Seyhanlı, Emel Gürkan, Demet Çekdemir, Burhan Ferhanoğlu
doi: 10.4274/tjh.galenos.2021.2021.0007  Pages 273 - 285
Objective: This study aimed to retrospectively evaluate the efficacy, safety, and survival outcome of single-agent ibrutinib therapy in chronic lymphocytic leukemia patients.
Materials and Methods: A total of 136 patients (mean age ± standard deviation: 64.6±10.3 years, 66.9% males) who had received at least one dose of ibrutinib were included in this retrospective multicenter, noninterventional hospital-registry study conducted at 33 centers across Turkey. Data on patient demographics, baseline characteristics, laboratory findings, and leukemia-cell cytogenetics were retrieved. Treatment response, survival outcome including overall survival (OS) and progression-free survival (PFS), and safety data were analyzed.
Results: Overall, 36.7% of patients were categorized as Eastern Cooperative Oncology Group (ECOG) class 2-3, while 44.9% were in Rai stage 4. Fluorescence in situ hybridization revealed the presence of del(17p) in 39.8% of the patients. Patients received a median of 2.0 (range: 0-7) lines of pre-ibrutinib therapy. Median duration of therapy was 8.8 months (range: 0.4-58.0 months). The 1-year PFS and OS rates were 82.2% and 84.6%, respectively, while median PFS time was 30.0 (standard error, 95% confidence interval: 5.1, 20.0-40.0) months and median OS time was 37.9 (3.2, 31.5-44.2) months. Treatment response (complete or partial response), PFS time, and OS time were better with 0-2 lines versus 3-7 lines of prior therapy (p<0.001, p=0.001, and p<0.001, respectively), with ECOG class 0-1 versus class 2-3 (p=0.006, p=0.011, and p=0.001, respectively), and with Rai stage 0-2 versus 3-4 (p=0.002, p=0.001, and p=0.002, respectively). No significant difference was noted in treatment response rates or survival outcome with respect to the presence of comorbidity, bulky disease, or del(17p). While 176 adverse events (AEs) were reported in 74 (54.4%) patients, 46 of those 176 AEs were grade 3-4, including pneumonia (n=12), neutropenia (n=11), anemia (n=5), thrombocytopenia (n=5), and fever (n=5).
Conclusion: This real-life analysis confirms the favorable efficacy and safety profile of long-term ibrutinib treatment while emphasizing the potential adverse impacts of poorer ECOG performance status, heavy treatment prior to ibrutinib, and advanced Rai stage on patient compliance, treatment response, and survival outcomes.

5. Pre-Conditioning Serum Uric Acid as a Risk Factor for Sinusoidal Obstruction Syndrome of the Liver in Children Undergoing Hematopoietic Stem Cell Transplantation
Fatma Visal Okur, Murat Karapapak, Khaled Warasnhe, Umut Ece Arslan, Barış Kuşkonmaz, Duygu Çetinkaya
doi: 10.4274/tjh.galenos.2021.2021.0174  Pages 286 - 293
Objective: Uric acid (UA), a known danger signal released from injured cells, is a valuable sign of inflammation. We aimed to evaluate the association of serum UA levels before the start of conditioning regimens with the risk of hepatic sinusoidal obstruction syndrome (SOS) development after hematopoietic stem cell transplantation (HSCT).
Materials and Methods: Two hundred and twenty-two children who underwent allogeneic HSCT at the Pediatric BMT Unit of Hacettepe University between 2000 and 2014 were included in this retrospective study. Serum UA levels were measured before conditioning as an indicator of the pre-transplant inflammatory status of the patients. Patients with and without a diagnosis of SOS were compared regarding primary diagnosis, previously described risk factors for SOS, and preconditioning serum UA.
Results: SOS was diagnosed in 42 patients who had higher pre-conditioning serum UA levels compared to those who did not. Pre-transplant serum creatinine, gamma-glutamyl transferase, bilirubin, ferritin, and C-reactive protein levels did not differ significantly among patients with and without SOS; however, serum albumin was lower in the patients who developed SOS. Receiver operating characteristic analysis revealed that a pre-conditioning UA level higher than 3.32 mg/dL was predictive of SOS. When applied to a multivariate model, only pre-conditioning UA and albumin levels remained significant risk factors for SOS (UA: odds ratio [OR], 2.54; 95% confidence interval [CI], 1.26-5.12, p=0.009; albumin: OR, 0.45, 95% CI, 0.22-0.95, p=0.037).
Conclusion: Our results suggest that pre-conditioning serum UA is an independent risk factor for SOS, and it might be used as an early predictor of hepatic SOS together with previously described clinical and laboratory parameters.

6. Thrombolysis with Systemic Recombinant Tissue Plasminogen Activator in Children: A Multicenter Retrospective Study
Emine Zengin, Nazan Sarper, Arzu Yazal Erdem, Işık Odaman Al, Melike Sezgin Evim, Neşe Yaralı, Burcu Belen, Arzu Akçay, Ayşen Yıldırım, Tuba Hilkay Karapınar, Adalet Meral Güneş, Sema Aylan Gelen, Hale Ören, Lale Olcay, Birol Baytan, Hüseyin Gülen, Gülyüz Öztürk, Mehmet Fatih Orhan, Yeşim Oymak, Sibel Akpınar, Özlem Tüfekçi, Meryem Albayrak, Burçak Tatlı Güneş, Aylin Canpolat, Namık Özbek
doi: 10.4274/tjh.galenos.2021.2021.0038  Pages 294 - 305
Objective: This study aimed to evaluate systemic thrombolysis experiences with recombinant tissue plasminogen activator (rtPA).
Materials and Methods: Retrospective data were collected from 13 Turkish pediatric hematology centers. The dose and duration of rtPA treatment, concomitant anticoagulant treatment, complete clot resolution (CCR), partial clot resolution (PCR), and bleeding complications were evaluated. Low-dose (LD) rtPA treatment was defined as 0.01-0.06 mg/kg/h and high-dose (HD) rtPA as 0.1-0.5 mg/kg/h.
Results: Between 2005 and 2019, 55 thrombotic episodes of 54 pediatric patients with a median age of 5 years (range: 1 day to 17.75 years) were evaluated. These patients had intracardiac thrombosis (n=16), deep vein thrombosis (DVT) (n=15), non-stroke arterial thrombosis (n=14), pulmonary thromboembolism (PE) (n=6), and stroke (n=4). The duration from thrombus detection to rtPA initiation was a median of 12 h (range: 2-504 h) and it was significantly longer in cases of DVT and PE compared to stroke, non-stroke arterial thrombosis, and intracardiac thrombosis (p=0.024). In 63.6% of the episodes, heparin was initiated before rtPA treatment. LD and HD rtPA were administered in 22 and 33 of the episodes, respectively. Concomitant anticoagulation was used in 90% and 36% of the episodes with LD and HD rtPA, respectively (p=0.0001). Median total duration of LD and HD rtPA infusions was 30 h (range: 2-120 h) and 18 h (2-120 h), respectively (p=0.044). Non-fatal major and minor bleeding rates were 12.5% and 16.7% for LD and 3.2% and 25.8% for HD rtPA, respectively. At the end of the rtPA infusions, CCR and PCR were achieved in 32.7% and 49.0% of the episodes, respectively. The most successful site for thrombolysis was intracardiac thrombosis. HD versus LD rtPA administration was not correlated with CCR/PCR or bleeding (p>0.05).
Conclusion: Systemic thrombolytic therapy may save lives and organs effectively if it is used at the right indications and the right times in children with high-risk thrombosis by experienced hematologists with close monitoring of recanalization and bleeding.

7. Assessment of Long-Term Hematologic Effects in Differentiated Thyroid Cancer Patients Treated with Radioactive Iodine
Bircan Sönmez, Özlen Bektaş, Nergiz Erkut, Mehmet Sönmez
doi: 10.4274/tjh.galenos.2021.2021.0092  Pages 306 - 313
Objective: Radioactive iodine (RAI) therapy may cause hematologic abnormalities. The aim of this study is to evaluate long-term hematologic effects in differentiated thyroid cancer (DTC) patients after RAI therapy.
Materials and Methods: A total of 1389 patients with DTC who were treated with RAI were retrospectively evaluated. Complete blood cell counts before RAI therapy and at last follow-up and hematologic malignancy development were obtained from the electronic records.
Results: In the long-term analysis, thrombocytopenia and lymphopenia were observed significantly in patients over 60 years of age. Thrombocytopenia was observed more frequently in men. Leukopenia, thrombocytopenia, and lymphopenia were observed significantly with doses of >175 mCi. Thrombocytopenia and lymphopenia were observed significantly with multiple dose administration. Higher frequencies of anemia, thrombocytopenia, leukopenia, neutropenia, and lymphopenia were found in patients with advanced-stage disease. However, patients with advanced-stage disease had higher doses and more multiple doses than patients with early-stage disease. The rate of hematologic malignancy was found to be higher than in the general population.
Conclusion: We suggest that cytopenia be surveyed more carefully in patients older than 60 years of age. The most important risk factor for lower platelets after RAI therapy is male gender. Clinically, the most important predictor for cytopenia is advanced disease stage, which is related to the combined effects of applied high dose activity, multiple dose applications, and high tumor burden.

PERSPECTIVE IN HEMATOLOGY
8. A Rare Lymphoproliferative Disease: Castleman Disease
Eren Gündüz, Nihal Özdemir, Şule Mine Bakanay, Sema Karakuş
doi: 10.4274/tjh.galenos.2021.2021.0440  Pages 314 - 320
Castleman disease is a rare lymphoproliferative disease also known as angiofollicular lymph node hyperplasia. It is classified as hyaline vascular and plasmacytic variants histologically but characteristics of both types can coexist. Most unicentric cases of the disease are hyaline vascular while most multicentric cases are of the plasmacytic type. Although the pathogenesis is not completely understood, the role of interleukin (IL)-6 in unicentric disease and the roles of IL-6 and human herpes virus-8 in multicentric disease are well defined. Unicentric disease is typically localized and symptoms are minimal and treated locally. Multicentric disease is systemic and clinically characterized by generalized lymphadenopathy, splenomegaly, anemia, and systemic inflammatory symptoms. Systemic therapies are primarily given. Several malignant diseases including lymphomas, POEMS syndrome, follicular dendritic cell sarcomas, paraneoplastic pemphigus, Kaposi sarcoma, and amyloidosis can be associated with Castleman disease. In this paper, recent information about Castleman disease, which is a rare disease, is summarized.

BRIEF REPORT
9. Convalescent Plasma Reduces Endogenous Antibody Response in COVID-19: A Retrospective Cross-Sectional Study
Ahmet Omma, Abdulsamet Erden, Serdar Can Güven, İhsan Ateş, Orhan Küçükşahin
doi: 10.4274/tjh.galenos.2021.2021.0277  Pages 321 - 324
Objective: The aim of this study is to investigate post-COVID-19 antibody titers in patients who received convalescent plasma (CP) in addition to standard-of-care treatment.
Materials and Methods: Hospitalized COVID-19 patients who received CP in addition to standard care were retrospectively investigated. Patients who received CP with a recorded total COVID-19 antibody test result after treatment were included. From among hospitalized COVID-19 patients who received only standard care with a recorded total COVID-19 antibody test result, a control group matched for age, gender, and comorbidities was formed. Total COVID-19 antibody index levels were compared.
Results: Thirty-three CP recipients were enrolled in the study. The control group consisted of 34 age-, gender-, and comorbiditymatched standard-care patients. Median total COVID-19 antibody index levels were significantly reduced in the CP group.
Conclusion: Although CP therapy may have benefits for disease outcome, its potential ability to hamper long-term immunity may be a problem.

IMAGES IN HEMATOLOGY
10. Simultaneous Presentation of Hairy Cell Leukemia and Acute Lymphoblastic Leukemia
Mingyong Li, Yuan He, Kang Jiang, Juan Zhang
doi: 10.4274/tjh.galenos.2021.2020.0503  Pages 325 - 326
Abstract |Full Text PDF

11. Bone Marrow Oxalosis: Crystal Flowers in the Bone Marrow Garden
Nabhajit Mallik, Man Updesh Singh Sachdeva
doi: 10.4274/tjh.galenos.2021.2020.0557  Pages 327 - 328
Abstract |Full Text PDF

LETTER TO EDITOR
12. Hematological Findings and Clinical Severity in Pediatric Patients with COVID-19
Pathum Sookaromdee, Viroj Wiwanitkit
doi: 10.4274/tjh.galenos.2021.2021.0488  Pages 329 - 330
Abstract |Full Text PDF

13. Hematological Malignancy Patients, COVID-19, and Favipiravir
Rujittika Mungmunpuntipantip, Viroj Wiwanitkit
doi: 10.4274/tjh.galenos.2021.2021.0582  Pages 331 - 332
Abstract |Full Text PDF

14. A Peculiar Disease in a Young Woman Wanting to Get Pregnant
Tülin Tiraje Celkan, Şeyma Fenercioğlu, Ayşe Gonca Kaçar
doi: 10.4274/tjh.galenos.2021.2021.0191  Pages 333 - 334
Abstract |Full Text PDF

15. Pulmonary Embolism Secondary to Intravenous Immunoglobulin in a Child with Leukemia
Işıl Seren Oğuz, Zühre Kaya, Serap Kirkiz, Ülker Koçak
doi: 10.4274/tjh.galenos.2021.2021.0400  Pages 335 - 336
Abstract |Full Text PDF

16. Severe Lymphocytosis in a Case of Diffuse Large B-Cell Lymphoma Treated by Ibrutinib
Semra Paydaş, Ertuğrul Bayram, Mehmet Türker, Turan Özer
doi: 10.4274/tjh.galenos.2021.2021.0362  Pages 337 - 338
Abstract |Full Text PDF

17. Leg Ulcers Associated with Anagrelide
Tuba Oskay, Mehmet Özen
doi: 10.4274/tjh.galenos.2021.2021.0399  Pages 338 - 340
Abstract |Full Text PDF

18. Acute Basophilic Leukemia Arising from Chronic Myeloid Leukemia with Isolated Thrombocytosis
Yun Zhang, Xiaosu Kang, Xiliang Chen, Ting Li
doi: 10.4274/tjh.galenos.2021.2021.0546  Pages 341 - 343
Abstract |Full Text PDF

19. Treatment with Venetoclax for Chronic Lymphocytic Leukemia with the Highest Known White Blood Cell Count: Safe and Effective
Mehmet Sönmez, Merve Kestane, Osman Akıdan, Nergiz Erkut, Özlen Bektaş
doi: 10.4274/tjh.galenos.2021.2021.0435  Pages 344 - 346
Abstract |Full Text PDF

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20. Author Index

Pages E1 - E3
Abstract |Full Text PDF

21. Subject Index

Pages E4 - E13
Abstract |Full Text PDF

22. Advisory Board of This Issue

Page E14
Abstract |Full Text PDF