Publications by authors named "Ayse Salihoglu"

42 Publications

An Overview of Lenalidomide in Combination with Rituximab for the Treatment of Adult Patients with Follicular Lymphoma: The Evidence to Date.

Drug Des Devel Ther 2021 7;15:3809-3820. Epub 2021 Sep 7.

Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.

Follicular lymphoma (FL) is an indolent (low-grade) malignancy of B cells and is among the most common hematological cancers affecting adults. Its clinical presentation, natural course, and severity are highly variable. Management of FL depends on the clinical setting; most patients require multiple lines of treatment. Chemoimmunotherapy is the standard of care for FL patients needing treatment; however, alternative treatments are limited for refractory patients or those unfit for chemoimmunotherapy. Multiple alternatives to chemoimmunotherapy for FL are being developed, with some showing significant promise. Lenalidomide combination with rituximab (LR) is among the most successful and extensively studied novel approaches. LR has been compared head-to-head in clinical trials with rituximab monotherapy and chemoimmunotherapy in the frontline and to lenalidomide or rituximab monotherapy in the relapsed or refractory setting for the treatment of FL. Initial reports of these nine trials have been published in the last decade, and their long-term data will be available in the coming years. LR offered superior efficacy to either lenalidomide or rituximab monotherapy alone. The RELEVANCE trial compared the efficacy of LR with chemoimmunotherapy among 1030 FL patients and demonstrated similar efficacy with a different side effect profile. Myelosuppression, rash, and fatigue were among the significant adverse events. Most patients treated with LR received thromboprophylaxis. This paper aims to summarize and comment on the published evidence regarding LR treatment for FL through a literature review. The clinical trials will be presented in detail, and methodological differences complicating their comparisons will be discussed.
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http://dx.doi.org/10.2147/DDDT.S281614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434836PMC
September 2021

Efficacy and Safety of Imatinib Treatment in Elderly Patients With Chronic Myeloid Leukemia: Real-Life Data and a Single-Center Experience.

Clin Lymphoma Myeloma Leuk 2021 Aug 20;21(8):549-557. Epub 2021 Apr 20.

Division of Hematology, Department of Internal Medicine, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey.

Background: In the era of tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) patients generally live close to a normal lifespan, and the number of elderly patients with CML with comorbidities is increasing.

Patients And Methods: We retrospectively compared the efficacy and safety of frontline imatinib between elderly patients (≥60 years old) and younger patients (<60 years old) with CML.

Results: The study included 33 elderly and 125 younger patients. Elderly patients had significantly higher Charlson comorbidity index (CCI) scores. Efficacy and toxicity were comparable among the older patients with CCI scores of 0 and ≥1. There were significantly more hematologic adverse events (AEs) in elderly patients (P = .005). Although not significant, nonhematologic AEs were also more common in older cases (P = .056). Elderly patients had significantly higher rates of imatinib dose reduction (P < .001). Cumulative response rates were similar in both groups. Event-free survival was comparable, and overall survival (OS)-when non-CML-related deaths were censored-was also similar. In the multivariate analysis, age at diagnosis and CCI were associated with OS, and patients ≥ 60 years of age had a 5.998-times higher risk of death compared with the patients < 60 years of age (P = .011). Similarly, patients with CCI scores ≥ 2 had a 3.758-times higher risk of death compared with patients with a CCI score of 0 (P = .033).

Conclusions: Upfront imatinib was generally well tolerated among elderly Turkish patients with CML with non-inferior responses and long-term outcomes when compared with younger patients. Comorbidities can be problematic in elderly patients, and today the survival of patients with CML is determined mostly by comorbidities.
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http://dx.doi.org/10.1016/j.clml.2021.04.005DOI Listing
August 2021

The prognostic value of serum levels of a proliferation-inducing ligand (APRIL) in treatment-naïve patients with chronic lymphocytic leukemia

Turk J Med Sci 2021 02 26;51(1):348-354. Epub 2021 Feb 26.

Department of Internal Medicine, Section of Hematology, Cerrahpaşa Medical Faculty, İstanbul University-Cerrahpaşa, İstanbul, Turkey

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-naïve patients were followed up for 6.5 years for any treatment need.

Results: Patients were divided into 3 groups: Treatment-naïve (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-naïve 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-naïve CLL patients.
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http://dx.doi.org/10.3906/sag-2004-282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991891PMC
February 2021

Copy-number variations in adult patients with chronic immune thrombocytopenia.

Expert Rev Hematol 2020 11 23;13(11):1277-1287. Epub 2020 Sep 23.

Cerrahpasa Faculty of Medicine, Division of Haematology, Department of Internal Medicine, Istanbul University-Cerrahpasa , Istanbul, Turkey.

Objectives: Immune thrombocytopenia (ITP) is an autoimmune disease with heterogeneous background. FCGR2C mutations were defined in one third of the patients but genetic players have not been fully elucidated yet. Although childhood ITP present as benign, ITP in adulthood is chronic disease with treatment challenges. This study aimed to focus on adult ITP patients using a whole genome genotyping that is valuable approach to identify the responsible genomic regions for the disease.

Methods: Herein 24 adult primary-refractory for ITP patients were evaluated using HumanCytoSNP12BeadChip,Illumina. Forty-six age and sex matched healthy individuals, and ptients awith nonhematological conditions were analyzed as controls. Identified CNV regions were verified by qRTPCR. T-cell receptor beta and delta (TCRB/TCRG) clonality were assessed by heteroduplex analysis in mosaic cases.

Results: Several CNV losses and gains were defined (losses:2q,7q,17q,19p, and gains: 1q,2p,3q,4q,7q,10q,12p,13q,14q,15q,17p,20q,21p,22q,Xp). Mosaic changes of different sizes (0.2-17.77Mb) were identified in five patients and three of them showed clonality. CNV regions that were unique to ITP patients were identified for the first time and among these genes, those related to immune regulation, and cellular trafficking were noteworthy. Conclusion: Identified CNV regions harbor several candidate genes, the functions of which might shed light on the pathogenesis of chronic ITP.
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http://dx.doi.org/10.1080/17474086.2020.1819786DOI Listing
November 2020

Age-Related Co-Expression of BCOR and BCORL1 mRNA in Acute Myeloid Leukemia.

Clin Lab 2020 Aug;66(8)

Background: Acute myeloid leukemia (AML) is an aggressive hematological malignancy caused by a variety of genetic abnormalities and epigenetic dysregulation. The incidence of AML is strongly related to age, with the highest incidence rates being in older adults. The loss of function mutations in BCOR and BCORL1 genes have been identified in AML. BCL6 corepressor (BCOR) and BCL6 corepressor like 1 (BCORL1) are important epigenetic regu-lators as a member of Polycomb repressive complex 1 (PRC1.1), involved in histone modification processes.

Methods: We analyzed the BCOR and BCORL1 mRNA expression in 74 adult and 22 pediatric patients with AML by Real-Time quantitative PCR in this study.

Results: Our results indicated that both BCOR and BCORL1 mRNA expressions decrease with age (p = 0.009 and p = 0.008, respectively) and there is a positive correlation between BCOR and BCORL1 mRNA expression (p < 0.001). BCOR and BCORL1 mRNA expressions were not significantly different in both adult and pediatric patients with AML compared to control (p > 0.05).

Conclusions: Our findings indicate that expression of BCOR and BCORL1 mRNA are down-regulated with age. The increase in AML incidence with age suggests that age-associated BCOR and BCORL1 down-regulation might potentially contribute to age-related epigenetic alterations and form a predisposing condition for the development of elderly AML.
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http://dx.doi.org/10.7754/Clin.Lab.2020.191119DOI Listing
August 2020

Hepatitis B reactivation in hematopoietic stem cell transplanted patients: 20 years of experience of a single center from a middle endemic country.

Ann Hematol 2020 Nov 31;99(11):2671-2677. Epub 2020 Jul 31.

Cerrahpasa Medical Faculty, Internal Medicine Department, Hematology Section, Istanbul University - Cerrahpasa, Istanbul, Turkey.

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.
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http://dx.doi.org/10.1007/s00277-020-04206-zDOI Listing
November 2020

An eleven-year cohort of bloodstream infections in 552 febrile neutropenic patients: resistance profiles of Gram-negative bacteria as a predictor of mortality.

Ann Hematol 2020 Aug 20;99(8):1925-1932. Epub 2020 Jun 20.

Department of Infectious Diseases and Clinical Microbiology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, 34098, Istanbul, Turkey.

Antimicrobial stewardship is of major importance in patients with febrile neutropenia (FN). In this study, we aimed to investigate the trends in resistance and the relationship with mortality rates in patients with FN. The single-center surveillance data of inpatients with FN and diagnosed as microbiologically confirmed bloodstream infections (BSIs) between 2006 and 2016 were reviewed retrospectively. A total of 950 episodes in 552 patients with BSIs were analyzed. Of whom, 55.9% were male, the median age was 43 years, and 35.6% had acute myeloid leukemia. In total, 1016 microorganisms were isolated from blood cultures. Gram-negatives accounted for 42.4% (n = 403) of the episodes. Among Gram-negatives, Enterobacteriaceae accounted for 346 (86%) (E. coli, n = 197; 34% extended-spectrum β-lactamases (ESBL) producers, and Klebsiella spp., n = 120; 48.3% ESBL producers). Also, 24 (20.0%) of Klebsiella spp. had carbapenemase activity. There were 6 (5.0%) colistin-resistant Klebsiella spp. Thirteen (26.5%) of Pseudomonas spp. and 17 (60.7%) of Acinetobacter spp. had carbapenemase activity. There were 2 (5.6%) colistin-resistant Acinetobacter spp. The 30-day mortality rates were 12.0%, 21.5%, 34.6%, and 29.0% in BSIs due to Gram-positive, Gram-negative bacterial, fungal, and polymicrobial etiology respectively (p = 0.001). BSIs with ESBL-producing (p = 0.001) isolates, carbapenem (p < 0.001), and colistin-resistant isolates (p < 0.001) were associated with increased mortality risk. The tremendous rise in resistance rates among Gram-negatives is dreadfully related to increasing mortality and leads to sharp shifts toward extreme restrictions of unnecessary antibiotic uses. Antimicrobial stewardship in patients with FN requires vigilance and tailoring of treatment upon local surveillance data.
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http://dx.doi.org/10.1007/s00277-020-04144-wDOI Listing
August 2020

Long-term results of brentuximab vedotin in relapsed and refractory Hodgkin lymphoma: multi-center real-life experience.

Ann Hematol 2020 Feb 17;99(2):301-307. Epub 2019 Dec 17.

Department of Hematology, Koc University School of Medicine and V.K.V. American Hospital, Istanbul, Turkey.

Classical Hodgkin lymphoma (cHL) is considered a curable disease; however, approximately one-third of responders experience disease relapse following first-line therapy. Several studies have shown the efficacy of brentuximab vedotin (BV) in patients with relapsed/refractory HL. We present a retrospective analysis of 58 patients with relapsed/refractory HL treated with BV in a named patient program from 11 centers. The median follow-up duration was 20 (range, 4-84) months. The best overall response rate was 64% (complete response [CR], 31%; partial response [PR], 33%). The 5-year progression-free survival (PFS) and overall survival (OS) rates were 12% (95% confidence interval [CI], 0.05-0.22) and 26% (95% CI, 0.16-0.38), respectively. Among patients who achieved CR, the estimated 5-year PFS and OS rates were 32% (95% CI, 0.13-0.54) and 60% (95% CI, 0.33-0.78), respectively. A total of 26 patients underwent subsequent stem cell transplantation. The 5-year PFS and OS rates for 10 patients who had consolidative stem cell transplantation were 28% and 30%, respectively. Twenty-seven patients required further therapy following BV. At the time of the analysis, 12 patients (21%) were alive. Five patients (9%) had long-term remission after achieving CR with BV monotherapy, with a median PFS of 76 months. Three of them (5%) did not receive any other treatment following BV and their median PFS was 75 months. Our long-term results showed that a small subset of patients with relapsed/refractory cHL may benefit from and even be cured with BV monotherapy.
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http://dx.doi.org/10.1007/s00277-019-03899-1DOI Listing
February 2020

Blastic Plasmacytoid Dendritic Cell Neoplasia: A Single Center Experience

Turk J Haematol 2020 02 22;37(1):48-52. Epub 2019 Nov 22.

İstanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Pathology, İstanbul, Turkey

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare malignancy with skin tropism. The entity was recently defined and the diagnosis is generally made by skin biopsies. It is necessary to apply appropriate immunohistochemistry to recognize this rare entity. There is no consensus on therapy and the survival rates are low. The aim of this study is to describe the clinical and histopathological features of BPDCN. We retrospectively reviewed 8 BPDCN cases of the Cerrahpaşa Medical Faculty diagnosed between 2005 and 2019. We documented the clinical findings, histopathologic diagnoses, and outcomes. The mean age of the patients was 58.7 years (range=11-86 years), and 7 patients were male. The patients presented with erythematous or purple papules, plaques, and papulonodular or nodular cutaneous lesions. Two had lymphadenomegaly at presentation. In microscopic evaluations, tumor cells infiltrated the entire dermis with a clear-cut subepidermal Grenz zone in all cases. CD4, CD56, and CD123 were the most frequently expressed immunohistochemical markers. The median follow-up of 7 cases was 14 months, ranging from 6 to 48 months. Three patients died of the disease, while 4 patients were still alive. Out of 7 patients, 5 received chemotherapy. We found that the outcomes of some patients were different from others but we did not link any distinct clinical or histopathological characteristics to these different outcomes.
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http://dx.doi.org/10.4274/tjh.galenos.2019.2019.0195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057751PMC
February 2020

Trisomy-8-Positive Hematologic Malignancies Associated with Intestinal Behçet's Syndrome: Keep This Entity in Mind.

Acta Haematol 2020 27;143(3):194-195. Epub 2019 Aug 27.

Division of Hematology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, İstanbul, Turkey.

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http://dx.doi.org/10.1159/000501841DOI Listing
August 2020

The Outcomes of Chronic Myeloid Leukemia Patients With Molecular Warning Responses During Imatinib Treatment According to the European LeukemiaNet 2013 Recommendations.

Clin Lymphoma Myeloma Leuk 2019 07 4;19(7):e377-e384. Epub 2019 Apr 4.

Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.

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.
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http://dx.doi.org/10.1016/j.clml.2019.03.028DOI Listing
July 2019

Vincristine as an Adjunct to Therapeutic Plasma Exchange for Thrombotic Thrombocytopenic Purpura: A Single-Institution Experience

Balkan Med J 2018 11 3;35(6):417-421. Epub 2018 Jul 3.

Department of Internal Medicine, Division of Hematology, İstanbul University Cerrahpaşa School of Medicine, İstanbul, Turkey

Background: Thrombotic thrombocytopenic purpura is a potentially life-threatening condition. Although the introduction of therapeutic plasma exchange has reduced mortality rates from over 90% to 10%-20%, approximately 40% of patients relapse, and outcomes may be fatal in refractory patients. There is clearly a need for additional therapeutic approaches.

Aims: To describe the outcomes of relapsed/refractory thrombotic thrombocytopenic purpura patients treated with vincristine as an adjunct to therapeutic plasma exchange.

Study Design: Cross-sectional study.

Methods: The medical records of all relapsed/refractory patients with thrombotic thrombocytopenic purpura treated with vincristine adjunct to therapeutic plasma exchange between October 2000 and December 2016 were retrospectively reviewed. Diagnosis of thrombotic thrombocytopenic purpura was based on clinical history, physical examination, and laboratory examinations. Patient demographics, laboratory findings, initial date and duration of therapeutic plasma exchange, dosage and time of administration of vincristine, and outcomes were recorded.

Results: The study included 15 patients [median age: 37 years (range: 26-65); 7 women and 8 men] with either relapsed or refractory thrombotic thrombocytopenic purpura who were treated with vincristine as an adjunct to therapeutic plasma exchange for a total of 22 episodes. Eighty-seven percent of patients achieved remissions in 20 of 22 episodes, with a median duration of remission of 29.5 months (range: 3-105). After a median follow-up of 55 months, 11 patients were alive. Vincristine was well tolerated with no safety concerns.

Conclusion: Vincristine offers a reasonable option for the treatment of patients with relapsed/refractory thrombotic thrombocytopenic purpura. Further studies evaluating vincristine in the front-line setting and in the relapsed/refractory setting are needed to validate the role of vincristine in thrombotic thrombocytopenic purpura patients.
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http://dx.doi.org/10.4274/balkanmedj.2017.1215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251381PMC
November 2018

Deep sequencing of BCR-ABL1 kinase domain mutations in chronic myeloid leukemia patients with resistance to tyrosine kinase inhibitors.

Leuk Lymphoma 2019 01 2;60(1):200-207. Epub 2018 Jul 2.

a Aziz Sancar Institute of Experimental Medicine Department of Genetics , Istanbul University , Istanbul , Turkey.

Tyrosine kinase inhibitor (TKI) therapy is the current treatment of choice for patients with chronic phase chronic myeloid leukemia (CML) leading to rapid and durable hematological as well as molecular responses. However, emergence of resistance to TKIs has been the major obstacle to treatment success on long term. In this regard kinase domain mutations are the most common mechanism of therapy failure. In this study, we analyzed peripheral blood samples from 17 CML patients who had developed resistance to various TKIs by using next-generation sequencing parallel to Sanger sequencing. BCR-ABL1 kinase domain mutations have been found in 59% of the cohort. Our results demonstrate that next-generation sequencing results in a higher mutational detection rate than reported with conventional sequencing methodology. Furthermore, it showed the clonal diversity more accurately.
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http://dx.doi.org/10.1080/10428194.2018.1473573DOI Listing
January 2019

Retrospective Evaluation of Hairy Cell Leukemia Patients Treated with Three Different First-Line Treatment Modalities in the Last Two Decades: A Single-Center Experience.

Turk J Haematol 2017 Dec;34(4):291-299

İstanbul University Cerrahpaşa Faculty of Medicine, Department of Hematology, İstanbul, Turkey.

Objective: In this study, we retrospectively analyzed the clinical outcome, treatment responses, infectious complications, and survival rates of 71 hairy cell leukemia (HCL) cases.

Materials And Methods: Sixty-seven patients received a first-line treatment and 2-chlorodeoxyadenosine (cladribine-2-CdA) was administered in 31 cases, 19 patients received interferon-alpha (INF-α), splenectomy was performed in 16 cases, and rituximab was used in one.

Results: Although the highest overall response rate (ORR) was observed in patients receiving 2-CdA upfront, ORRs were comparable in the 2-CdA, INF-α, and splenectomy subgroups. Relapse rates were significantly lower in patients who received first-line 2-CdA. The progression-free survival (PFS) rate with 2-CdA was significantly higher than in patients with INF-α and splenectomy, but we found similar overall survival rates with all three upfront treatment modalities. Infections including tuberculosis were a major problem.

Conclusion: Although purine analogues have improved the ORRs and PFS, there is still much progress to make with regard to overall survival and relapsed/refractory disease in patients with HCL.
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http://dx.doi.org/10.4274/tjh.2016.0443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774373PMC
December 2017

Third-line treatment with second-generation tyrosine kinase inhibitors (dasatinib or nilotinib) in patients with chronic myeloid leukemia after two prior TKIs: real-life data on a single center experience along with the review of the literature.

Hematology 2018 May 9;23(4):212-220. Epub 2017 Oct 9.

a Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine , Istanbul University , Istanbul , Turkey.

Objectives: Newer tyrosine kinase inhibitors (TKIs) (bosutinib, ponatinib) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be utilized as a salvage therapy in patients with chronic myeloid leukemia (CML) who failed two lines (imatinib → nilotinib or imatinib → dasatinib) of TKI therapy. However, these TKIs are not available in many countries and not all patients can undergo allo-HSCT.

Methods: In this study, CML patients who received dasatinib or nilotinib as a third-line treatment were retrospectively evaluated.

Results: Out of 209 patients, third-line dasatinib/nilotinib was administered in 21. During the follow-up, 16 out of 21 patients gained and/or maintained an optimal response, and 4 patients died due to progression. Seventeen patients were alive at the time of the analysis, of which 13 were still on TKI, whereas 4 patients quit treatment.

Discussion: In patients failing two lines of TKI, dasatinib or nilotinib can be beneficial and safely administered as a third-line treatment especially in nations with restricted resources.
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http://dx.doi.org/10.1080/10245332.2017.1385193DOI Listing
May 2018

Outcomes of Chronic Myeloid Leukemia Patients With Early Molecular Response at 3 and 6 Months: A Comparative Analysis of Generic Imatinib and Glivec.

Clin Lymphoma Myeloma Leuk 2017 Dec 4;17(12):804-811. Epub 2017 Aug 4.

Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey. Electronic address:

Background: The molecular response at 3 months of the original imatinib (OI) in patients with chronic myeloid leukemia has prognostic significance; however, this has never been tested for generic imatinib (GI).

Patients And Methods: We evaluated the BCR-ABL1 [international reporting scale (IS)] transcript levels at 3 and 6 months to determine whether an early molecular response (EMR) had a prognostic effect on the outcome among chronic myeloid leukemia patients receiving GI. Ninety patients were divided into 2 groups, according to the imatinib they received, as OI (group A) and GI (group B).

Results: Two groups were equally balanced for age, gender, Sokal risk score, and optimal response. The 2 groups did not differ in achieving an EMR at 3 months, and patients with EMR at 3 months had significantly superior complete cytogenetic response and major molecular response rates compared with patients who did not achieve an EMR in both groups. The percentage of an optimal response [BCR-ABL1 (IS), < 1%] and a warning response [BCR-ABL1 (IS), 1%-10%] at 6 months was 93% and 95% for groups A and B, respectively (P = .553). Patients with an optimal response (OR) at both 3 and 6 months had significantly superior event-free survival rates compared with patients without an OR in groups A and B.

Conclusion: The results of the present study have demonstrated most probably for the first time that an OR at 3 and 6 months in patients receiving either first-line GI and OI is clearly associated with greater response and event-free survival rates. Prospective randomized trials with larger numbers of patients and longer follow-up periods are needed to address the effect of EMR in patients receiving GI.
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http://dx.doi.org/10.1016/j.clml.2017.07.255DOI Listing
December 2017

Clinical Outcomes Related to the Use of Bendamustine Therapy for Multiple Myeloma Patients Relapsed/Refractory to Immunomodulatory Drugs and Proteasome Inhibitors.

Turk J Haematol 2017 Aug 8;34(3):233-238. Epub 2017 Mar 8.

İstanbul University Cerrahpaşa Faculty of Medicine, Department of Internal Medicine, Division of Hematology, İstanbul, Turkey.

Objective: Multiple myeloma patients who are relapsed or refractory to both proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) have been reported to have poor outcomes. Bendamustine has been reported to have an antitumor effect in newly diagnosed as well as relapsed/refractory multiple myeloma (RRMM). The aim of this retrospective study was to evaluate the efficacy of bendamustine therapy in heavily pretreated MM patients who were refractory to PIs and IMiDs.

Materials And Methods: Nineteen RRMM patients treated either with bendamustine and steroids (n=13) or a combination of bendamustine with novel drugs (n=6) were included. The median number of previous treatment lines was 5 (minimum-maximum: 3-8) and median time from diagnosis was 6 years (minimum-maximum: 1-16). All of the patients were resistant to at least one of the IMiDs and one of the PIs. Bendamustine was given at doses ranging from 90 mg/m2 to 120 mg/m2 on days 1 and 2 of 28-day cycles.

Results: A median of 2 (minimum-maximum: 1-8) treatment cycles was administered per patient. The toxicity of bendamustine was mild and mostly of hematological origin. No complete remission was achieved. There was partial remission and stable disease in 21% and 11% of the patients, respectively. Sixty-eight percent of patients had progressive disease. The median progression-free survival and overall survival was 2 and 4 months, respectively.

Conclusion: Bendamustine therapy was well tolerated but showed limited anti-myeloma activity in heavily pretreated patients who were refractory to IMiDs and PIs.
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http://dx.doi.org/10.4274/tjh.2016.0397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544042PMC
August 2017

Congenital Dyserythropoietic Anemia Type 1: Report of One Patient and Analysis of Previously Reported Patients Treated with Interferon Alpha.

Indian J Hematol Blood Transfus 2016 Jun 21;32(Suppl 1):272-7. Epub 2015 Sep 21.

Division of Hematology, Department of Internal Medicine, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey.

Congenital dyserythropoietic anemias are a rare group of inherited anemias characterized by ineffective erythropoiesis and distinct morphological abnormalities in the erythroblasts. Interferon alpha has been shown to be effective in type 1 congenital dyserythropoietic anemia but the optimal duration of therapy is undefined. We present here a 32-years-old female patient diagnosed with type 1 congenital dyserythropoietic anemia precipitated by pregnancy and treated successfully with a short course of interferon alpha resulting in a durable response. A literature search including PubMed database on previously published articles regarding congenital dyserythropoietic anemia type 1 patients treated with interferon is conducted.
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http://dx.doi.org/10.1007/s12288-015-0600-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925531PMC
June 2016

Treatment of patients with immune thrombocytopenia admitted to the emergency room.

Int J Hematol 2016 Aug 29;104(2):216-22. Epub 2016 Apr 29.

Division of Hematology, Department of Internal Medicine, Cerrahpaşa Faculty of Medicine, Istanbul University, Fatih, Istanbul, Turkey.

Immune thrombocytopenia (ITP) is the most frequent cause of acquired thrombocytopenia. In adult ITP patients, corticosteroids and intravenous immunoglobulin (IVIg) are used as first-line treatment. The aim of the present study was to investigate retrospectively the demographic and etiologic characteristics of patients with ITP admitted to the emergency room at our hospital. Seventy-five adult patients with ITP were included, and demographic data, bleeding characteristics, etiologic features and responses to treatments were evaluated retrospectively. Fifty-six patients (75 %) were female, and the median age was 43 years. Eighteen patients had a history of ITP, whereas in 57, thrombocytopenia was identified for the first time. During admission, the median platelet count was 5 × 10(9)/L. Cutaneous and/or mucosal bleeding was the most common clinical feature. High-dose dexamethasone was administered in 60 episodes, whereas IVIg and conventional-dose methylprednisolone were used in nine and six episodes, respectively. The overall response rate of the entire cohort following first-line treatments was 67 %, and complete remission was achieved in 31 patients, 19 patients achieved partial remission, and 25 patients were non-responders. In cases with life-threatening bleeding, concomitant infection, post-traumatic bleeding and need for emergency surgery, IVIg can be used as the first line of treatment option in addition to platelet transfusions.
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http://dx.doi.org/10.1007/s12185-016-2003-5DOI Listing
August 2016

Imatinib reduces bone marrow fibrosis and overwhelms the adverse prognostic impact of reticulin formation in patients with chronic myeloid leukaemia.

J Clin Pathol 2016 Sep 25;69(9):810-6. Epub 2016 Jan 25.

Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Aims: Before the era of tyrosine kinase inhibitors (TKIs), the presence of bone marrow fibrosis (MF) in patients with chronic myeloid leukaemia (CML) has been established as a poor prognostic factor. The aim of the present study was to evaluate the effects of imatinib treatment on MF and the prognostic significance of MF at this new era of CML therapy.

Methods: The study cohort consisted of 135 patients with CML who were exposed to imatinib. The grades of MF pre and post imatinib together with cytogenetic and molecular responses were evaluated.

Results: Severe MF (grade II-III) was observed in 44 (33%) patients prior to imatinib therapy, and in 8 (8%) after 12 months of imatinib treatment (p=0.001). The complete cytogenetic response (CCyR) rates at 12 months did not differ according to the pre-imatinib MF grades, and CCyR rates in patients with grades 0, I, II and III MF were 36/47 (76.5%), 26/33 (78.7%), 12/23 (52.1%) and 7/10 (70%), respectively (p=0.127). There was no significant difference between patients with or without CCyR at 12 months of imatinib regarding grades of MF (p=0.785). The distribution of the major molecular response rates at 18 months according to pre-treatment grades of MF were determined as grade 0 in 38/45 (84.4%), grade I in 21/28 (75%), grade II in 14/21 (66.6%) and grade III in 7/10 (70%) (p=0.112). There was no significant difference in overall survival rates between initial MF mild (grade 0-I) and severe (grade II-III) groups (p=0.278).

Conclusions: According to our findings, MF regresses with imatinib therapy over time, and the MF grades at diagnosis do not have a negative impact on the responses to imatinib treatment. Therefore, the adverse prognostic impact of the MF among patients with CML seems to disappear in the era of the TKIs.
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http://dx.doi.org/10.1136/jclinpath-2015-203320DOI Listing
September 2016

Novelties in the management of B-cell malignancies: B-cell receptor signaling inhibitors and lenalidomide.

Expert Rev Hematol 2015 Dec 28;8(6):765-83. Epub 2015 Sep 28.

a Department of Internal Medicine, Division of Haematology, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey.

B-cell lymphoproliferative disorders comprise 85% of Non-Hodgkin's lymphomas. Despite successful chemoimmunotherapy regimens, responses are not durable and the outcome is fatal in a considerable portion of patients. There is an inevitable need for less toxic and more potent therapeutic agents. Over the recent years, a plethora of agents including monoclonal antibodies, Bcl-2 antagonists, tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, mTOR inhibitors and immunomodulatory drugs have been developed in B-cell malignancies. The aim of this paper is to focus on B-cell receptor signaling inhibitors and lenalidomide as an immunomodulatory drug and to provide insight on how and when to incorporate these agents into the treatment algorithms.
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http://dx.doi.org/10.1586/17474086.2015.1091301DOI Listing
December 2015

Treatment and Outcome of Primary and Secondary Thrombotic Microangiopathies.

Am J Nephrol 2015 14;41(6):427-8. Epub 2015 Jul 14.

Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey.

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http://dx.doi.org/10.1159/000437002DOI Listing
June 2016

The Changing Epidemiology of Bloodstream Infections and Resistance in Hematopoietic Stem Cell Transplantation Recipients.

Turk J Haematol 2016 Sep 4;33(3):216-22. Epub 2015 May 4.

İstanbul University Cerrahpaşa Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, İstanbul, Turkey Phone : +90 212 414 30 95 E-mail:

Objective: Patients receiving hematopoietic stem cell transplantation (HSCT) are exposed to highly immunosuppressive conditions and bloodstream infections (BSIs) are one of the most common major complications within this period. Our aim, in this study, was to evaluate the epidemiology of BSIs in these patients retrospectively.

Materials And Methods: The epidemiological properties of 312 patients with HSCT were retrospectively evaluated.

Results: A total of 312 patients, followed between 2000 and 2011, who underwent autologous (62%) and allogeneic (38%) HSCT were included in the study. The most common underlying malignancies were multiple myeloma (28%) and Hodgkin lymphoma (21.5%). A total of 142 (45%) patients developed at least 1 episode of BSI and 193 separate pathogens were isolated from the blood cultures. There was a trend of increase in the numbers of BSIs in 2005-2008 and a relative increase in the proportion of gram-positive infections in recent years (2009-2011), and central venous catheter-related BSI was found to be most common source. Coagulase-negative staphylococci (49.2%) and Acinetobacter baumannii (8.8%) were the most common pathogens. Extended-spectrum beta-lactamase-producing strains were 23% and 22% among Escherichia coli and Klebsiella spp. isolates, respectively. Quinolone resistance was detected in 10% of Enterobacteriaceae. Resistance to carbapenems was not detected in Enterobacteriaceae, while it was seen at 11.1% and 23.5% in Pseudomonas and Acinetobacter strains, respectively.

Conclusion: A shift was detected from gram-negative bacteria to gram-positive in the etiology over the years and central lines were the most common sources of BSIs.
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http://dx.doi.org/10.4274/tjh.2014.0378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111467PMC
September 2016

Relapse after allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia: tyrosine kinase inhibitors, donor lymphocyte infusions or both?

Leuk Lymphoma 2015 28;56(10):2995-6. Epub 2015 Mar 28.

a Division of Hematology, Department of Internal Medicine , Cerrahpasa Faculty of Medicine, Istanbul University , Istanbul , Turkey.

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http://dx.doi.org/10.3109/10428194.2015.1026819DOI Listing
September 2016

A reappraisal of the association between Behçet's disease, myelodysplastic syndrome and the presence of trisomy 8: a systematic literature review.

Clin Exp Rheumatol 2015 Nov-Dec;33(6 Suppl 94):S145-51. Epub 2015 Feb 9.

Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey.

Objectives: A number of patients with Behçet's disease (BD) associated with myelodysplastic syndrome (MDS) with or without trisomy 8 have been reported. A high frequency of gastrointestinal (GI) involvement was reported in such patients. The aim of this systematic literature review was to delineate whether GI involvement is an inherent feature of BD associated with MDS, whether these patients do actually have BD rather than GI symptoms related to MDS, and whether the presence of trisomy 8 plays a role in the disease expression of BD associated with MDS.

Methods: A systematic literature review was performed in PubMed using the keywords (Behçet's disease OR Behçet's syndrome) AND (myelodysplastic syndrome OR trisomy 8) until December 2013.

Results: Data from 39 manuscripts that met the inclusion criteria, reporting on 52 patients were analysed. GI involvement was common in reports from both the Far East and non-Far East countries (75% vs. 50.0%, p=0.15). These patients had typical BD manifestations, except for 1 patient who had only oral ulcers and gastrointestinal involvement. The presence of trisomy 8 seems to be associated with an increased frequency of fever (79.5% vs. 33.3%, p=0.005).

Conclusions: GI involvement seems to be an inherent feature of BD associated with MDS regardless of geographic differences. Despite the increased frequency of GI involvement in these patients, MDS does not seem to modify the clinical expression of gastrointestinal involvement. Presence of trisomy 8 seems to modify the disease expression with an increased frequency of fever.
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January 2016

Chronic myeloid leukemia patients who develop grade I/II pleural effusion under second-line dasatinib have better responses and outcomes than patients without pleural effusion.

Leuk Res 2014 Jul 18;38(7):781-7. Epub 2014 Apr 18.

Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Dasatinib is a potent second generation TKI, and it is widely used in patients with CML, both in the up-front setting and failure after imatinib. Lymphocytosis in cases receiving dasatinib therapy has been shown to be associated with pleural effusion (PE) and better outcome. Although patients who gather lymphocytosis during dasatinib have superior responses, there is only little data about the correlation between PE, response rates, and survival. In order to answer this question, the aim of our study was to determine the frequency of PE and lymphocytosis among our CML patients receiving second-line dasatinib, and to compare the responses and outcomes between patients with or without PE. There were 18 patients (44%) who developed PE, in a total of 41 patients, with a median time of 15 months. Lymphocytosis was observed in nine patients (9/41, 22%) with a median duration of 6.5 months of dasatinib treatment. There were fourteen patients with at least one comorbidity that may play a role in the generation of PE. The cumulative MMR and CCyR rates were greater in PE+ patients (p<0.05). The PFS was significantly higher in PE+ group than PE- patients (p=0.013), also the OS was higher among PE+ patients than PE- group (p=0.042). In patients with a grade I/II PE, and durable responses under dasatinib, performing the management strategies for the recovery of effusion, together with continuing dasatinib can be a reasonable choice mainly in countries where third generation TKIs are not available. But alternative treatment strategies such as nilotinib or third generation TKIs can be chosen in patients with grade III/IV PE especially if the quality of life is severely affected.
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http://dx.doi.org/10.1016/j.leukres.2014.04.004DOI Listing
July 2014

The efficacy of generic formulations of imatinib mesylate in the treatment of chronic myeloid leukemia.

Leuk Lymphoma 2014 Dec 6;55(12):2935-7. Epub 2014 May 6.

Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University , Istanbul , Turkey.

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http://dx.doi.org/10.3109/10428194.2014.905774DOI Listing
December 2014
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