Unmet clinical needs and challenges in the management of acute leukemia in Turkey: a modified Delphi study.

Aim: To determine the unmet needs and challenges in management, diagnosis, treatment, follow-up and patient-physician communication in acute leukemia (AL). Materials & methods: The study was based on a modified Delphi approach. A questionnaire including the major potential obstacles was circulated twice among 13 hematologists. Results: The obstacles in AL management were limited access to the novel treatments and genetic tests, limited bed capacity, insufficient level of knowledge among allied health personnel, limited availability of psycho-oncological support and low levels of awareness in the population about the importance of stem cell donation. Conclusion: The challenges in the management of AL are critical to guide the efforts to improve the quality of healthcare delivery and the evidence-based decision making at treatment of AL patients.

International Forum: The Turkish perspective on apheresis activity: The Turkish apheresis registry report.

Therapeutic apheresis is an extracorporeal treatment that selectively removes abnormal cells or harmful substances in the blood that are associated with or cause certain diseases. During the last decades the application of therapeutic apheresis has expanded to a broad spectrum of hematological and non-hematological diseases due to various studies on the clinical efficacy of this procedure. In this context there are more than 30 centers performing therapeutic apheresis and registered in the apheresis database in Turkey. Herein, we, The Turkish Apheresis Registry, aimed to analyze some key articles published so far from Turkey regarding the use of apheresis for various indications.

The Turkish experience with therapeutic plasma exchange: A national survey.

Therapeutic plasma exchange (TPE) is used to treat more than 60 diseases worldwide and has drawn growing interest. Little is known about the current situation of TPE activity in Turkey, so we developed a survey to obtain information about this timely topic. We collected data on TPE from 28 apheresis units throughout Turkey. We performed a total of 24,912 TPE procedures with 3203 patients over the past decade. Twenty years ago, the majority of procedures were performed for neurological and hematological disorders, and today, most TPE procedures are done for the same reasons. The only historical change has been an increase in TPE procedures in renal conditions. Currently, renal conditions were more frequently an indication for TPE than rheumatic conditions. Fresh frozen plasma was the most frequently used replacement fluid, followed by 5% albumin, used in 57.9% and 34.6% of procedures, respectively. The most frequently used anticoagulants in TPE were ACD-A and heparin/ACD-A, used with 1671 (52.2%) and 1164 (36.4%) patients, respectively. The frequency of adverse events (AEs) was 12.6%. The most common AEs were hypocalcemia-related symptoms, hypotension, and urticaria. We encountered no severe AEs that led to severe morbidity and mortality. Overall, more than two thirds of the patients showed improvement in the underlying disease. Here, we report on a nationwide survey on TPE activity in Turkey. We conclude that there has been a great increase in apheresis science, and the number of TPE procedures conducted in Turkey has increased steadily over time. Finally, we would like to point out that our past experiences and published international guidelines were the most important tools in gaining expertise regarding TPE.

Autologous stem cell transplantation for adult acute myelocytic leukemia in first remission-Better outcomes after busulfan and melphalan compared with busulfan and cyclophosphamide: A retrospective study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

BACKGROUND: Autologous stem cell transplantation (ASCT) for adult acute myelogenous leukemia (AML) is a valid therapeutic option for patients with good-risk and intermediate-risk disease. The authors used the registry of the European Society for Blood and Marrow Transplantation to compare combined busulfan and melphalan (BUMEL) with combined busulfan and cyclophosphamide (BUCY) before transplantation. METHODS: From 2005 to 2013, 853 patients with available cytogenetics underwent ASCT in first remission, including 257 after receiving BUMEL and 596 after receiving BUCY. The proportion of patients with good-risk AML was lower in those who received BUMEL (14% vs 20%; P = .02). More patients who received BUMEL underwent autograft in molecular remission (89% vs 78%; P = .02). Three years after transplantation, the relapse incidence (RI) was 48.7%, the leukemia-free survival (LFS) rate was 47.7%, the overall survival (OS) rate was 66.2%, and the nonrelapse mortality (NRM) rate was 3.6%. RESULTS: Patients who underwent an autograft after receiving BUMEL fared better than those who underwent an autograft after receiving BUCY with a lower RI (39.5% vs 52.2%; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49-0.87; P = .003) a better LFS (55.4% vs 44.6%; HR, 0.69; 95% CI, 0.53-0.89; P = .005), and a better OS (73.8% vs 63%; HR, 0.62; 95% CI, 0.47-0.82; P = .0007). There was no difference in the NRM rate (BUMEL vs BUCY, 4.5% vs 3.2%, respectively). Among 74 patients in the BUMEL group and 187 in the BUCY group who underwent autograft in molecular remission, the RI was 30% versus 51%, respectively (univariate analysis; P = .01), and the LFS rate was 66% versus 47%, respectively (univariate analysis; P = .03). CONCLUSIONS: In patients with AML in first complete remission who undergo ASCT, the BUMEL combination is a better preparative regimen. Cancer 2017;123:824-31. © 2016 American Cancer Society.

Effects of single-agent bortezomib as post-transplant consolidation therapy on multiple myeloma-related bone disease: a randomized phase II study.

This phase II study explored the effects of bortezomib consolidation versus observation on myeloma-related bone disease in patients who had a partial response or better after frontline high-dose therapy and autologous stem cell transplantation. Patients were randomized to receive four 35-day cycles of bortezomib 1·6 mg/m2 intravenously on days 1, 8, 15 and 22, or an equivalent observation period, and followed up for disease status/survival. The modified intent-to-treat population included 104 patients (51 bortezomib, 53 observation). There were no meaningful differences in the primary endpoint of change from baseline to end of treatment in bone mineral density (BMD). End-of-treatment rates (bortezomib versus observation) of complete response/stringent complete response were 22% vs. 11% (P = 0·19), very good partial response or better of 80% vs. 68% (P = 0·17), and progressive disease of 8% vs. 23% (P = 0·06); median progression-free survival was 44·9 months vs. 21·8 months (P = 0·22). Adverse events observed ≥15% more frequently with bortezomib versus observation were diarrhoea (37% vs. 0), peripheral sensory neuropathy (20% vs. 4%), nausea (18% vs. 0) and vomiting (16% vs. 0). Compared with observation, bortezomib appeared to have little impact on bone metabolism/health, but was associated with trends for improved myeloma response and survival.

Age does not matter: Mobilization and harvesting are safe and effective for elderly allogeneic peripheral hematopoietic stem cell donors.

It took several years to succeed safe hematopoietic stem cell transplantations. HLA-matched unrelated donors have become the most common donor source for allogeneic hematopoietic stem cell transplants worldwide. The sibling donor may have more comorbidity and decreased regenerative potential of stem and immune cells. The purpose of this retrospective study was to examine whether aging had any negative effect on aging donor or patient. 27 patients who received a hematopoietic stem cell transplantation (HSCT) from February 2013 to May 2016 and their donors were analyzed. We showed that transplantation from older relative donor was feasible. Adverse event rate was low. Donors tolerated the procedure very well. Good CD34+ cell harvest was possible.

Autologous hematopoietic progenitor cell mobilization and collection in adult patients presenting with multiple myeloma and lymphoma: A position-statement from the Turkish Society of Apheresis (TSA).

Autologous hematopoietic cell transplantation (AHCT) is a routinely used procedure in the treatment of adult patients presenting with multiple myeloma (MM), Hodgkin lymphoma (HL) and various subtypes of non-Hodgkin lymphoma (NHL) in upfront and relapsed/refractory settings. Successful hematopoietic progenitor cell mobilization (HPCM) and collection are the rate limiting first steps for application of AHCT. In 2015, almost 1700 AHCT procedures have been performed for MM, HL and NHL in Turkey. Although there are recently published consensus guidelines addressing critical issues regarding autologous HPCM, there is a tremendous heterogeneity in terms of mobilization strategies of transplant centers across the world. In order to pave the way to a more standardized HPCM approach in Turkey, Turkish Society of Apheresis (TSA) assembled a working group consisting of experts in the field. Here we report the position statement of TSA regarding autologous HPCM mobilization strategies in adult patients presenting with MM and lymphoma.

Autologous stem cell transplantation and stem cell mobilization kinetics in elderly patients with B cell non-Hodgkin lymphoma.

As known, the world population is aging and as the life span increases the number of advanced-age lymphomas also shows an upward trend. Autologous hematopoietic stem cell transplantation (HSCT) is the standard treatment modality in chemotherapy-sensitive relapsed or refractory aggressive lymphomas. Increased morbidity and mortality related to both the transplant itself and comorbid diseases can be observed in elderly lymphoma patients. Patients who are 65 years or older and underwent autologous HSCT with B-cell non-Hodgkin lymphoma were retrospectively included in our study. In terms of survival analysis, median follow-up was 34.5 months (8-159) while the overall survival (OS) was 58%. In the univariate analysis of prognostic data in OS, patients who were referred to transplantation with complete response had a statistically significant survival advantage (p=0.043). In terms of the effect of pre-transplant conditioning regimens on survival, BEAM regimen yielded better results, though not statistically significant. Age, number of chemotherapy cycles received before mobilization and radiation therapy had no significant effect on the CD34 (+) cell count in the final product (p=0.492, 0.746 and 0.078 respectively). In conclusion, autologous HSCT is a practicable treatment modality that provides survival advantage in suitable advanced-age patients with a diagnosis of B-cell non-Hodgkin lymphoma.

Current practice of autologous hematopoietic progenitor cell mobilization in adult patients with multiple myeloma and lymphoma: The results of a survey from Turkish hematology research and education group (ThREG).

Autologous hematopoietic cell transplantation (AHCT) is an established treatment option for adult patients presenting with multiple myeloma (MM), Hodgkin lymphoma (HL) and various subtypes of non-Hodgkin lymphoma (NHL) in upfront and/or relapsed/refractory disease settings. Although there are recently published consensus guidelines addressing critical issues regarding autologous hematopoietic progenitor cell mobilization (HPCM), mobilization strategies of transplant centers show high variability in terms of routine practice. In order to understand the current institutional policies regarding HPCM in Turkey and to obtain the required basic data for preparation of a national positional statement on this issue, Turkish Hematology Research and Education Group (ThREG) conducted a web-based HPCM survey. The survey was designed to include multiple-choice questions regarding institutional practice of HPCM in adults presenting MM, HL, and NHL. The representatives of 27 adult HCT centers participated to the study. Here we report the results of this survey shedding light on the real-world experience in Turkey in terms of autologous HPCM mobilization strategies in patients presenting with MM and lymphoma.

The loss of CD34+ cells in peripheral hematopoietic stem cell products cryopreserved by non-controlled rate freezing and stored at -80 °C after overnight storage.

Although peripheral blood stem cell (PBSC) products cryopreserved by non-controlled rate freezing and stored at -80 °C after overnight storage are used frequently, data regarding the rate of loss of CD34+ cells in these products are limited. In this prospective study, CD34+ cells were counted at three (fresh, post-overnight and post-thaw) points in 83 PBSC products from 41 patients by flow cytometry. Compared to fresh products, the mean losses of post-overnight and post-thaw total CD34+ cells are 16.3% and 38.4% (p = 0.02), and the mean losses of post-overnight and post-thaw viable CD34+ cells are 16.5% and 48.5%, respectively (p < 0.001). The numbers of fresh viable, post-thaw total and post-thaw viable CD34+ cells were inversely correlated with the durations of neutrophil and platelet engraftment. Our results indicate that the mean loss of post-thaw total and viable CD34+ cells is approximately 20% higher than that observed in standard cryopreservation methods. In addition, fresh viable, post-thaw total and especially post-thaw viable CD34+ cell levels are valuable predictors of both neutrophil and platelet engraftments.

The clearance time of infused hematopoietic stem cell from the blood circulation.

There is no detailed information about the clearance time of infused hematopoietic stem cell (HSC) from the blood circulation in humans. In this prospective study, peripheral blood CD34+ cell counts were detected during the 4days period following autologous HSC transplantation in 20 patients by means of flow cytometry. The median CD34+ cells were at the highest level in the first hour and decreased below pre-infusion values on the first day after HSC infusion. By nonparametric analysis, positive correlation was found between CD34+ cell levels at the first hour and the post-thaw CD34+ cell dose (r=0.57, p=0.01). An inverse correlation was determined between CD34+ cell levels at the first hour and neutrophil engraftment (r=-0.54, p=0.01). Compared with the patients having CD34+ cell count of ⩾2µL(-1) in the first hour following HSC infusion, the patients having CD34+ cell count of <2µL(-1) had delayed both neutrophil (20 vs. 12, p=0.008) and platelet (47 vs. 11, p=0.01) engraftments. Our results indicated that infused HSCs were removed from the blood circulation within 1day. In addition, CD34+ cell levels at the first hour may be used as an important indicator to predict the delay of neutrophil and platelet engraftments.

CD31 expression on peripheral blood stem cells predicts both early neutrophil and platelet engraftments.

No detailed information currently exists about the immune phenotypic profiles of peripheral blood stem cells (PBSCs) obtained by different mobilization regimens. The effects of these profiles on the outcome of transplantation are largely unknown. In this prospective study, the surface immune phenotypic features (CD11a, CD18, CD31, CD38, CD44, CD62e, CD62L, CD90, CD117, CD135 and CD184 expression) of sorted PBSCs that had been mobilized by growth factor with (group I and group II) or without (group III) disease-specific chemotherapies were investigated. The immune phenotypic features on mobilized PBSCs in groups I, II and III were not significantly different. The CD31 (platelet endothelial cell adhesion molecule-1) positivity ratio on PBSCs inversely correlated with both the duration of neutrophil (r=-0.32, p=0.03) and platelet (r=-0.36, p=0.02) engraftment. No relationship was found between the engraftment (neutrophil and platelet) durations and CD184 (chemokine receptor CXC motif receptor 4 [CXCR4]) expression on PBSCs. We demonstrated that the surface immune phenotypic profiles on PBSCs obtained by several mobilization regimens were not different. To our knowledge, this is the first study to demonstrate that CD31 expression on human PBSCs may positively affect both neutrophil and platelet engraftment. Contrary to our expectations, CD184 (CXCR4) expression on PBSCs has no effect on neutrophil or platelet engraftment. Considered together, our results suggest that additional surface antigens (such as CD31) may be more effective in the homing process.

Metastatic pulmonary calcinosis and leukocytoclastic vasculitis in a patient with multiple myeloma.

UNLABELLED: Both leukocytoclastic vasculitis and metastatic pulmonary calcification are conditions that rarely occur during the course of multiple myeloma. We present a multiple myeloma patient that had severe dyspnea due to metastatic pulmonary calcinosis, and ulceronecrotic skin lesions caused by leukocytoclastic vasculitis. After 3 courses of standarddose chemotherapy all skin and pulmonary lesions disappeared. Autologous peripheral stem cell transplantation was performed and during 1 year of follow-up the patient was in complete remission; after 1 year, laboratory test results indicated disease relapse. Although the patient was treated with bortezomib and dexamethasone, the disease progressed. Non-myeloablative allogeneic stem cell transplantation was performed, but despite of all treatment the patient died due to disease progression. CONFLICT OF INTEREST: None declared.

Molecular Evaluation of t(14;18)(bcl-2/IgH) Translocation in Follicular Lymphoma at Diagnosis Using Paraffin-Embedded Tissue Sections.

OBJECTIVE: Follicular lymphoma (FL) is one of the most common lymphomas, and is characterized by t(14;18)(q32;q21) in more than 80% of patients. The aim of this study was to determine the rate of t(14;18) positivity based onthe detection of mbr or mcr in paraffin-embedded tissue samples. MATERIAL AND METHODS: The study included 32 paraffin-embedded tissue samples collected from 32 consecutive FL patients that were diagnosed and followed-up at our hospital between 1999 and 2006. The MBR breakpoint wasidentified based on real-time PCR using a LightCycler v.2.0 t(14;18) Quantification Kit (MBR), multiplex PCR, and seminestedPCR. To identify the mcr breakpoint, real-time PCR was performed using specific primers and the FastStart DNAMaster SYBR Green I Kit. To detect t(14;18) via fluorescence in situ hybridization (FISH) nuclei from paraffin-embeddedtissue sections were extracted and used together with LSI IgH (immunoglobulin heavy chain) (spectrum green)/bcl-2(B-cell leukemia-lymphoma 2) (spectrum orange) probes. RESULTS: The DNA and nuclei isolation success rate for B5 formalin-fixed, paraffin-embedded tissue sections (n = 12)was 42% and 33%, respectively, versus 95% and 60%, respectively, for 20 tissue sections fixed in formalin only. In all,24 paraffin-embedded tissue sections were analyzed and mbr positivity was observed in the DNA of 82.14% via seminested PCR, in 53.57% via multiplex PCR, and in 28.57% via real-time PCR. We did not detect mcr rearrangementin any of the samples. In all, 15 of 16 patients (93.75%) whose nuclei were successfully isolated were observed to bet(14;18) positive via the FISH method. CONCLUSION: Semi-nested PCR and FISH facilitated the genetic characterization of FL tumors. As such, FISH and PCR complement each other and are both essential for detecting t(14;18) translocation.

Hepatitis B sero-prevalence among hematology patients: importance of Anti-HbcAb and efficiency of antiviral prophylaxis.

Objectives: Hepatitis B infection is an important problem in immune suppressed patients. Anti HbcAb is an important marker that shows past exposure to virus. In this study, we retrospectively searched HBV serology among the patients who had Bone Marrow Transplantation (BMT) or chemotherapies (CT) at Medicalpark Izmir Hospital Bone Marrow Transplantation Unit; changes in viral parameters throughout therapy; and tried to find the efficiency of antiviral prophylaxis. Methods: We retrospectively evaluated the viral parameters; HbsAg, Anti HbsAb, Anti Hbc IgG, HbeAg, Anti Hbe Ab, HBV DNA, HCV RNA which were carried out before BMT and CT. We grouped the patients as latent HBV infection and inactive carriers. Started antiviral treatment as prophylaxis, monitored the changes in serological parameters and defined HBV related situations. Results: A total of 584 patients were evaluated retrospectively. Twenty patients were having latent HBV infection. Ten patients were inactive carriers of HBV. In post-transplant period, the patients were screened for 11 months (1-38 months). None of the patients experienced HBV activation during follow period. Conclusion: The best approach in HbcAb positive patients with planned immunosuppressive treatment is the use of anti-viral agents before immune suppression and close monitoring of the patients HBV-related markers.

Risk factors for adverse events during collection of peripheral blood stem cells.

We retrospectively reviewed peripheral blood stem cell (PBSCs) collections following 528 mobilization cycles over a 10-year period. A total of 206 (13.1%) AEs occurred in association with the 1572 procedures. One hundred and ninety-one (12.15%) of the AEs were classified as clinical AEs and 15 (0.95%) were classified as apheresis instrument related AEs. The most common clinical AE was numbness of the lips, tongue, or extremities (161 procedures, 10.2%) related to the infusion of acid citrate dextrose-A (ACD). Multivariate analysis revealed high amounts of ACD/weight (odds ratio [OR]=1.11, p=0.009), high numbers of procedures (OR=1.33, p<0.001) and female gender (OR=2.83, p<0.001) as being significantly associated with clinical AEs. Female gender was shown to be the most important risk factor for clinical AEs. Females who have a significantly increased risk of AEs would benefit from prophylactic calcium before and/or during PBSC collection.

Non-Hodgkin's lymphoma following treatment with etanercept in ankylosing spondylitis.

Anti-TNF drugs may increase lymphoma risk in autoimmune rheumatic diseases, such as rheumatoid arthritis, but there have been no reports stating increased risk of lymphoma in ankylosing spondylitis (AS). Before 2 years, we had presented a case with AS developing Hodgkin's lymphoma following 6 months of etanercept treatment. Hereby, we present another case with AS developing non-Hodgkin's lymphoma (NHL), subsequent to 11 months of etanercept treatment. Pathological analysis revealed diffuse large B cell NHL. Although this is a report of a single case, cautious use of anti-TNF drugs is strongly recommended as they might cause lymphoma development even in AS.

Factor V G1691A (Leiden) and prothrombiG20210A gene mutation status, and thrombosis in patients with chronic myeloproliferative disorders.

OBJECTIVE: The aim of this study was to examine Factor V G1691A (Leiden) (FVL) and prothrombin G20210A (PT) gene mutation status, and their relationship with thrombosis in patients with chronic myeloproliferative disorders (CMPDs). METHODS: The study included 160 patients with a CMPD that were regularly followed-up between 1993 and 2009. FVL and PT mutation status was established based on blood samples analyzed via PCR using specific primers. RESULTS: The frequency of FVL and PT mutation was 12.5% and 4.4%, respectively. In total, 27 episodes of thrombosis occurred in 24 (15%) of the patients, and there wasn't an association between the observed thrombotic events, and FVL or PT mutations. Hepatic vein thrombosis was noted in 3 patients that had FVL mutation, of which 1 also had PT mutation. CONCLUSION: We did not observe a relationship between thrombosis, and FVL or PT mutations in CMPD patients; however, 3 of the patients that had hepatic vein thrombosis also had FVL mutation. Larger studies are needed to more clearly determine if all CMPD patients with hepatic vein thrombosis need be investigated for FVL and PT mutation.

The Effect of Cryotherapy on the Prevention of Oral Mucositis and on the Oral pH Value in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of cryotherapy on the prevention of oral mucositis (OM) and on the oral pH value in patients with multiple myeloma undergoing autologous stem cell transplantation. DATA SOURCES: This nonrandomized controlled clinical trial was carried out in Bone Marrow Transplant Centers of three hospitals with total 32 patients. In addition to standard oral care, a total of 80 minutes of cryotherapy was applied to the experimental group. OM was assessed according to the World Health Organization's Oral Toxicity Scale before chemotherapy and for 21 days after chemotherapy (every day in the first 14 days, then every other day until the 21st day [if not discharged]). CONCLUSION: According to the findings, cryotherapy did not change the incidence of oral OM, and neither affected the severity of nor decreased the duration of it. Oral pH value was found to be significantly different between the patient groups only before and 1 day after chemotherapy. IMPLICATIONS FOR NURSING PRACTICE: Cryotherapy is an inexpensive, easy-to-use method with no side effects; it would be beneficial to continue cryotherapy to prevent the development of OM in patients with cancer receiving drugs with a short half-life such as melphalan. It is also recommended to conduct further studies with different chemotherapy drugs with short half-lives to determine its effect on the prevention of OM development.

Non-Hodgkin's lymphoma with bone involvement: a single center experience with 18 patients.

OBJECTIVE: Non-Hodgkin's lymphoma (NHL) of bone is a rare entity. The most common histological subtype is diffuse large B cell lymphoma (DLBCL). The major presenting symptoms are soft tissue swelling, bone pain and pathological fracture. Treatment options are chemotherapy, radiotherapy, surgery, or a combination of these modalities. METHODS: We retrospectively analyzed the 18 patients (11 females, 7 males) with NHL of bone who were diagnosed and treated between 1995-2005. The median age was 56.5 years. The median duration of symptoms was 4.5 months. The bone pain was the first symptom in all patients. Tru-cut biopsy was performed for diagnosis in most of the cases. Diagnosis in five patients (27.8%) required open biopsy. RESULTS: DLBCL (77.8%) was the most common histological type among all patients. Other histological subtypes were anaplastic large cell lymphoma (11.1%), Burkitt-like lymphoma (5.6%) and marginal zone lymphoma (5.6%). According to Ann Arbor staging system, 44.4% of patients were Stage I, 11.1% were Stage II and 44.4% were Stage IV. Bone marrow involvement was determined in four patients (22.2%). All patients except one were treated with anthracycline-containing regimens and eight patients (44.4%) received rituximab combination with chemotherapy. Radiation therapy was performed as the first-line therapy in 9 (50%) patients. The median follow-up was 37 months (range, 2-124 months). Among the 17 patients who achieved complete remission, five (27.8%) relapsed. All patients were still alive. The five-year relapse-free survival was 73.5%. CONCLUSION: The treatment of bone lymphoma can be planned according to the stage and location of the disease. Although we had a relatively low number of patients, it could be concluded that whether or not radiation therapy is performed, rituximab in combination with systemic chemotherapy has been proven beneficial on survival.