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

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.

Splenic Marginal Zone Lymphoma in Turkey: Association with Hepatitis B Instead of Hepatitis C Virus as an Etiologic and Possible Prognostic Factor - A Multicenter Cohort Study

Objective: Chronic antigenic stimulation is frequently blamed in the pathogenesis of extranodal marginal zone lymphomas including splenic marginal zone lymphoma (SMZL). Chronic hepatitis C is frequently observed in SMZL patients in some geographical regions. However, these reports are largely from North America and Europe, and data from other countries are insufficient. In this multicenter study we aimed to identify the clinical characteristics of SMZL patients in Turkey, including viral hepatitis status and treatment details. Materials and Methods: Data were gathered from participating centers from different regions of Turkey using IBM SPSS Statistics 23 for Windows. Hepatitis B virus surface antigen (HBsAg), anti-HBs antibody, anti-HB core antigen antibody (anti-HBcAg), HB viral load, anti-hepatitis C virus (HCV) antibody, HCV viral load results were analyzed. Results: One hundred and four patients were reported. Hepatitis C virus positivity was observed in only one patient. However, hepatitis B virus surface antigen (HBsAg) positivity was observed in 11.2% and HBsAg and/or anti-HB core antigen antibody (anti-HBcAg) positivities were seen in 34.2% of the patients. The median age was 60 years (range=35-87). Median follow-up duration was 21.2 months (range=00.2-212; 23.2 months for surviving patients). Median overall survival was not reached. Estimated 3-year and 10-year survival rates were 84.8% and 68.9%, respectively. Older age, no splenectomy during follow-up, platelet count of <90x103/µL, lower albumin, higher lactate dehydrogenase, higher ß2-microglobulin, and HBsAg positivity were associated with increased risk of death. Only albumin remained significant in multivariable analysis. Conclusion: These results indicate that hepatitis B virus may be a possible risk factor for SMZL in our population. It may also be an indirect prognostic factor.

Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Daily Practice: A Multicenter Experience.

BACKGROUND: The prognosis of Philadelphia-positive acute lymphoblastic leukemia (Ph(+) ALL) is generally poor. Currently, allogeneic hematopoietic cell transplantation (allo-HCT) is the only accepted therapy with curative potential. PATIENTS AND METHODS: Herein, we report our multicenter, retrospective experience with 46 (23 female; 23 male) Ph(+) ALL patients, who were treated off-study between 2005 and 2012. RESULTS: The median age of the patients was 46 years (range, 19-73 years). During induction, 30 (65%), 13 (28%), and 3 (7%) patients received tyrosine kinase inhibitors (TKIs) concurrent with chemotherapy (TKIs/chemotherapy), chemotherapy only, and TKIs only, respectively. Following induction, rates of complete remission (CR) of the study population were 85% (n = 39). CR rate in patients receiving TKIs during induction (n = 33) was significantly higher compared with patients who received chemotherapy only (n = 13; P = .011). Taking TKIs during induction significantly reduced induction mortality (3.3% vs. 38%; P = .01). Allo-HCT was performed subsequently in 21 (46%) patients. More patients who received TKIs with or without chemotherapy (19/33; 58%) during induction were able to undergo to allo-HCT compared with patients who received chemotherapy only (2/13; 15%; P = .005). Median overall survival of patients who were treated with TKIs during induction and received allo-HCT (not reached; NR) was significantly prolonged compared with patients who received allo-HCT but without TKIs during induction (23.2 months) and to the rest of the cohort (21.2 months; P = .019). CONCLUSIONS: Current state-of-the art management of Ph(+) ALL in real-life seems to be incorporation of TKIs to chemotherapy regimens and proceeding to allo-HCT, whenever possible.

Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic hematopoietic stem cell transplantation for acute leukemia patients: a single center experience.

Due to the high transplant related morbidity and mortality (TRM), relatively younger acute leukemia patients that have a good performance status and no comorbidity are eligible for myeloablative conditioning (MAC) followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). The outcomes of 84 consecutive adult patients with ALL (n=38) or AML (n=46) who underwent allo-HSCT from their HLA-identical siblings were evaluated retrospectively. The median age at transplantation was 34 (17-58 years) for the whole patient population. Of these, 24 patients received a MAC and 60 patients received a fludarabine-based reduced intensity conditioning regimen (RIC). After a median follow-up of 32 months (range, 1-119), for the entire group, the 3-year estimated overall survival (OS) was 57.5% and the disease-free survival (DFS) was 51.5%. The OS for ALL and AML patients were 53.9% vs 62.1%: and DFS were 50.5% and 53.4%, respectively. The 3-year estimated OS for RIC and MAC patients were 63.2% and 41.7%; and DFS were 57.1% and 34.7%, respectively. In ALL patients, conditioning regimens (RIC vs MAC) led to similar OS and DFS; however, in AML patients both OS (70.1% vs 21.4%) and DFS (59.3% vs 42.9%) were found to be higher in RIC patients compared to MAC recipients. Overall, the TRM at day 100 was 1.7% and has increased up to 5.1% at 1st year. In multivariate analysis, the diagnosis (p=0.03) and RIC regimen (p=0.027) were the prognostic variables for prolonged OS in all patients; and RIC regimen (p=0.031) was the only prognostic factor for prolonged OS in AML patients. The first complete remission (CR1) was correlated with a prolonged DFS as an independent variable for all patients (p=0.09). Eleven of the RIC patients (18.3%) and 6 of the MAC patients (25%) developed acute graft-versus-host disease (GvHD). Seventeen of the RIC patients (33.3%) and 4 of the MAC patients (16.7%) developed chronic GvHD. In conclusion, RIC conditioning regimens may provide a longer OS and DFS, especially in patients with AML who are in first CR, not eligible for MAC conditioning.

Hyper-CVAD regimen in routine management of adult acute lymphoblastic leukemia: a retrospective multicenter study.

Treatment of acute lymphoblastic leukemia is unsatisfactory in adults due to disease and patient-related factors and probably because adult chemotherapy regimens are weaker than pediatric protocols. Worries about inadequacy of adult regimens urged many hematologists, including us, to reconsider their routine treatment practices. In this retrospective multicenter study, we aimed to evaluate results of hyper-CVAD treatment in comparison to other intensive protocols. All patients aged ≤65 years who were commenced on intensive induction chemotherapy between 1999 and 2011 were included in the study. Sixty-eight of 166 patients received hyper-CVAD, 65 were treated with CALGB-8811 regimen and 33 with multiple other protocols. Limited number of patients who were treated with other intensive protocols and mature B-acute lymphoblastic leukemia cases who were mostly given hyper-CVAD were eliminated from the statistical analyses. In spite of a favorable complete remission rate (84.2%), overall (26.3 vs. 44.2% at 5 years, p = 0.05) and disease-free (24.9 vs. 48.2%, p = 0.001) survival rates were inferior with hyper-CVAD compared to CALGB-8811 due to higher cumulative nonrelapse mortality risk (29.7 vs. 5.9%, p = 0.003) and no superiority in cumulative relapse incidence comparison (45% for both arms, p = 0.44). Hyper-CVAD, in its original form, was a less favorable regimen in our practice.

The effect of granulocyte colony stimulating factor receptor gene missense single nucleotide polymorphisms on peripheral blood stem cell enrichment.

Granulocyte-colony stimulating factor (G-CSF) has become the most effective agent supporting hematopoietic stem cell transplantation (HSCT). The cognate interaction between G-CSF and its specific receptor, G-CSFR, induces the mobilization of HSCs and increases their pool in the peripheral blood. G-CSFR has a highly conserved structure which may be functionally modulated by the presence of missense single nucleotide polymorphisms (SNPs). In this study, we asked whether the missense SNPs in G-CSFR could affect the response to G-CSF in HSCT patients and donors. Here, for the first time, G-CSFR missense SNPs were screened and minor allele frequencies were determined in a specific population with Turkish racial background. Five (rs3917991, rs3918001, rs3918018, rs3918019, and rs146617729) out of 16 missense SNPs screened were determined with minor allele frequencies lower than 0.04. Subsequent association analyses indicated potential impact of rs3918001, rs3918018, and rs3918019 minor alleles on peripheral blood CD34(+) cell enrichment. Although their frequency is rather low, certain missense SNPs, especially which are placed in the conserved regions of G-CSFR may possess the capacity to influence the response to G-CSF treatment.

Deep Vein Thrombosis Following Non-myeloablative Allogeneic Stem Cell Transplantation: Presentation of Three Cases and Literature Review.

UNLABELLED: The incidence of deep vein thrombosis (DVT) after non-myeloablative (NMA) allogeneic stem cell transplantation (allo-SCT) is unknown. In addition, very few studies on the predisposing factors for DVT post SCT have been published. The incidence of DVT among patients that underwent NMA allo-SCT at our hospital was 4.1% (3 of 73) over the course of last 8 years, and to the best of our knowledge this is the first study to report the incidence of DVT following NMA allo-SCT. The present findings show that NMA allo-SCT patients may have multiple risk factors for DVT. Herein we present 3 cases of DVT following NMA allo-SCT and a literature review. CONFLICT OF INTEREST: None declared.

Relationship between LYVE-1, VEGFR-3 and CD44 gene expressions and lymphatic metastasis in gastric cancer.

AIM: To investigate the expression levels of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), vascular endothelial growth factor receptor-3 (VEGFR-3) and CD44 genes and the relationship between their levels and clinicopathological parameters in gastric cancer. METHODS: Tissue samples were obtained from 33 patients (8 females) with gastric cancer. mRNA levels of LYVE-1, VEGFR-3 and CD44 in normal and tumor tissues were quantitatively measured using real time polymerase chain reaction. The results were correlated with lymph node metastasis, histological type and differentiation of the tumor, T-stage, and presence of vascular, perineural and lymphatic invasions. The distribution of molecules in the tissue was evaluated using immunohistochemistry. RESULTS: LYVE-1, CD44 and VEGFR-3 gene expression levels were significantly higher in gastric cancer than in normal tissue. While there was no correlation between gene expressions and clinicopathologic features such as histologic type, differentiation and stage, gene expression levels were found to be increased in conjunction with positive lymph node/total lymph node ratio and the presence of perineural invasion. A significant correlation was also found between LYVE-1 and CD44 over-expressions and perineural invasion and lymph node positivity in gastric cancers. When the distribution of LYVE-1 antibody-stained lymphatic vessels in tissue was evaluated, lymphatic vessels were located intra-tumorally in 13% and peri-tumorally in 27% of the patients. Moreover, lymph node metastases were also positive in all patients with LYVE-1-staining. CONCLUSION: LYVE-1, VEGFR-3 and CD44 all play an important role in lymphangiogenesis, invasion and metastasis. LYVE-1 is a perfectly reliable lymphatic vessel marker and useful for immunohistochemistry.

Late relapse of a light-chain myeloma as extramedullary plasmacytoma of the thyroid gland after second allogeneic stem-cell transplantation.

We present a rare experience with a myeloma patient who had a late relapse as isolated extramedullary plasmacytoma of the thyroid gland after a second allogeneic transplantation. We give PET/CT scan findings at diagnosis and during follow up of the disease after subsequent management. The possible pathogenesis of the late extramedullary relapse of myeloma after allogeneic stem-cell transplantation and management options are discussed.

High complete remission rate and durable remissions achieved with rational use of autologous stem-cell transplantation, thalidomide maintenance, and non-myeloablative allogeneic transplantation in patients with multiple myeloma.

Autologous stem-cell transplantation (ASCT) has emerged as the standard approach in patients with multiple myeloma, although it is unlikely to achieve cure. Thalidomide maintenance and non-myeloablative allogeneic transplantation (NST) may increase complete remission (CR) rate and increase overall survival. In this study, 35 ASCT and 10 NST were performed in 33 patients. Patients, who were resistant or relapsed following ASCT, underwent NST if they had an HLA-matched sibling, otherwise treated with a second ASCT. Thalidomide was started as maintenance after ASCT. After first transplantation, three patients underwent second ASCT and 10 patients underwent NST. Following first transplantation, CR rate was 39% and increased to 60% (overall response 93%) with addition of thalidomide, bortezomib, and second transplantation. CR was durable in 14 (42%) patients. During a median follow-up of 24 months, 18 patients progressed and nine patients died. The 100-d transplant-related mortality was <5%. The four-yr progression-free survival (PFS) was 52.4%. In conclusion, ASCT followed by thalidomide and NST in resistant patients can lead to high CR and PFS rates. As a second transplantation has not been performed routinely, patients having durable CR had a chance to avoid or delay a second transplantation without compromising disease control.

The lollipop with strawberry aroma may be promising in reduction of infusion-related nausea and vomiting during the infusion of cryopreserved peripheral blood stem cells.

Nausea and vomiting during the infusion of cryopreserved peripheral blood stem cells (PBSC) are common. The aim of this study was to explore the effect of lollipop with strawberry aroma on the infusion-related nausea and vomiting of cryopreserved autologous PBSCs. We compared 2 groups of adult patients receiving lollipop with strawberry aroma during cryopreserved PBSC infusions or not to assess the incidences of nausea and vomiting occurring during infusions. All patients received granisetron 3 mg i.v. twice a day, and lorazepam 1 mg every 4 hours orally for prophylaxis of the nausea and vomiting during conditioning phase and infusion day. Before infusion, all patients were premedicated with pheniramine maleate 45.5 mg i.v. and paracetamol 500 mg orally. The patients had no evidence of nausea or vomiting prior to cryopreserved PBSC infusions. The patients with ongoing nausea or vomiting owing to conditioning regimens and/or receiving additional antiemetics were excluded from the study. One hundred fifty-eight patients who consecutively underwent autologous stem cell transplantation for malignancy were included in the study. The first 110 patients (median age: 42.5, range: 17-75) were observed for the infusion related adverse effects only. The consecutive 48 patients (median age: 48, range: 18-80) were given a lollipop with strawberry aroma during cryopreserved PBSC infusions and observed for the infusion-related adverse effects. The 2 groups were comparable with respect to age, sex, diagnosis, stem cell collection methods, conditioning regimens administered, total mononuclear cell dose infused, number of total nucleated cells (TNCs) infused, number of CD34+ cells infused, number of bags infused, total volume infused, amount of dimethylsulfoxide (DMSO), and infusion rate. Patients who received a lollipop with a strawberry aroma during infusions had significantly less nausea (6.3%, n = 3 versus 21.8%, n = 24, P = .02) and vomiting (2%, n = 1 versus 13.6%, n = 15, P = .04) than the ones who did not (observation only group). Other infusion-related adverse events were as follows; hypoxia, cough, dyspnea, abdominal cramping, tachycardia, hiccup, fever, chills, chest pain, hypotension, hypertension, agitation, sore throat, and arrhythmia. Incidences of each of these adverse events were <5% in both groups and were comparable. The use of a lollipop with a strawberry aroma during infusion of cryopreserved autologous PBSCs may be promising in reduction of infusion-related nausea and vomiting, with an easy administration at a very cheap cost.

High dose sequential chemotherapy and autologous stem cell transplantation in patients with relapsed/refractory lymphoma.

Although high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for patients with relapsed/refractory Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL), more than 50% of patients will experience relapse following ASCT. High-dose sequential chemotherapy (HDSC) can intensify the conventional salvage treatment and improve the outcome of ASCT by maximal debulking of the tumor load with the use of non-cross resistant drugs, each at their maximal tolerated doses. We conducted a phase II study in 40 patients with relapsed/refractory HD (n = 18) and NHL (n = 22) using HDSC followed by ASCT. Only patients sensitive to salvage chemotherapy were eligible for the protocol, consisting of three phases. Phase I consisted of cyclophosphamide (4.5 g/m2) followed by G-CSF and peripheral blood stem cell (PBSC) collection. Phase II consisted of etoposide (2 g/m2). The transplant phase consisted of mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) followed by PBSC infusion. Eleven out of nineteen patients with B-cell lymphoma received rituximab. Prior to HDSC, 45% of the patients were in complete remission (CR) and 55% were in partial remission (PR). After completion of all phases of the protocol, 35 out of 39 evaluable patients achieved CR (90%) and this was durable in 30 (75%) patients with a projected progression-free survival (PFS) rate at 4 years of 71.7%. Treatment-related mortality rate at day +100 was 2.5% (n = 1). At a median follow-up of 32 months (range, 3 - 61), nine patients relapsed/progressed and eleven patients died. The estimated 4-year PFS and overall survival (OS) were 72.2% and 47.6% in HD patients and 70.3% and 69.4% in NHL patients, respectively. Factors predicting OS were response to conventional salvage therapy and stage prior to salvage therapy. When compared to patients achieving PR, patients who attained CR prior to HDSC had a significantly higher probability of 4-year OS (78.4% vs 31.3%, p = 0.02). Three prognostic subgroups were defined according to the score determined by stage prior to initiation of salvage chemotherapy, remission duration prior to salvage (refractory/early relapse vs. late relapse) and response to salvage. Prognostic score was found to predict OS, PFS and event free survival (EFS). In conclusion, HDSC followed by ASCT is an effective salvage therapy with acceptable toxicity, allowing further consolidation of response attained by conventional salvage therapy.