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Barbara Jezeršek Novaković, Lučka Boltežar, Aleksander NovakovićDivision of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, 1000, SloveniaCorrespondence: Barbara Jezeršek NovakovićDivision of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, Ljubljana, 1000, SloveniaTel +38615879631Fax +38615879305Email bjezersek@onko-i.siAbstract: Not many treatment options exist for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) in whom first- and second-line therapies were unsuccessful. This is especially true for patients with aggressive lymphomas. The innovative agent pixantrone has shown some promising results in terms of disease-free and overall survival, both in monotherapy as well as in combinations. However, recent trials (Phase III and real-world studies) reported unsatisfactory results, thereby raising the question about the role of pixantrone in the current treatment of R/R aggressive lymphomas. Nonetheless, there might still be a potential position for this drug in combinations, for use as first-line treatment of patients with cardiac dysfunction. This article summarizes the definition, structure, mechanism of action and reduced cardiotoxicity of pixantrone as well as efficacy and toxicity both in monotherapy and in combinations, as treatment for aggressive and indolent non-Hodgkin lymphomas.Keywords: pixantrone, B-cell non-Hodgkin lymphomas, efficacy, toxicity

t(14;18)(q32;q21) translocation is an important genetic feature of follicular lymphoma resulting in antiapoptotic B-cell lymphoma 2 (BCL2) protein overexpression. On chromosome 18 breakpoint-site variation is high but does not affect BCL2. Breakpoint most commonly occurs at major breakpoint region (MBR) but may happen at minor cluster region (mcr) and between MBR and mcr at 3′MBR and 5′mcr. The aim of this study was to analyze the correlation of t(14;18)(q32;q21) breakpoint site with clinical characteristics in follicular lymphoma.

Background: This study assessed the prognostic value of tumor burden in bone marrow (BM) and total disease (TD), as depicted on 18F-FDG PET/CT in 140 DLBCL patients, for complete remission after first-line systemic treatment (iCR) and 3- and 5-year overall survival (OS3 and OS5)., Methods: Baseline 18F-FDG PET/CT scans of 140 DLBCL patients were segmented to quantify metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax in BMI, findings elsewhere (XL), and TD., Results: Bone marrow involvement (BMI) presented in 35 (25%) patients. Median follow-up time was 47 months; 79 patients (56%) achieved iCR. iCR was significantly associated with TD MTV, XL MTV, BM PET positivity, and International Prognostic Index (IPI). OS3 was significantly worse with TD MTV, XL MTV, IPI, and age. OS5 was significantly associated with IPI, but not with MTVs and TLGs. Univariate factors predicting OS3 were XL MTV (hazard ratio [HR] = 1.29), BMI SUVmax (HR = 0.56), and IPI (HR = 1.92). By multivariate analysis, higher IPI (HR = 2.26) and BMI SUVmax (HR = 0.91) were significant independent predictors for OS3. BMI SUVmax resulted in a negative coefficient and hence indicated a protective effect., Conclusions: Baseline 18F-FDG PET/CT MTV is significantly associated with survival. BMI identified on 18F-FDG PET/CT allows appropriate treatment that may improve survival.

High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are known for their aggressive clinical course and so are the ones with MYC and BCL2 protein overexpression. The optimal therapy for these lymphomas remains to be elucidated. A retrospective analysis of all diffuse large B-cell lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements diagnosed between 2017 and 2021 at the Institute of Oncology Ljubljana, Slovenia, has been performed. Only patients with double-expressor lymphoma (DEL), double-hit lymphoma (DHL), or triple-hit lymphoma (THL) were included. Demographic and clinical parameters were assessed, as well as progression-free survival (PFS) and overall survival (OS). In total, 161 cases out of 309 (161/309; 52,1%) were classified as DEL. Sixteen patients had DHL, MYC / BCL2 rearrangement was observed in eleven patients, and MYC / BCL6 rearrangement was observed in five patients. Five patients were diagnosed with THL. Out of 154 patients (according to inclusion/exclusion criteria) included in further evaluation, one-hundred and thirty-five patients had double-expressor lymphoma (DEL), sixteen patients had DHL, and three patients had THL. In total, 169 patients were treated with R-CHOP, 10 with R-CHOP and intermediate-dose methotrexate, 19 with R-DA-EPOCH, and 16 with other regimens. The median follow-up was 22 months. The 5-year OS for the whole DEL group was 57.1% (95% CI 45.9-68.3%) and the 5-year PFS was 76.5% (95% CI 72.6-80.4%). The log-rank test disclosed no differences in survival between treatment groups ( p = 0.712) while the high-risk international prognostic index (IPI) carried a significantly higher risk of death (HR 7.68, 95% CI 2.32-25.49, p = 0.001). The 5-year OS for DHL patients was 32.4% (95% CI 16.6-48.2%) while all three TH patients were deceased or lost to follow-up. Our analyses of real-life data disclose that the R-CHOP protocol with CNS prophylaxis is a successful and curative treatment for a substantial proportion of DEL patients.

Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas that mostly derive from Cajal cell precursors. They are by far the most common soft tissue sarcomas. Clinically, they present as gastrointestinal malignancies, most often with bleeding, pain, or intestinal obstruction. They are identified using characteristic immunohistochemical staining for CD117 and DOG1. Improved understanding of the molecular biology of these tumors and identification of oncogenic drivers have altered the systemic treatment of primarily disseminated disease, which is becoming increasingly complex. Gain-of-function mutations in KIT or PDGFRA genes represent the driving mutations in more than 90% of all GISTs. These patients exhibit good responses to targeted therapy with tyrosine kinase inhibitors (TKIs). Gastrointestinal stromal tumors lacking the KIT/PDGFRA mutations, however, represent distinct clinico-pathological entities with diverse molecular mechanisms of oncogenesis. In these patients, therapy with TKIs is hardly ever as effective as for KIT/PDGFRA -mutated GISTs. This review provides an outline of current diagnostics aimed at identifying clinically relevant driver alterations and a comprehensive summary of current treatments with targeted therapies for patients with GISTs in both adjuvant and metastatic settings. The role of molecular testing and the selection of the optimal targeted therapy according to the identified oncogenic driver are reviewed and some future directions are proposed.

In patients with gastrointestinal stromal tumors (GIST), it has become mandatory to determine the driver mutation in order to predict the response to standard treatment with tyrosine kinase inhibitors (TKI). A total of 10‑15% of all GIST lack activating mutations in KIT proto‑oncogene, receptor tyrosine kinase ( KIT )/platelet‑derived growth factor receptor alpha ( PDGFRA ) and have been classified as KIT/PDGFRA wild‑type (WT) GIST. They are characterized by poor response to TKI. From a group of 119 metastatic GIST patients, 17 patients with KIT/PDGFRA/BRAF WT GIST as determined by reverse transcription‑quantitative (RT‑q) PCR and Sanger sequencing were profiled by a targeted next‑generation sequencing (NGS) approach and their treatment outcome was assessed. In the present study, 41.2% of patients as KIT/PDGFRA/BRAF WT GIST examined with RT‑qPCR and Sanger sequencing were confirmed to be carriers of pathogenic KIT/PDGFRA mutations by NGS and were responsive to TKI. The percentage of genuinely KIT/PDGFRA WT GIST in the present study thereby dropped from the initial 14.3% detected with the RT‑qPCR and Sanger sequencing to 7.6% after NGS. Their outcome was universally poor. The reliability of RT‑qPCR and direct Sanger sequencing results in this setting is therefore insufficient and it is recommended that NGS becomes a requirement for treatment decision at least in KIT/PDGFRA/BRAF WT GIST as determined by RT‑qPCR and Sanger sequencing.

The present retrospective study was undertaken to investigate the association of relative dose intensity (RDI) with the outcome of patients with advanced stage Hodgkin lymphoma (HL) receiving ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and escalated BEACOPP regimens (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). A total of 114 patients with HL treated between 2004 and 2013 were enrolled for evaluation. The association of variables with overall survival (OS) and progression-free survival (PFS) was analysed using univariate and multivariate Cox proportional hazards models. The median age of patients was 39 years, and the majority were male and had stage IV disease. A total of 54 patients received ABVD and 60 received BEACOPP chemotherapy with 24 and four deaths, respectively. Patients in the BEACOPP group were significantly younger with lower Charlson comorbidity index (CCI) and better performance status in comparison with the ABVD group, making the comparison of groups not possible. In the ABVD group, RDI was not significantly associated with OS (P=0.590) or PFS (P=0.354) in a multivariate model where age was controlled. The low number of events prevented this analysis in the BEACOPP group. The age of patients was strongly associated with both OS and PFS; all statistically significant predictors for OS and PFS from univariate analyses (chemotherapy regimen, CCI, RDI, performance status) lost their effect in multivariate analyses where age was controlled. Based on these observations, it was concluded that RDI was not associated with OS or PFS after age is controlled, neither in all patients combined nor in the ABVD group., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Rožman et al.)

Treatment with rituximab plus a regimen of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) for patients with diffuse large B-cell lymphoma (DLBCL) has proven efficacy in clinical trials. The present study investigated its application in clinical practice. This single-center, retrospective database analysis included patients with DLBCL treated at the Slovenian Institute of Oncology Ljubljana between 2004 and 2013. Overall survival (OS) and progression-free survival (PFS) were assessed according to International Prognostic Index (IPI) and revised IPI (R-IPI) categories. Overall, 573 patients with DLBCL were included in the study (median follow-up, 45.3 months; range, 0.1-143.0). Patients were categorized as IPI 'low' (n=170; 30%), 'low-intermediate' (n=134; 23%), 'high-intermediate' (n=129; 23%) and 'high' (n=140; 24%) risk. R-IPI groups were indicated with 'very good' (n=59; 10%), 'good' (n=245; 43%) and 'poor' (n=269; 47%) prognosis. Ten-year OS and PFS rates were 51 and 72%, respectively; median OS was 124 months and median PFS was not reached. Ten-year OS rates were 80 and 87% in low-risk and 'very good' prognosis groups, respectively, and 30 and 37% in high-risk and poor prognosis patients, respectively. This analysis of patients with DLBCL indicated that many patients treated with R-CHOP and R-CHOP-like regimens in the real-world setting have excellent outcomes.

Aims: Pharmacokinetic (PK) studies suggest that there is a room for improvement in clinical use of rituximab through more individualized treatment. The objective of this study was to characterize rituximab PK in 29 newly diagnosed patients with diffuse large B-cell lymphoma treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine and methylprednisolone every 3 weeks. We also evaluated the association of rituximab PK with clinical outcome., Methods: Rituximab serum levels were determined by enzyme-linked immunosorbent assay and evaluated by a population PK analysis applying nonlinear mixed effects modelling., Results: The data were best described by a two-compartment model comprising linear nonspecific clearance of 0.252 [95% confidence interval (CI): 0.227-0.279] l day -1 and time-varying specific clearance of 0.278 (95% CI: 0.181-0.390) l day -1 , corresponding to target-mediated drug disposition of rituximab. Nonspecific clearance was lower in older patients and those with lower body weight. Additionally, volume of the central compartment was higher in males. A clear association of clinical response with rituximab PK has been observed. Rate constant of specific clearance decay was 0.143 day -1 (95% CI: 0.0478-0.418) in patients with no disease progression, while in patients with disease progression it was 82.2% lower (95% CI: 33.4-95.0)., Conclusions: This finding indicates that time-changes in clearance could serve as a predictive marker of response to rituximab. Our report demonstrates the rationale for studies evaluating higher doses of rituximab in selected patients., (© 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Hodgkin's lymphoma is unusual among cancers in that it consists of a small number of malignant Hodgkin/Reed-Sternberg cells in a sea of immune system cells, including T cells. Most of these T cells are reversibly inactivated in different ways and their reactivation may induce a very strong immune response to cancer cells. One way of reactivation of T cells is with antibodies blocking the CTLA-4 and especially with antibodies directed against PD-1 or the PD-L1 ligand thereby reversing the tumor-induced downregulation of T-cell function and augmenting antitumor immune activity at the priming (CTLA-4) or tissue effector (PD-1) phase. Immune checkpoint inhibitors have been evidenced as an additional treatment option with substantial effectiveness and acceptable toxicity in heavily pretreated patients with Hodgkin's lymphoma. Particularly, PD-1 blockade with nivolumab and pembrolizumab has demonstrated significant single-agent activity in this select population., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: The purpose of this study was to determine the fertility rates following treatment by means of the BEACOPP regimen (regular and escalated) (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) as compared to the ABVD regimen (doxorubicin, vinblastine, dacarbazine, bleomycin) in Hodgkin lymphoma patients under the age of 40 at the time of treatment., Methods: A questionnaire was sent to 180 Hodgkin lymphoma (HL) patients. The questionnaire was composed of questions concerning reproduction and also menopausal and aging symptoms in females and males. The analyses were made using data collected from 123 patients (76 females and 47 males) who returned the questionnaire. All of the patients were treated between 1999 and 2012., Results: In comparing the ABVD and BEACOPP groups of female patients, the frequency of the therapy-induced amenorrhea and the restored menses following treatment were found to be significantly different statistically (p = 0.002 and p = 0.012, respectively). The secondary amenorrhea statistically appeared more often in the BEACOPP group (p = 0.003) while the cases of achieving pregnancy and having children after chemotherapy were not significantly different (p = 0.630, p = 0.070, respectively). In comparing the ABVD and BEACOPP treatments in male patients, the only significant difference was in the number of artificially inseminated or in vitro pregnancies achieved in the BEACOPP and escalated BEACOPP group, p = 0.008 and p = 0.002, respectively. In total, 45.2% of patients in the ABVD female group, 34.6% in the BEACOPP female group, 52.6% in the ABVD male group, and 33.3% in the male BEACOPP group, respectively, of patients attempting conception post-therapy, had children after chemotherapy., Conclusions: Based on these high rates of childbirth following BEACOPP chemotherapy, we have concluded that intensified chemotherapy is not a definite predictor of reduced fertility in young HL patients.

Background: The outcome of follicular lymphoma (FL) patients has dramatically improved over the last 2 decades by introduction of rituximab in combination chemotherapy and into maintenance setting. We retrospectively analyzed the treatment outcomes in Slovene FL patients in the era of rituximab and compared them to the results reported by pivotal clinical studies., Patients and Methods: Two hundred seventy-eight patients with FL treated in Slovenia between 2000 and 2010 with a median follow-up of 5.7 years were included in our retrospective analysis. One hundred ninety-three (69%) received systemic treatment (ST)., Results: With a median follow-up of 5.7 years, the 5- and 10-year overall survival (OS) rates for the whole series were 77% and 53%, respectively. The 5-year progression-free survival (PFS) for 193 FL patients treated with ST was 37%. Patients treated with rituximab chemotherapy had a significantly better OS than patients treated with chemotherapy alone, with a 5-year OS of 79% versus 53% (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.22-0.67; P = .001). Adding rituximab to the first-line chemotherapy significantly improved PFS compared to chemotherapy alone (HR, 0.26; 95% CI 0.18-0.36; P < .001). Maintenance rituximab after immunochemotherapy in first-line treatment reduced the risk for progression by 61% and significantly prolonged the time to progression (HR, 0.39; 95% CI 0.20-0.73; P < .003)., Conclusion: The outcomes in our routinely treated FL patients confirm the benefit of adding rituximab to chemotherapy and are comparable to the results of pivotal clinical studies. The outcome of our FL patients was improved in terms of both PFS and OS., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)