No outcome disparities in patients with diffuse large B-cell lymphoma and a low socioeconomic status.

INTRODUCTION: In patients with diffuse large B-cell lymphoma (DLBCL) socioeconomic status (SES) is associated with outcome in several population-based studies. The aim of this study was to further investigate the existence of disparities in treatment and survival. METHODS: A population-based cohort study was performed including 343 consecutive patients with DLBCL, diagnosed between 2005 and 2012, in the North-west of the Netherlands. SES was based on the socioeconomic position within the Netherlands by use of postal code and categorized as low, intermediate or high. With multivariable logistic regression and Cox proportional hazard models the association between SES and respectively treatment and overall survival (OS) was evaluated. RESULTS: Two-third of patients was positioned in low SES. Irrespective of SES an equal proportion of patients received standard immunochemotherapy. SES was not a significant risk indicator for OS (intermediate versus low SES: hazard ratio (HR) 1.31 (95%CI 0.78-2.18); high versus low SES: HR 0.83 (95%CI 0.48-1.46)). The mortality risk remained significantly increased with higher age, advanced performance status, elevated LDH and presence of comorbidity. CONCLUSION: Within the setting of free access to health care, in this cohort of patients with DLBCL no disparities in treatment and survival were seen in those with lower SES.

Progression of a solitary plasmacytoma to multiple myeloma. A population-based registry of the northern Netherlands.

Plasmacytoma is characterized by a local accumulation of monoclonal plasma cells without criteria for multiple myeloma (MM). The current treatment regimen is local radiotherapy. However, more than 50% of patients develop MM within 2 years after treatment. A population-based registry was consulted for the diagnosis of solitary plasmacytoma between 1988 and 2011. Progression to MM and prognostic features for progression to MM were scored, including hypoxia inducible factors (HIF), vascular endothelial growth factor (VEGF, also termed VEGFA) and micro-vessel density (MVD) expression in biopsy material. A total of 76 patients were included, 34% having extramedullary plasmacytoma (EMP) while 66% had a solitary plasmacytoma of the bone (SBP). Median follow-up was 89 months, (7-293 months). In Seventy per cent of SBP patients developed MM with a median time to progression of 19 months (5-293). Three patients (12%) with EMP developed MM. High expression of VEGF and HIF-2α (also termed EPAS1) was demonstrated in conjunction with an increased MVD in 66% of the patients. No association could be shown between angiogenesis parameters and progression to MM. In conclusion, this population-based study demonstrates that SBP patients have a higher risk of developing MM following local radiotherapy, indicating that this group might benefit from added systemic chemotherapy.

Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients.

Combination therapy for longer periods but at low dose might be an effective and tolerable manner to treat patients with relapsed multiple myeloma (MM). We used bortezomib, dexamethasone and low-dose oral cyclophosphamide as an induction regimen, followed by 1 year of maintenance consisting of bortezomib and cyclophosphamide. Relapsed MM patients were treated with six cycles of bortezomib twice weekly, cyclophosphamide 50 mg daily and dexamethasone. Maintenance therapy was given for 1 year. Primary endpoints were toxicity during re-induction and maintenance therapy. Secondary endpoints were response to treatment and progression-free (PFS) and overall survival (OS). This study included 59 patients. Myelosuppression and neuropathy were the most common side effects. Median follow-up was 27·1 (0·46-54·4) months with an overall response of 71%, and a very good partial response or more of 33%. During maintenance, improved responsiveness was observed in 19% of the patients. The median PFS was 18·4 months (range 0·13-43·5) and the median OS was 28·1 months (range 0·13-54·4). In conclusion, our study demonstrates that treatment with bortezomib, dexamethasone and low-dose cyclophosphamide is an effective and manageable regimen. Adding 1 year of maintenance was feasible, with limited side effects and an increased response rate.

Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone is beneficial but toxic in very elderly patients with diffuse large B-cell lymphoma: a population-based cohort study on treatment, toxicity and outcome.

To assess treatment strategies, toxicity and outcome in very elderly patients (aged ≥ 75 years) diagnosed with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, an observational population-based cohort study was performed. From 103 patients with a median age of 81 years, data of clinical characteristics, treatment, toxicity and outcome were evaluated. Advanced stage DLBCL was documented in 74 patients. In 80 patients chemotherapy was initiated; 70 patients received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). In this group, 39 patients completed all cycles and 30 patients achieved a complete remission. Severe chemotherapy-related toxicity occurred in 69%. Two-year overall survival was 70% for elderly patients who completed chemotherapy, 28% for those treated with incomplete or suboptimal chemotherapy and 21% for those receiving palliative radiotherapy or supportive care. In conclusion, the ability to complete R-CHOP was associated with better overall survival compared to other treatment strategies at the expense of severe treatment-related toxicity.

Hereditary leiomyomatosis and renal cell cancer presenting as metastatic kidney cancer at 18 years of age: implications for surveillance.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome characterized by skin piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer caused by germline mutations in the fumarate hydratase (FH) gene. Previously, we proposed renal imaging for FH mutation carriers starting at the age of 20 years. However, recently an 18-year-old woman from a Dutch family with HLRCC presented with metastatic renal cancer. We describe the patient and family data, evaluate current evidence on renal cancer risk and surveillance in HLRCC and consider the advantages and disadvantages of starting surveillance for renal cancer in childhood. We also discuss the targeted therapies administered to our patient.

Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients: a prospective phase II study.

Thalidomide is an effective agent for patients with refractory multiple myeloma (MM) with a response rate of 30-40% at doses of 200-800 mg but with considerable side effects. We questioned whether lower doses of thalidomide in combination with a daily dose of cyclophosphamide might be an effective regimen with fewer side effects. We included 38 patients with relapsed or refractory MM. The median doses of thalidomide and cyclophosphamide were 100 and 95 mg/day, respectively. Side effects were observed in all patients, with neurotoxicity as the most troublesome. With a median follow-up of 14 months 84% of the patients responded, including 64% partial responses. The median time of progression-free survival was 30 months and the median overall survival time was 20 months. In conclusion, the results demonstrate that the combination of low-dose thalidomide with a daily dose of cyclophosphamide is an effective regimen with a high overall response rate and manageable side effects.

Heterogeneity in the multiple myeloma tumor clone.

Multiple Myeloma (MM) is a plasma cell malignancy which is characterized by a very heterogeneous disease outcome. Heterogeneity in plasma cell characteristics, including morphology, maturation status, immunophenotype and genetic abnormalities partly account for the variable disease outcome. Although the plasma cell is the predominant cell type in MM, several studies have shown that less mature B cells, which are clonally related to the malignant plasma cells, are present in the bone marrow and peripheral blood of MM patients. The significance of these so-called myeloma clonotypic B cells in the disease process remains largely unknown. In this review the role of myeloma clonotypic B cells and myeloma tumor clone heterogeneity in relation to prognosis and clinical outcome are discussed.

CD27-triggering on primary plasma cell leukaemia cells has anti-apoptotic effects involving mitogen activated protein kinases.

Primary plasma cell leukaemia (PCL) is a rare plasma cell malignancy, which is related to multiple myeloma (MM) and is characterized by a poor prognosis. In a previous study we demonstrated that PCL plasma cells display a high expression of CD27, in contrast to MM plasma cells. The present study was set out to assess the functional properties of CD27 expressed on PCL plasma cells by triggering with its ligand CD70. Using CD27-expressing purified plasma cells from a PCL patient we demonstrated that CD27-triggering modestly inhibited spontaneous and dexamethasone-induced apoptosis. In vitro stimulation and Western blotting showed that activation of p38 and extracellular-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinases (MAPK) was associated with CD27-mediated signal transduction. Specific inhibition of p38 and ERK1/2 MAPK abolished the anti-apoptotic effects of CD27-triggering. Interestingly, simultaneous inhibition of p38 and ERK1/2 strongly sensitized PCL cells for dexamethasone-induced apoptosis. Finally, in dexamethasone-treated PCL cells, CD27-triggering was associated with persistent DNA-binding activity of activator protein 1 (AP-1) but not of nuclear factor-kappaB. These findings suggest that, in primary PCL, specific anti-apoptotic pathways exist that might provide novel therapeutic targets.

CD27 is heterogeneously expressed in multiple myeloma: low CD27 expression in patients with high-risk disease.

Expression of CD27 on malignant plasma cells (PC) (CD138+CD38++) was analysed in a cross-sectional study of bone marrow (BM) samples from multiple myeloma (MM) patients (n = 28), monoclonal gammopathy of undetermined significance (MGUS) patients (n = 6) and BM PC from healthy donors (n = 4). MM PC expressed CD27 with a variable, lower intensity pattern compared with the consistent high expression in MGUS and healthy donors. MM patients in complete clinical remission displayed a higher percentage of CD27+ PC compared with patients at diagnosis, relapse or in partial remission. In MM, loss of CD27 correlated with loss of CD19 (R2 = 0.4, P < 0.0001). Human MM cell lines (n = 9) did not express CD27 whereas de novo plasma cell leukaemia (PCL) (n = 3) had a high expression. Re-analysis of a cDNA microarray data set, generated from newly diagnosed MM patients (n = 74), demonstrated that the MM subgroup with the highest prevalence of poor prognostic factors had the lowest CD27 mRNA expression. Fluorescence-activated cell sorting and allele-specific oligonucleotide polymerase chain reaction showed that both CD27+ and CD27- PC subpopulations in MM can belong to the clonal disorder. In conclusion, CD27 is heterogeneously expressed on MM PC and loss of CD27 expression might have prognostic value in MM.