Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma.

BACKGROUND: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors. METHODS: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression. RESULTS: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab. CONCLUSION: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.

Cost-effectiveness of obinutuzumab for chronic lymphocytic leukaemia in The Netherlands.

BACKGROUND: Obinutuzumab combined with chlorambucil (GClb) has shown to be superior to rituximab combined with chlorambucil (RClb) and chlorambucil (Clb) in newly diagnosed patients with chronic lymphocytic leukaemia (CLL). This study evaluates the cost-effectiveness per life-year and quality-adjusted life-year (QALY) of GClb compared to RClb, Clb, and ofatumumab plus chlorambucil (OClb) in The Netherlands. METHODS: A Markov model was developed to assess the cost-effectiveness of GClb, RClb, Clb and other treatments in the United Kingdom. A country adaptation was made to estimate the cost-effectiveness of these therapies in The Netherlands using Dutch unit costs and Dutch data sources for background mortality and post-progression survival. RESULTS: An incremental gain of 1.06 and 0.64 QALYs was estimated for GClb compared to Clb and RClb respectively, at additional costs of €23,208 and €7254 per patient. Corresponding incremental cost-effectiveness ratios (ICERs) were €21,823 and €11,344 per QALY. Indirect treatment comparisons showed an incremental gain varying from 0.44 to 0.77 QALYs for GClb compared to OClb and additional costs varying from €7041 to €5028 per patient. The ICER varied from €6556 to €16,180 per QALY. Sensitivity analyses showed the robustness of the results. CONCLUSION: GClb appeared to be a cost-effective treatment strategy compared to RClb, OClb and Clb.

The beneficial local and abscopal effect of splenic irradiation in frail patients with chronic lymphocytic leukaemia.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is a common haematological malignancy that mainly occurs in the elderly population. Patients frequently have comorbidities compromising the use of old and new systemic therapies. METHODS AND RESULTS: We report the prevalence of comorbidities in patients with CLL as present in the southern region of the Netherlands Cancer Registry. Comorbid conditions were present in 67% of the male and 63% of the female patients, and became more common with increasing age. Furthermore, we describe the beneficial local and abscopal effects of splenic irradiation in four patients with CLL who were not suitable for systemic chemoimmunotherapy because of severe comorbidities, or who were unwilling to undergo systemic therapy. CONCLUSION: Our results show that, although an old tool, splenic irradiation should not be forgotten as a potentially effective palliative treatment option in frail patients with symptomatic CLL.

Quality of life of patients with chronic lymphocytic leukaemia in the Netherlands: results of a longitudinal multicentre study.

PURPOSE: To describe the health-related quality of life (HRQoL) of an unselected population of patients with chronic lymphocytic leukaemia (CLL) including untreated patients. METHODS: HRQoL was measured by the EORTC QLQ-C30 including the CLL16 module, EQ-5D, and VAS in an observational study over multiple years. All HRQoL measurements per patient were connected and analysed using area under the curve analysis over the entire study duration. The total patient group was compared with the general population, and three groups of CLL patients were described separately, i.e. patients without any active treatment ("watch and wait"), chlorambucil treatment only, and patients with other treatment(s). RESULTS: HRQoL in the total group of CLL patients was compromised when compared with age- and gender-matched norm scores of the general population. CLL patients scored statistically worse on the VAS and utility score of the EQ-5D, all functioning scales of the EORTC QLQ-C30, and the symptoms of fatigue, dyspnoea, sleeping disturbance, appetite loss, and financial difficulties. In untreated patients, the HRQoL was slightly reduced. In all treatment stages, HRQoL was compromised considerably. Patients treated with chlorambucil only scored worse on the EORTC QLQ-C30 than patients who were treated with other treatments with regard to emotional functioning, cognitive functioning, bruises, uncomfortable stomach, and apathy. CONCLUSIONS: CLL patients differ most from the general population on role functioning, fatigue, concerns about future health, and having not enough energy. Once treatment is indicated, HRQoL becomes considerably compromised. This applies to all treatments, including chlorambucil, which is considered to be a mild treatment.

Increased risk of chronic lymphocytic leukaemia among cancer survivors in the Netherlands: increased detection, causal factors or both?

We assessed the risk of chronic lymphocytic leukaemia (CLL) following earlier primary malignancies (EPM) to explore the extent and determinants of this risk. We used the Netherlands Cancer Registry data of 1,313,232 cancer survivors who were at risk to be subsequently diagnosed with CLL between 1989 and 2008. Cancer survivors were categorized based on gender, age, time since diagnosis of EPM and type of EPM. CLL was regarded synchronous when diagnosed within 3 months after diagnosis of EPM; metachronous CLLs were those diagnosed later. Overall, we found that cancer survivors had a 90 % higher risk to be diagnosed with CLL than the general population. In the first year after diagnosis, we found a more than four-fold increased risk of CLL (standardized incidence ratio (SIR), 4.4; 95 % confidence interval (CI), 4.1-4.8); however, no increased risk was observed after excluding synchronous cases. After 1 year, the excess risk of subsequent CLL ranged from 1.2 to 1.8. An increased risk for metachronous CLL was found in prostate (SIR 1.3; 95 % CI 1.1-1.5) and squamous cell skin cancer survivors (SIR 2.3; 95 % CI 1.9-2.7). Intensive clinical checkups after/around diagnosis of the EPM seemed to be the main cause for the increased risk of CLL among cancer survivors. However, possible shared risk factors between prostate cancer and CLL and skin cancer and CLL cannot be excluded. Further clinical research aimed at CLL as subsequent primary malignancy (SPM) is warranted to elucidate possible shared biological and predisposing risk factors.

Real-world costs of chronic lymphocytic leukaemia in the Netherlands.

We performed a comprehensive cost calculation identifying the main cost drivers of treatment of chronic lymphocytic leukaemia in daily practice. In our observational study 160 patient charts were reviewed repeatedly to assess the treatment strategies from diagnosis till the study end. Ninety-seven patients (61%) received ≥1 treatment lines during an average follow-up time of 6.4 years. The average total costs per patient were €41,417 (€539 per month). The costs varied considerably between treatment groups and between treatment lines. Although patients were treated with expensive chemo(immuno-)therapy, the main cost driver was inpatient days for other reasons than administration of chemo(immuno-)therapy.

Chronic lymphocytic leukaemia in the Netherlands: trends in incidence, treatment and survival, 1989-2008.

We present trends in incidence, early treatment and survival of Chronic Lymphocytic Leukaemia (CLL) between 1989 and 2008, based on population-based data from the Netherlands Cancer Registry. Incidence rates were stable at 5.1 per 100,000 person-years for males, but increased from 2.3 to 2.5 for females, especially for females aged 50-64 years (from 3.6 to 4.3). Patients were less likely to receive chemotherapy within six months, i.e. from 29% to 24% among males and from 25% to 21% among females. Five-year relative survival increased from 61% in 1989-1993 to 70% 2004-2008 for males, and from 71% to 76% for females. The relative excess risk of dying decreased in time to 0.7 (males) and 0.9 (females) in 2004-2008, reference 1989-1993, and increased with age to 2.9 (males) and 1.8 (females) in patients aged 75-94 years, reference 30-64 years. The increasing incidence among females aged 50-64 coincided with the introduction of mass screening for breast cancer, which resulted in a large group of women under increased surveillance and possibly led to increased detection of CLL. The increase in survival might be underestimated due to possible decreased or delayed registration of indolent cases and the retroactive effect of the introduction of new therapies.

[Peripheral intravenous catheter-related phlebitis]. / Flebitis bij perifeer infuus.

Phlebitis is a very common complication of the use of intravenous catheters. Two patients with an i.v. catheter complicated by thrombophlebitis are described. Patient A was immunocompromised due to chronic lymphatic leukaemia and developed septic thrombophlebitis with positive blood cultures for S. Aureus. Patient B was being treated with flucloxacillin because of an S. Aureus infection and developed chemical phlebitis. Septic phlebitis is rare, but potentially serious. Chemical or mechanical types of thrombophlebitis are usually less severe, but happen very frequently. Risk factors include: female sex, previous episode of phlebitis, insertion at (ventral) forearm, emergency placement and administration of antibiotics. Until recently, routine replacement of peripheral intravenous catheters after 72-96 h was recommended, but randomised controlled trials have not shown any benefit of this routine. A recent Cochrane Review recommends replacement of peripheral intravenous catheters when clinically indicated only.

Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.

BACKGROUND: Low NT-proBNP levels are associated with an uncomplicated course in patients with pulmonary embolism (PE). The aim of this multicenter management study was to investigate the safety of home treatment of patients with PE with low (< 500 pg mL(-1)) NT-proBNP. METHODS AND RESULTS: Hemodynamically stable outpatients with acute PE and NT-proBNP level < 500 pg mL(-1) were included. Patients were discharged immediately from the emergency room or within a maximum of 24 h after admission. The primary study objective was the absence of mortality during the first 10 days of treatment. Secondary objectives were the incidence of re-admission due to PE or its treatment and the patient's satisfaction during the first 10 days of treatment as well as the incidence of serious adverse events during the 3-month follow-up period. Of 351 patients, 152 (43%) fulfilled the inclusion criteria and were treated as outpatients. No deaths, major bleedings or recurrent venous thromboembolism occurred in the first 10 days of treatment or in the follow-up period of 3 months in these patients. Seven patients required readmission in the first 10 days: three because of complaints that could be related to PE and four due to an illness unrelated to PE. The HADS-A anxiety score did not change significantly between day 0 and day 10. The PSQ-18 showed a high score for satisfaction with home treatment. CONCLUSION: Out of hospital treatment is safe in hemodynamically stable patients with PE with low (< 500 pg mL(-1)) NT-proBNP levels. Approximately 45% of patients with PE can be treated in an outpatient setting. Patients do not consider out of hospital treatment as inconvenient and have no increase in anxiety scores. CLINICAL TRIAL REGISTRATION INFORMATION: http://clinicaltrials.gov/ct2/show/NCT00455819.

Pulmonary coccidioidomycosis: import illness and the importance of travel history.

A 35-year-old man presented at the outpatient department of pulmonary diseases with fever, rhinitis and coughing. He had recently been on holiday in California. Except for a body temperature of 39.7 degrees C there were no other abnormal findings at the physical examination. Chest X-ray showed a consolidation in the left upper lobe. Under antibiotic treatment his clinical condition deteriorated. Coccidioidomycosis was the suspected diagnosis and confirmed by the results of CT scanning and culture of bronchoalveolar lavage fluid. Treatment with itraconazole resulted in lasting improvement. The case stipulates the importance of travel history.

Splenectomy-induced long-term remission in a patient with multicentric Castleman's disease.

Castleman's disease (CD) is a rare lymphoproliferative disorder with a poorly understood pathogenesis. Multicentric CD can progress in different patterns, none of which can be cured with the current treatment options. We present a patient with multicentric CD in complete remission, eight years after a splenectomy without any other systemic treatment. We discuss the possible mechanism causing this long episode of complete remission in this patient.

Improved survival for patients with large B-cell lymphoma after introduction of rituximab.

BACKGROUND: To determine whether the reported increase in survival of patients with diffuse large B-cell malignant lymphoma (DLBCL) after the introduction of rituximab is also seen in a non-academic hospital in the Netherlands. A retrospective study. METHODS: A dataset was made containing all newly diagnosed patients with DLBCL in a period of 2.5 years before until 2.5 years after introduction of rituximab in the standard treatment. Total follow-up time was 6.5 years with a minimal follow-up of 18 months. RESULTS: The study population consisted of 65 patients; 32 in the prerituximab group (median follow-up time 60 months) and 33 in the postrituximab group (median follow-up time 29 months). Progression-free survival increased significantly in the postrituximab group (hazard ratio 0.31; 95% CI 0.12 to 0.78; p=0.013; log rank p=0.008). The overall survival also showed a significant increase (p=0.048). The 18-month progression-free survival increased from 59.4 to 81.8%; the overall survival at 18 months showed an increase from 65.5 to 81.8%. CONCLUSION: The introduction of rituximab in the treatment of DLB CL with CHOP chemotherapy has resulted in a significantly better prognosis for patients with DLBCL, treated in the Reinier de Graaf Gasthuis in Delft.

HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia.

Mismatching for human leukocyte antigen (HLA)-DPB1 in unrelated donor hematopoietic stem cell transplantation (URD-SCT) has been associated with a decreased risk of disease relapse, indicating that HLA-DP may represent a target for graft-versus-leukemia (GVL) reactivity in HLA class II-expressing hematological malignancies. To investigate whether HLA-DP-specific T cells could mediate GVL reactivity following HLA-DPB1-mismatched URD-SCT and donor lymphocyte infusion (DLI), we analyzed the immune response in a patient with leukemic lymphoplasmacytic lymphoma responding to DLI without graft-versus-host disease. The emergence of leukemia-reactive CD4+ T cells during the clinical immune response was demonstrated by interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot(ELISPOT)analysis. Following clonal isolation of these leukemia-reactive CD4+ T cells, blocking studies, panel studies and retroviral transduction experiments of both mismatched HLA-DPB1 alleles identified HLA-DPB1(*)0201 and HLA-DPB1(*)0301 as the targets of this immune response. The HLA-DPB1-specific CD4+ T-cell clones were capable of recognizing and lysing several HLA-DP-expressing myeloid and lymphoid hematological malignant cells. Since HLA-DP expression is mainly restricted to hematopoietic cells, HLA-DP may be used as a specific target for immunotherapy following T-cell-depleted URD-SCT. Therefore, in patients with HLA class II-expressing hematological malignancies HLA-DP-mismatched SCT may be preferable over fully matched SCT allowing DLI to induce a GVL effect.