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Introduction: To assess the value of the Mini-Mental State Examination (MMSE)-score at baseline in predicting survival in adult primary central nervous system lymphoma (PCNSL) patients. Methods: In the HOVON 105/ ALLG NHL 24 phase III study patients with newly-diagnosed PCNSL were randomized between high-dose methotrexate-based chemotherapy with or without rituximab. Data on potential (MMSE-score), and known baseline prognostic factors (age, performance status, serum LDH, cerebrospinal fluid total protein, involvement of deep brain structures, multiple cerebral lesions, and the IELSG-score) were collected prospectively. Multivariable stepwise Cox regression analyses were used to assess the prognostic value of all factors on progression-free survival (PFS) and overall survival (OS) among patients with available MMSE score at baseline. Age was analyzed as continuous variable, the MMSE-score both as a continuous and as a categorical variable. Results: In univariable analysis, age, MMSE-score and whether the patient received rituximab were statistically significantly prognostic factors for PFS. Age and MMSE-score were statistically significantly associated with OS. In a multivariable analysis of the univariately significant factors only MMSE-score was independently associated with the survival endpoints, as a continuous variable (HR for PFS 1.04, 95% CI 1.01–1.08; OS 1.06 (95% CI 1.02–1.10) and as categorical variable HR (< 27 versus ≥ 27 for PFS 1.55 (1.02–2.35); OS 1.68 (1.05–2.70). In our population, performance status, serum LDH, and CSF protein level were not of prognostic value. Conclusion: Neurocognitive disturbances, measured with the MMSE at baseline, are an unfavorable prognostic factor for both PFS and OS in adult PCNSL patients up to 70 years-old.

Despite recent identification of several prognostic markers, there is still a need for new prognostic parameters able to predict clinical outcome in chronic lymphocytic leukemia (CLL) patients. Here, we aimed to validate the prognostic ability of known (proteomic) markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL. To this end, baseline serum samples of 51 CLL patients treated with chemo-immunotherapy were analyzed for 360 proteomic markers, using Olink technology. Median event-free survival (EFS) was 23 months (range: 1.25–60.9). Patients with high levels of sCD23 (>11.27, p = 0.026), sCD27 (>11.03, p = 0.04), SPINT1 (>1.6, p = 0.001), and LY9 (>8.22, p = 0.0003) had a shorter EFS than those with marker levels below the median. The effect of sCD23 on EFS differed between immunoglobulin heavy chain variable gene-mutated and unmutated patients, with the shortest EFS for unmutated CLL patients with sCD23 levels above the median. Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients.

Rituximab-containing chemotherapy remains a viable frontline treatment option for patients with chronic lymphocytic leukemia (CLL) in the era of novel agents. However, its effectiveness in the second-line setting—in relation to previous rituximab exposure in firs

Background: The impact of rituximab on health-related quality of life (HRQoL) in primary central nervous system lymphoma patients is not well known. We determined the impact of rituximab added to standard high-dose methotrexate-based treatment on HRQoL in patients in a large randomised trial. Patients and methods: Patients from a large phase III trial (HOVON 105/ALLG NHL 24), randomly assigned to receive standard chemotherapy with or without rituximab and followed by 30 Gy whole brain radiotherapy (WBRT) in patients ≤60 years, completed the EORTC QLQ-C30 and QLQ-BN20 questionnaires before and during treatment, and up to 24 months of follow-up or progression. Differences between treatment arms over time in global health status, role functioning, social functioning, fatigue, and motor dysfunction were assessed. Differences ≥10 points were deemed clinically relevant. The effect of WBRT on HRQoL was analysed in irradiated patients. Results: A total of 160/175 patients eligible for the HRQoL study completed at least one questionnaire and were included. Over time, scores improved statistically significantly and were clinically relevant in both arms. Between arms, there were no differences on any scale (range: −3.8 to +4.0). Scores on all scales were improved to a clinically relevant extent at 12 and 24 months compared with baseline in both arms, except for fatigue and motor dysfunction at 12 months (−7.4 and −8.8, respectively). In irradiated patients (n = 59), scores in all preselected scales, except motor dysfunction, remained stable up to 24 months compared with shortly after WBRT, overall mean difference ranging between 0.02 and 4.570. Conclusion: Compared with baseline, treatment resulted in improved HRQoL scores. The addition of rituximab to standard chemotherapy did not impact

Purpose of Review: The treatment of primary central nervous system lymphoma (PCNSL) is still under debate. One of the issues is the role of rituximab in improving the outcome. Here, we summarize the existing evidence, and comment on the literature on this topic. Recent Findings: Two randomized controlled studies have been published recently, with conflicting results. Although the evidence of the benefit of rituximab is limited, it is already incorporated into many treatment regimens, both in studies and in standard clinical practice. Summary: The use of rituximab in PCNSL is still a matter of debate. A positive effect on the outcome is uncertain. However, there are no clinical signs of significantly increased toxicity. The uncertain positive effect should therefore be weighed against the increased costs of the treatment.

Rituximab-containing induction followed by autologous stem cell transplantation (ASCT) is the standard first-line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo-immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high-dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m2 intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow-up of 77·5 months for patients still alive, 5-year event-free survival (EFS) was 51% (95% CI 42–59%); 5-year overall survival (OS) was 73% (95% CI 65–80%). The median follow-up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5-year EFS of 63% (95% CI 44–78%) and 5-year OS of 90% (95% CI 72–97%). The patients randomised to observation had 5-year PFS of 60% (95% CI, 40–75%) and OS of 90% (95% CI 72–97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT.

Introduction: HIV-infected patients are more than 100-fold greater at risk for developing malignant AIDS-related lymphoma (ARL) compared to the general population. Most ARLs are EBV related. The main purpose of this study was to investigate whether a high peak EBV DNA load in HIV-infected patients is predictive of ARL, including classical Hodgkin lymphoma. Methods: From an ongoing prospective HIV positive cohort study, we conducted a case-control study between 2004 and 2016 among patients from whom at least one EBV DNA load in serum or plasma was available. We compared peak EBV DNA load between patients with (49 cases) and without ARL (156 controls). Results: The geometric mean of the peak EBV DNA load measured before diagnosis of malignant lymphoma was 52,565 IU/mL in EBER-positive lymphoma patients vs. 127 IU/mL in controls (p <.001). Patients with EBV DNA loads >100,000 IU/mL have an increased risk for diagnosis of malignant lymphoma compared to patients with EBV DNA loads ≤100,000 IU/mL (adjusted OR 12.53; 95%CI: 4.08; 38.42). In the longitudinal study, including 13 patients with at least three left-over plasma samples available for retesting, measurements of EBV-DNA during the preceding 12 months proved to be of poor value for predicting subsequent lymphoma diagnosis. Conclusions: A EBV DNA load >100,000 IU/mL can be useful in clinical setting to accelerate time to diagnosis and treatment. EBV-DNA loads in samples taken during the preceding year of ARL diagnosis showed to be of poor predictive value.

Background: To assess the sensitivity, specificity and turnaround time of flow cytometric analysis on brain biopsies compared to histology plus immunohistochemistry analysis in tumors with clinical suspicion of lymphoma. Methods: All brain biopsies performed between 2010 and 2015 at our institution and analyzed by both immunohistochemistry and flow cytometry were included in this retrospective study. Immunohistochemistry was considered the gold standard. Results: In a total of 77 biopsies from 71 patients, 49 lymphomas were diagnosed by immunohistochemistry, flow cytometry results were concordant in 71 biopsies (92.2%). We found a specificity and sensitivity of flow cytometry of 100% and 87.8%, respectively. The time between the biopsy and reporting the result (turnaround time) was significantly shorter for flow cytometry, compared to immunohistochemistry (median: 1 vs. 5 days). Conclusions: Flow cytometry has a high specificity and can confirm the diagnosis of a lymphoma significantly faster than immunohistochemistry. This allows for rapid initiation of treatment in this highly aggressive tumor. However, since its sensitivity is less than 100%, we recommend to perform histology plus immunohistochemistry in parallel to flow cytometry.

Patients with haematological malignancies are at risk for invasive fungal diseases (IFD). A survey was conducted in all Dutch academic haematology centres on their current diagnostic, prophylactic and therapeutic approach towards IFD in the context of azole-resistance. In all 8 centres, a haematologist and microbiologist filled in the questionnaire that focused on different subgroups of haematology patients. Fungal prophylaxis during neutropaenia was directed against Candida and consisted of fluconazole and/or amphotericin B suspension. Mould-active prophylaxis was given to acute myeloid leukaemia patients during chemotherapy in 2 of 8 centres. All centres used azole prophylaxis in a subset of patients with graft-versus-host disease. A uniform approach towards the diagnosis and treatment of IFD and in particular azole-resistant Aspergillus fumigatus was lacking. In 2017, all centres agreed to implement a uniform diagnostic and treatment algorithm regarding invasive aspergillosis with a central role for comprehensive diagnostics and PCR-based detection of azole-resistance. This study (DB-MSG 002) will re-evaluate this algorithm when 280 patients have been treated. A heterogeneous approach towards antifungal prophylaxis, diagnosis and treatment was apparent in the Netherlands. Facing triazole-resistance, consensus was reached on the implementation of a uniform diagnostic approach in all 8 centres.

Purpose: Cyclosporine A (CsA) is the most widely used immunosuppressive agent after a hematopoietic stem cell transplantation (HSCT). Although recommendations for CsA dose conversion from intravenous to oral administration differ from 1:1 to 1:3, most studies did not consider the role of azole antifungals as an important confounder. Therefore, we assess the optimal conversion rate of CsA from intravenous to oral administration in HSCT recipients, taking into account the concomitant use of azole antifungals. Methods: We retrospectively included patients from a large database of 483 patients who underwent a HSCT and received intravenous CsA as part of the conditioning regimen and peritransplant immunosuppression. All patients were converted from intravenous to oral administration in a 1:1 conversion rate. We collected for each patient three CsA trough concentrations during intravenous and oral administration, directly before and after conversion to oral administration. Results: We included 71 patients; 50 patients co-treated with fluconazole, 10 with voriconazole, and 11 without azole co-medication. In patients with voriconazole, the dose-corrected CsA concentration (CsA concentration divided by CsA dosage) was not different between intravenous and oral administration (2.6% difference, p = 0.754), suggesting a CsA oral bioavailability of nearly 100%. In patients with fluconazole and without azole co-medication, the dose-corrected CsA concentration was respectively 21.5% (p < 0.001) and 25.2% (p = 0.069) lower during oral administration. Conclusions: In patients with voriconazole, CsA should be converted 1:1 from intravenous to oral administration. In patients with fluconazole and without azole co-medication, a 1:1.3 substitution is advised to prevent subtherapeutic CsA concentrations.

Central nervous system (CNS) involvement in systemic B-cell non-Hodgkin lymphoma (B-NHL) at diagnosis (sysCNS) is rare. We investigated the outcome of 21 patients with sysCNS, most commonly diffuse large B-cell lymphoma, treated with high dose methotrexate (HD-MTX) and R-CHOP. The median number of cycles of HD-MTX and R-CHOP was 4 (range 1–8) and 6 (range 0–8), respectively. Consolidative whole brain radiotherapy (WBRT) was given to 33% (7/21) patients. With a median follow-up of 44 months the 3-year progression free survival (PFS) and overall survival (OS) were 45% (95%CI 34–56%) and 49% (95%CI 38–60%), respectively. Over 90% of patients had an unfavorable international prognostic index score, reflected by treatment-related mortality of 19% (4/21) and relapse-related mortality of 28% (6/21). The outcome of these patients was, however, unexpectedly good when compared to secondary CNS relapses. Prospective studies are needed to define the optimal treatment for patients with sysCNS, but its rarity might be challenging.

Burkitt lymphoma is an aggressive B cell malignancy accounting for 1–2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14–74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.

Purpose: Cyclosporine A (CsA) and imatinib are both CYP3A4 and P-glycoprotein substrates. Concomitant use after hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) may therefore result in a pharmacokinetic interaction. Although case reports and a recent small study in children indeed suggested there is a relevant pharmacokinetic interaction, a larger study in adults is lacking. In this study, we assessed the presence and extent of this interaction in patients with CML or Ph+ ALL undergoing HSCT. Methods: From a large database containing data of all patients receiving HSCT in our center between 2005 and 2015, we selected 16 patients using this drug combination. The average dose-corrected CsA concentration was calculated before and after initiation of imatinib. Results: The average dose-corrected CsA concentration increased during imatinib use in all patients, on average by 94 % (p < 0.001). Based on measured drug conc

Mantle cell lymphoma is a relatively rare B-cell lymphoma with a specific genetic lesion and a typical immunophenotypic profile. The median age is 65 years. There is no curative treatment, except allogeneic stem cell transplantation for a selected group of patients. For the majority of patients, especially the elderly, the aim of therapy should therefore be a long progression-free survival. Age and comorbidity may hamper the use of the most active treatment regimen, such as high dose cytarabine and autologous stem cell transplantation. Therefore, it is a challenge to select the most appropriate therapy for an elderly patient. Studies specifically designed for elderly patients are rare. A recently performed large randomized study for elderly patients, however, has shown that R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy followed by maintenance rituximab can result in a long progression-free survival. For patients too frail for R-CHOP chemotherapy, a treatment should be offered that benefits the patient in reducing the symptoms of the disease without causing too many side effects. Progression or relapse will occur in all patients sooner or later. Second-line treatment should again be carefully selected. Several options are mentioned. New drugs are being developed, and new combinations are investigated. Further improvement in the outcome of patients with mantle cell lymphoma is expected. Participation in well-designed clinical trials, also by elderly patients, is important to find the real benefit that can be achieved, and to get information on the tolerability of these treatments in this age group.

Autologous stem cell transplantation has greatly improved the prognosis of systemic recurrent non-Hodgkin's lymphoma. However, no prospective data are available concerning the feasibility and efficacy of this strategy for systemic lymphoma relapsing in the central nervous system. We, therefore, we performed an international multicenter retrospective study of patients with a central nervous system recurrence of systemic lymphoma to assess the outcome of these patients in the era of stem cell transplantation. We collected clinical and treatment data on patients with a first central nervous system recurrence of systemic lymphoma treated between 2000 and 2010 in one of five centers in four countries. Patient- and treatment-related factors were analyzed and compared descriptively. Primary outcome measures were overall survival and percentage of patients transplanted. We identified 92 patients, with a median age of 59 years and a median Eastern Cooperative Oncology Group/World Health Organization performance

Purpose: We investigated the impact of Hodgkin lymphoma (HL) on parenthood, including factors influencing parenthood probability, by comparing long-term HL survivors with matched general population controls. Patients and Methods: A Life Situation Questionnaire was sent to 3,604 survivors treated from 1964 to 2004 in successive clinical trials. Responders were matched with controls (1:3 or 4) for sex, country, education, and year of birth (10-year groups). Controls were given an artificial date of start of treatment equal to that of their matched case. The main end point was presence of biologic children after treatment, which was evaluated by using conditional logistic regression analysis. Logistic regression analysis was used to analyze factors influencing spontaneous post-treatment parenthood. Results: In all, 1,654 French and Dutch survivors were matched with 6,414 controls. Median follow-up was 14 years (range, 5 to 44 years). After treatment, the odds ratio (OR) for having children was 0.77 (95% CI, 0.68 to 0.87; P < .001) for survivors compared with controls. Of 898 survivors who were childless before treatment, 46.7% achieved post-treatment parenthood compared with 49.3% of 3,196 childless controls (OR, 0.87; P < .08). Among 756 survivors with children before treatment, 12.4% became parents after HL treatment compared with 22.2% of 3,218 controls with children before treatment (OR, 0.49; P < .001). Treatment with alkylating agents, second-line therapy, and age older than 35 years at treatment appeared to reduce the chances of spontaneous posttreatment parenthood. Conclusion: Survivors of HL had slightly but significantly fewer children after treatment than matched general population controls. The difference concerned only survivors who had children before treatment and appears to have more personal than biologic reasons. The chance of successful posttreatment parenthood was 76%.

Purpose: In this large cohort of Hodgkin's lymphoma survivors with long follow-up, we estimated the impact of treatment regimens on premature ovarian failure (POF) occurrence and motherhood, including safety of nonalkylating chemotherapy and dose-response relationships for alkylating chemotherapy and age at treatment. Patients and Methods: The Life Situation Questionnaire was sent to 1,700 women treated in European Organisation for Research and Treatment of Cancer and Groupe d'Étude des Lymphomes de l'Adulte trials between 1964 and 2004. Women treated between ages 15 and 40 years and currently not using hormonal contraceptives (n = 460) were selected to assess occurrence of POF. Cumulative POF risk was estimated using the life-table method. Predictive factors were assessed by Cox regression analysis. Results: Median follow-up was 16 years (range, 5 to 45 years). Cumulative risk of POF after alkylating chemotherapy was 60% (95% CI, 41% to 79%) and only 3% (95% CI, 1% to 7%) after nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine; epirubicin, bleomycin, vinblastine, and prednisone). Dose relationship between alkylating chemotherapy and POF occurrence was linear. POF risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy at age younger than 32 years and age 32 years or older, cumulative POF risks were 3% (95% CI, 1% to 16%) and 9% (95% CI, 4% to 18%), respectively. If menstruation returned after treatment, cumulative POF risk was independent of age at treatment. Among women who ultimately developed POF, 22% had one or more children after treatment, compared with 41% of women without POF. Conclusion: Nonalkylating chemotherapy carries little to no excess risk of POF. Dose-response relationships for alkylating chemotherapy and age at treatment are both linear. Timely family planning is important for women at risk of POF.

BACKGROUND: The long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission. METHODS: We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression. RESULTS: Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P = 0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P = 0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P = 0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved

Background: Catheter-related bloodstream infection (CRBSI) results in significant attributable morbidity and mortality. In this randomized, double-blind, placebo-controlled trial, we studied the efficacy and safety of a daily ethanol lock for the prevention of CRBSI in patients with a tunnelled central venous catheter (CVC). Methodology: From 2005 through 2008, each lumen of the CVC of adult hematology patients was locked for 15 minutes per day with either 70%-ethanol or placebo, where after the lock solution was flushed through. As a primary endpoint, the incidence rates of endoluminal CRBSI were compared. Principal Findings: The intent-to-treat analysis was based on 376 patients, accounting for 448 CVCs and 27,745 catheter days. For ethanol locks, the incidence of endoluminal CRBSI per 1000 CVC-days was 0.70 (95%-CI, 0.4-1.3), compared to 1.19 (95% confidence interval, 0.7-1.9) for placebo (incidence rate-ratio, 0.59; 95% confidence interval, 0.27-1.30; P = .19). For endoluminal CRBSI according to the strictest definition (positive hub culture and identical bacterial strain in blood), a 3.6-fold, non-significant, reduction was observed for patients receiving ethanol (2 of 226 versus 7 of 222; P = .103). No lifethreatening adverse events were observed. More patients receiving ethanol discontinued lock-therapy (11 of 226 versus 1 of 222; P = .006) or continued with decreased lock-frequency (10 of 226 versus 0 of 222; P = .002), due to non-severe adverse events. Conclusions: In this study, the reduction in the incidence of endoluminal CRBSI using preventive ethanol locks was nonsignificant, although the low incidence of endoluminal CRBSI precludes definite conclusions. Therefore, the lack of statistical significance may partially reflect a lack of power. Significantly more patients treated with ethanol locks discontinued their prophylactic treatment due to adverse effects, which were non-severe but reasonably ethanol related. Additional studies should be performed in

Background. Invasive aspergillosis (IA) is a leading cause of mortality in patients with acute leukemia. Management of IA is expensive, which makes prevention desirable. Because hospital resources are limited, prevention costs have to be compared with treatment costs and outcome. Methods. In 269 patients treated for acute myelogenous leukemia-myelodysplastic syndrome (AML-MDS) during 2002-2007, evidence of IA was collected using high-resolution computed tomography and galactomannan measurement in bronchoalveolar lavage fluid specimens. IA was classified on the basis of updated European Organization for Research and Treatment of Cancer/Mycoses Study Group definitions. Outcome of infection was registered. Diagnostic and therapeutic IA-related costs, corrected for neutropenia duration, were comprehensively analyzed from a hospital perspective. Voriconazole treatment was given orally from day 1 if possible. Results. A total of 80 patients developed IA; 48 (18%) had probable or proven infection, and 32 (12%) had possible IA. Seventy-three patients were treated with voriconazole; 55 (75%) took oral voriconazole from day 1. In patients with IA, the mortality rate 12 weeks after starting antifungal therapy was 22% (16 of 73 patients). The overall mortality rate, registered 12 weeks after neutrophil recovery from the last dose of antileukemic treatment, was 26% in patients with IA versus 16% in patients without IA (P = .08), reflecting an IA-attributable mortality rate of 10%. In a Cox regression analysis, IA was associated with an increased mortality risk (hazard ratio, 2.4; 95% confidence interval, 1.3-4.4). Total IA-related costs increased to €8360 and €15,280 for patients with possible and probable or proven IA, respectively, compared with patients without IA (P < .001). Conclusions. Early diagnosis and treatment of IA with oral voriconazole result in acceptable mortality rates. Nevertheless, IA continues to have substantial attributable mortality combined with a major i

Optimal dose and timing of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy for aggressive non-Hodgkin lymphoma (NHL) is still an unresolved issue. We assessed whether dose intensifications with cyclophosphamide and doxorubicin mig

The treatment of elderly patients with an aggressive non-Hodgkin’s lymphoma has gradually changed over the last decades. The first publications concerning elderly patients with lymphoma emphasized the increased toxicity and poor outcome of this patient group.(1-3) The aim of many subsequent studies has been to decrease toxicity.(4-6) Most of these studies however reported decreased response rates and deterioration of survival if age adapted therapy was used. It also became evident that doxorubicin proved to be a toxic, but essential drug in any regimen prescribed with a curative intention.(7-9) The development of recombinant granulocyte colony-stimulating factor (G-CSF) raised expectations that this growth factor could improve the results of therapy because it would become possible to maintain the dose-intensity of the chemotherapy regimen by inducing rapid hematopoietic recovery.(10) Moreover, a shorter duration of the neutropenic phase could probably reduce the incidence of neutropenic fever, bacterial infections and the number of hospital admissions.(11, 12) In the current thesis the results of a large prospective multicenter clinical trial are reported. This trial was designed to investigate if prophylactic G-CSF administration could improve the poor results of treatment in elderly patients with an aggressive non-Hodgkin’s lymphoma. The primary question was whether a higher relative dose-intensity would lead to improved treatment outcome. Secondary endpoints were the quality of life and the cost-effectiveness associated with such treatment. This trial was supported by the Dutch government.