Lipegfilgrastim for prophylaxis of chemotherapy-induced neutropenia in Dutch patients.

BACKGROUND: Chemotherapy (CT)-induced neutropenia and febrile neutropenia (FN) can lead to changes in the treatment plan, potentially worsening the cancer outcome. This study evaluated the effect of the glycopegylated granulocyte-colony stimulating factor lipegfilgrastim, used as primary (PP) or secondary prophylaxis (SP), on treatment modifications in adult patients receiving cytotoxic CT with or without biological/targeted therapy (BT) for solid and haematological tumours. METHODS: This phase 4, prospective, observational study was conducted in eight centres in the Netherlands, in 2015-2017. Other study objectives were to characterise the population of cancer patients receiving lipegfilgrastim, to evaluate the incidence of CT-induced neutropenic events, and to assess safety. RESULTS: Of 142 patients, 73.94% had breast cancer and 55.63% received CT in the adjuvant setting. Most patients received lipegfilgrastim as PP (74.65%) and were at low (34.51%) or high risk (39.44%) of FN. CT dose delays were recorded for 22.64% and 36.11% of patients receiving lipegfilgrastim for PP and SP, respectively. CT dose reductions were recorded for 2.11% of patients; no CT dose omissions and one BT dose omission occurred. FN and grade III/IV neutropenia were reported for 5.63% and 9.86% of patients, respectively; associated hospitalisations were rare. The most frequently lipegfilgrastimrelated adverse events (AE) were myalgia, bone pain, and back pain. Serious AEs (55) were reported for 30 (21.13%) patients. There were two deaths, unrelated to lipegfilgrastim administration. CONCLUSION: Administration of lipegfilgrastim in routine clinical practice in the Netherlands results in limited CT/BT dose modifications and low incidence of neutropenic events, with no new safety concerns.

No added value of the age-adjusted D-dimer cut-off to the YEARS algorithm in patients with suspected pulmonary embolism.

Essentials Imaging is warranted in the majority of patients to confirm or rule out pulmonary embolism (PE). The age-adjusted D-dimer (ADJUST) reduced the number of required imaging tests in patients ≥ 50 years. The YEARS algorithm was designed to improve the efficiency in patients with suspected PE. There was no added value of implementing ADJUST in the YEARS algorithm in our cohort. SUMMARY: Background The YEARS algorithm was designed to simplify the diagnostic work-up of pulmonary embolism (PE) and to reduce the number of necessary computed tomography pulmonary angiography (CTPA) scans. An alternative strategy to reduce the number of CTPAs is the age-adjusted D-dimer cut-off (ADJUST) in patients aged 50 years or older. We aimed to investigate whether a combination of both diagnostic strategies might save additional CTPAs. Methods The YEARS algorithm consists of three items (clinical signs of deep venous thrombosis, hemoptysis, 'PE most likely diagnosis') with simultaneous D-dimer testing using a pre-test dependent threshold. We performed a post hoc analysis in 3465 patients managed according to YEARS to compare the number of patients managed without CTPA scans and associated diagnostic failures in hypothetical scenarios with different YEARS-ADJUST combinations. Results Following the YEARS algorithm, 1651 patients (48%) were managed without CTPA; PE was diagnosed in 456 (13%) patients at baseline and 18 patients with initial normal testing suffered venous thromboembolism (VTE) during 3-month follow-up (failure rate 0.61%; 95% confidence interval [CI], 0.36-0.96). If ADJUST had been fully integrated in YEARS, 1627 patients (47%) would have been managed without CTPA (absolute decrease of 0.69%; 95% CI -1.7 to 3.0), at cost of four additional missed PE diagnoses at baseline, for a projected 3-month VTE failure rate of 0.75% (95% CI, 0.49-1.13). None of the other studied scenarios showed relevant improvements in efficiency as well, but all led to more missed diagnoses. Conclusion In our cohort, there was no added value of implementing ADJUST in the YEARS algorithm.

Hepatitis E during lenalidomide treatment for multiple myeloma in complete remission.

Lenalidomide has a central role in the treatment of multiple myeloma and results in improved survival. As with other chemotherapeutics, it can cause several serious side effects. This is the first reported case of hepatitis E during lenalidomide treatment for multiple myeloma in complete remission. In case of liver chemistry abnormalities during lenalidomide treatment, the differential diagnosis should include hepatitis E infection.

Hestia criteria can safely select patients with pulmonary embolism for outpatient treatment irrespective of right ventricular function.

BACKGROUND: There has been debate over how patients with pulmonary embolism (PE) can be safely selected for outpatient treatment. OBJECTIVES: To compare the Hestia criteria with the European Society of Cardiology (ESC) criteria for selecting low-risk patients with PE for outpatient treatment. METHODS: From 2008 to 2010, 496 patients with acute, symptomatic PE were screened and 275 treated at home and 221 treated in the hospital according to the Hestia Study protocol. The Hestia criteria were used to select patients for outpatient treatment. Right and left ventricular (RV and LV) diameters were measured on computed tomography images. RV dysfunction was defined as an RV/LV ratio > 1.0. Patients were classified according to the ESC criteria into low, intermediate and high-risk groups, based on blood pressure and RV dysfunction. During 3 months follow-up adverse events were scored. RESULTS: Adverse events occurred in 22 patients (4.5%) treated in the hospital vs. none of the patients treated at home (P < 0.001). Sensitivity and negative predictive value for adverse outcome were 100% for the Hestia criteria and 96% and 99% for the ESC criteria, respectively. Of the patients treated at home according to the Hestia criteria, 35% were normotensive but had RV dysfunction and were classified as intermediate risk according to the ESC criteria. No adverse events happened in these patients treated at home. CONCLUSIONS: Clinical criteria, such as the Hestia criteria, could be helpful in selecting patients, including those with RV dysfunction who have a low risk of adverse clinical outcome and could be candidates for outpatient treatment.

Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.

BACKGROUND: Traditionally, patients with pulmonary embolism (PE) are initially treated in the hospital with low molecular weight heparin (LMWH). The results of a few small non-randomized studies suggest that, in selected patients with proven PE, outpatient treatment is potentially feasible and safe. OBJECTIVE: To evaluate the efficacy and safety of outpatient treatment according to predefined criteria in patients with acute PE. PATIENTS AND METHODS: A prospective cohort study of patients with objectively proven acute PE was conducted in 12 hospitals in The Netherlands between 2008 and 2010. Patients with acute PE were triaged with the predefined criteria for eligibility for outpatient treatment, with LMWH (nadroparin) followed by vitamin K antagonists. All patients eligible for outpatient treatment were sent home either immediately or within 24 h after PE was objectively diagnosed. Outpatient treatment was evaluated with respect to recurrent venous thromboembolism (VTE), including PE or deep vein thrombosis (DVT), major hemorrhage and total mortality during 3 months of follow-up. RESULTS: Of 297 included patients, who all completed the follow-up, six (2.0%; 95% confidence interval [CI] 0.8-4.3) had recurrent VTE (five PE [1.7%] and one DVT [0.3%]). Three patients (1.0%, 95% CI 0.2-2.9) died during the 3 months of follow-up, none of fatal PE. Two patients had a major bleeding event, one of which was fatal intracranial bleeding (0.7%, 95% CI 0.08-2.4). CONCLUSION: Patients with PE selected for outpatient treatment with predefined criteria can be treated with anticoagulants on an outpatient basis. (Dutch Trial Register No 1319; http://www.trialregister.nl/trialreg/index.asp).

Two Dutch families with hereditary hyperferritinaemia-cataract syndrome and heterozygosity for an HFE-related haemochromatosis gene mutation.

Hereditary haemochromatosis is an autosomal recessive disorder, leading to progressive iron overload, which is very common among the Caucasian population. In the vast majority of the cases, the hereditary iron overload is caused by mutations in the HFE gene. Most prominently this is the homozygous Cys282Tyr mutation. We report two Dutch families in which both propositi were found to be heterozygous for Cys282Tyr in the work-up of hyperferritinaemia. Frequent phlebotomies had no effect on the ferritin level, but led to microcytic anaemia. Finally, the family history with bilateral cataracts was the clue for the correct diagnosis. Hereditary hyperferritinaemia-cataract syndrome (HHCS) is an autosomal dominant disease characterised by elevated serum ferritin levels and bilateral cataracts in the absence of iron overload. Several point mutations and deletions within the iron-responsive element (IRE) in the 5' noncoding region of the L-ferritin gene have been found in HHCS families. In the first Dutch family a G to C transition at position 32 was found and a G to A mutation at the same location was found in the second Dutch family. In individuals with an isolated hyperferritinaemia (normal transferrin saturation), the presence of early onset (familial) cataract should raise the possibility of HHCS, even when Cys282Tyr heterozygosity is found.

Cost analysis of CHOP (-like) chemotherapy regimens for patients with newly diagnosed aggressive non-Hodgkin's lymphoma.

Many cost analyses of stem-cell transplantations are available, which is in sharp contrast to the level of cost analyses on first-line chemotherapy for aggressive non-Hodgkin's lymphoma (NHL). Given the scarcity of cost analyses of first-line chemotherapy for NHL, it is difficult to assess the economic impact of upcoming new treatment modalities. Therefore we performed an analysis on costs of diagnosis and treatment of patients with newly diagnosed NHL who were treated with standard CHOP (-like) chemotherapy. As many NHL patients are treated in trials and the economic effects of the trial participation are unknown, our analysis included both patients treated according to trial protocols and patients treated according to standard local practice (SLP). The cost analysis was based on the total medical consumption of the patients. It was found that costs of the trial and SLP groups are within comparable ranges, although costs of diagnostic tests were somewhat higher within the trials. In elderly patients, SLP chemotherapy was discontinued more frequently in case of leucocytopenia or thrombocytopenia. This analysis provides basic information about the costs of first-line standard chemotherapy for patients with newly diagnosed aggressive NHL and the plausible ranges in which these costs may vary. Given the results, we will initiate larger studies to investigate whether trial treatments (showing more or less similar costs as SLP treatments) are more cost-effective for patients with aggressive NHL.

[Diagnosis and treatment of non-Hodgkin lymphoma in Netherlands: variation in guidelines and in practice]. / Diagnostiek en behandeling van het non-Hodgkin-lymfoom in Nederland: variëteit in richtlijnen en in de praktijk.

OBJECTIVE: To investigate current guidelines for diagnosis and treatment of intermediate or high grade non-Hodgkin's lymphoma (NHL), stage I-IV (Burkitt's and lymphoblastic lymphoma excluded) and to compare this with current clinical practice. DESIGN: Descriptive. METHOD: An inventory of guidelines for diagnosis and treatment of NHL of the Regional Cancer Centres (RCCs) was made in mid-1998, an enquiry containing questions about the practical situation concerning the diagnosis and treatment of NHL patients was sent to 59 internists-haematologists in non-university hospitals of the RCC regions Amsterdam, Rotterdam and South. RESULTS: Apart from the standard diagnostics, the RCCs recommended several examinations for staging. For the initial staging the haematologists not always requested the recommended CTs of chest and abdomen and most of them did no restaging after the last course of chemotherapy. Half of them left the assessment of lymph node biopsy samples to a lymphoma panel. The recommended primary treatment consisted mainly of chemotherapy with cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP). In certain regions, the schedule was slightly changed, with additional tenoposide and bleomycin (CHVmP/BV). The treatment schedules were heterogeneous, especially for stage I NHL. In leukopenia and/or thrombocytopenia, postponement was recommended, but dosage reduction was carried out immediately, especially in older patients, sometimes with administration of a haemopoietic growth factor. Recurrence NHL was treated in accordance with the guidelines with second-line chemotherapy, if possible followed by peripheral stem cell transplantation in a haematooncological centre. CONCLUSION: Considering these results development of national guidelines for NHL would seem to be desirable.

Minor histocompatibility antigen-specific, leukemia-reactive cytotoxic T cell clones can be generated in vitro without in vivo priming using chronic myeloid leukemia cells as stimulators in the presence of alpha-interferon.

At present, allogeneic bone marrow transplantation (BMT) is the only curative treatment for chronic myeloid leukemia (CML) in chronic phase (CP). The graft-vs.-leukemia (GVL) effect appears to play an important role in this treatment. Direct evidence for a GVL effect has been reported in Ph1-positive CML patients who relapsed after allogeneic BMT and who were treated with leukocyte transfusion from the original marrow donor. Alpha-interferon (alpha-IFN) may have facilitated this GVL effect since many patients were treated with it also. We investigated whether leukemia-reactive cytotoxic T lymphocytes (CTLs) can be generated from human leukocyte antigen (HLA)-genotypically identical sibling bone marrow (BM) donors who donated marrow for two patients with Ph1-positive CML in CP and one patient with Ph1-positive acute lymphoblastic leukemia (ALL). We also investigated alpha-IFN's ability to facilitate the generation of CTLs. In the absence of alpha-IFN, CTL lines with only low cytotoxicity and no CTL clones could be generated. In the presence of alpha-IFN, however, alloreactive, leukemia-reactive CTL lines with high cytotoxicity could be generated, and CD8+ CTL clones could be established with HLA class I restricted minor histocompatibility antigen (mHa)-specific recognition. In a cell-mediated clonogenic cytotoxicity assay, the CTL clones showed specific growth inhibition of leukemic precursor cells from the recipient and a second CML patient, but the clones did not inhibit growth of hematopoietic precursor cells (HPCs) from the donor. The normal HPCs from an unrelated donor with the HLA class I restriction molecule were also recognized by the CTL clones, illustrating that the antigen recognized is not leukemia-specific. The mechanism of the immunomodulating effect by alpha-IFN is not clear. Addition of alpha-IFN to medium did not alter the expression of HLA or adhesion molecules on CML cells. In the treatment of CML, administration of alpha-IFN as adjuvant immunotherapy after allogeneic BMT may increase GVL reactivity.

Generation of CD4+ cytotoxic T-lymphocyte clones from a patient with severe graft-versus-host disease after allogeneic bone marrow transplantation: implications for graft-versus-leukemia reactivity.

HLA-identical bone marrow transplantation (BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivity. Different T-cell subsets from the bone marrow (BM) graft may be responsible for GVHD and GVL reactivity after BMT. In the etiology of GVHD, not only CD8+ but also CD4+ donor T lymphocytes may play an important role. Here we report a patient with chronic myeloid leukemia (CML) who was transplanted with the BM from his HLA-genotypically identical sister. After BMT there was complete engraftment, but the patient died because of acute GVHD grade III-IV in complete remission. Cytotoxic T-lymphocyte (CTL) lines were generated after BMT using the irradiated leukemic cells from the patient as stimulator cells and the donor-originated peripheral blood mononuclear cells, procured from the patient after BMT, as responder cells. The generated CTL lines showed specific lysis of the recipient lymphocytes and leukemic cells in a 51Cr release assay. Two types of CTL clones could be established from these CTL lines, both phenotypically CD4+. Clone type I showed male-specific HLA-DQ5-restricted lysis of the recipient lymphocytes, but not of the circulating relatively mature leukemic cells from the patient. This may be explained by the low HLA-DQ5 expression of the more mature CML cells. Clone type II showed HLA-DR2-restricted minor histocompatibility antigen-specific lysis of the recipient lymphocytes and leukemic cells. Both types of CTL clones showed antigen-specific cell-mediated growth inhibition of the recipient clonogenic leukemic precursor cells. These CD4+ CTL clones produced several activating cytokines including tumor necrosis factor alpha, interferon gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage CSF. Our results illustrate that these CD4+ CTL clones may have induced GVHD directly by cytolysis and indirectly by activating cytokines. Because both types of CTL clones recognized the recipient leukemic progenitor cells, they may also contribute to GVL reactivity after BMT.

Recognition of clonogenic leukemic cells, remission bone marrow and HLA-identical donor bone marrow by CD8+ or CD4+ minor histocompatibility antigen-specific cytotoxic T lymphocytes.

We investigated whether minor histocompatibility (mH) antigen-specific cytotoxic T lymphocytes (CTL) can discriminate between leukemic hematopoietic progenitor cells (leukemic-HPC) from AML or CML patients, the HPC from their remission bone marrow (remission-HPC), and normal HPC from their HLA-identical sibling bone marrow donor (donor-HPC). Specific lysis by CD8+ CTL clones was observed not only of the leukemic-HPC but also of the donor-HPC in 3/4 patient/donor combinations expressing mH antigen HA-1, 3/5 combinations expressing mH antigen HA-2, 2/3 combinations expressing mH antigen HA-3, and 2/2 combinations expressing mH antigen HY-A1. In four patient/donor combinations the recognition of the donor-HPC was clearly less than of the leukemic-HPC, indicating differential susceptibility to lysis by these mH CTL clones. In addition, differential recognition of leukemic-HPC and remission-HPC within seven patients was analyzed. In one patient expressing the HA-2 antigen on the leukemic cells the recognition of the remission-HPC was clearly less than of the leukemic-HPC. One CD4+ CTL clone showed specific lysis of the leukemic-HPC from an AML patient and a CML patient as well as of normal remission-HPC and donor-HPC. These results illustrate that in general CD8+ and CD4+ mH antigen specific CTL clones do not differentially recognize leukemic-HPC and normal-HPC. However, differences in susceptibility to lysis of malignant versus normal cells may contribute to a differential GVL effect.

Generation of donor-derived antileukemic cytotoxic T-lymphocyte responses for treatment of relapsed leukemia after allogeneic HLA-identical bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) has been associated with an antileukemic effect, the graft-versus-leukemia (GVL) reactivity. Since T-cell depletion of the bone marrow graft performed to reduce the incidence and severity of graft-versus-host disease (GVHD) after BMT has been associated with an increase risk of relapse, the GVL reactivity has been attributed to the T lymphocytes from the graft. Previously, we demonstrated that leukemia-reactive cytotoxic T-lymphocyte (CTL) lines and clones could be generated from the peripheral blood of HLA-genotypically identical siblings of patients with leukemia by stimulation of the donor cells with irradiated leukemic cells from the patients. HLA class I as well as class II restricted CTL clones could be generated that recognized the leukemic cells. Some clones recognized the leukemic cells from the patient, but not the interleukin (IL)-2-stimulated lymphocytes from the same individual. To explore the possibility of clinically using donor-derived CTL lines directed against the leukemic cells from patients who relapsed after allogeneic BMT, a pilot study was performed using eight donor-recipient combinations. In seven of eight combinations donor-derived CTL lines could be generated that showed specific lysis of the leukemic cells from the patient. In five of these cases, the CTL lines showed reactivity with the leukemic cells, but not with the IL-2-stimulated lymphocytes from the same individual. In two cases, the CTL lines were cytotoxic for the IL-2-stimulated lymphoblasts as well as the leukemic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Generation of leukemia-reactive cytotoxic T lymphocyte clones from the HLA-identical bone marrow donor of a patient with leukemia.

Allogeneic bone marrow transplantation (BMT) has been associated with a graft-vs.-leukemia (GVL) reactivity. Since T cell depletion of the bone marrow graft has decreased the risk of graft-vs.-host disease (GVHD), but has been associated with higher rates of leukemia relapse, GVL reactivity is probably caused by donor-derived T lymphocytes. Previously, we demonstrated that minor histocompatibility (mH) antigen-specific cytotoxic T lymphocyte (CTL) clones, generated from patients after BMT, are capable of major histocompatibility complex-(MHC) restricted lysis of (clonogenic) myeloid leukemic cells. Here, we investigated whether donor-derived leukemia-specific CTL clones can be generated in vitro, before BMT, using irradiated leukemic cells from a patient with acute myeloid leukemia as stimulator cells, and peripheral blood or bone marrow from the HLA genotypically identical sibling donor as responder cells. Several CTL lines were generated that showed specific lysis (> 50%) of the recipient leukemic cells in a 51Cr-release assay. Two of these CTL lines were cloned by limiting dilution in the presence of the irradiated recipient cells. Multiple leukemia-reactive, HLA class I and II-restricted clones with various specificities could be established. These alloreactive, antileukemic CTL clones may cause GVL reactivity after BMT, and may be used as adjuvant immunotherapy in the treatment of leukemia.

Growth inhibition of clonogenic leukemic precursor cells by minor histocompatibility antigen-specific cytotoxic T lymphocytes.

Minor histocompatibility (mH) antigens appear to play a major role in bone marrow transplantation (BMT) using HLA-identical donors. Previously, we reported the isolation of major histocompatibility complex (MHC)-restricted mH antigen-specific cytotoxic T lymphocytes (CTL) from patients with graft-vs.-host disease or rejection after HLA-identical BMT. We have demonstrated that mH antigens can be recognized on hematopoietic progenitor cells, and residual recipient CTL specific for mH antigens expressed on donor hematopoietic progenitor cells may be responsible for graft rejection in spite of intensive conditioning regimens in HLA-identical BMT. Here, we investigated whether mH antigen-specific CTL directed against the mH antigens HA-1 to HA-5 and the male-specific antigen H-Y were capable of antigen-specific inhibition of in vitro growth of clonogenic leukemic precursor cells. We demonstrate that mH antigen-specific CTL against all mH antigens tested can lyse freshly obtained myeloid leukemic cells, that these mH antigen-specific CTL can inhibit their clonogenic leukemic growth in vitro, and that this recognition is MHC restricted. We illustrate that leukemic (precursor) cells can escape elimination by mH antigen-specific CTL by impaired expression of the relevant MHC restriction molecule. We suggest that mH antigen-specific MHC-restricted CTL may be involved in vivo in the graft-vs.-leukemia reactivity after BMT.

Citrate haemodialysis.

We describe our experience with sodium citrate as anticoagulant in the haemodialysis of 15 patients who were at high risk for bleeding. Furthermore, in six of these patients who were on prolonged citrate dialysis, the last month of heparin dialysis was compared with the first month in which citrate was used as anticoagulant. Our series confirms the suitability of citrate as anticoagulant in patients who are at high risk for bleeding. In the prolonged citrate dialysis group, however, there were complaints of paraesthesias. Probably, the citrate-induced metabolic alkalosis and the relatively low serum calcium concentration observed in these patients contributed to these complaints. To limit these side effects the acetate concentration in the dialysate needs to be reduced and, as magnesium also complexes with citrate, a calcium- and magnesium-free dialysate should be used to reduce the citrate infusion rate and thus the alkaline load in these patients. Furthermore, lowering the calcium infusion rate in order to lower the citrate infusion rate is not indicated because this induces low serum calcium concentration.

An unusual late manifestation of a Salmonella typhi infection.

We report the case history of a patient in whom we diagnosed purulent lymphadenitis due to Salmonella typhi, a late complication of a febris typhoidea that occurred 11 yr previously. We also review the literature concerning complications of Salmonella infections, and particularly discuss their hematogenous spread and lodgment.