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.

Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial.

Thalidomide with melphalan/prednisone (MPT) was defined as standard treatment in elderly patients with multiple myeloma (MM) based on five randomized trials. In one of these trials, HOVON49, a prospective health-related quality-of-life (HRQoL) study was initiated in order to assess the impact of thalidomide on QoL. Patients aged >65 years with newly diagnosed MM were randomized to receive melphalan plus prednisone (MP) or MPT, followed by thalidomide maintenance in the MPT arm. Two hundred eighty-four patients were included in this side study (MP, n=149; MPT n=135). HRQoL was assessed with the EORTC Core QoL Questionnaire (QLQ-C30) and the myeloma-specific module (QLQ-MY24) at baseline and at predetermined intervals during treatment. The QLQ-C30 subscales physical function (P=0.044) and constipation (P<0.001) showed an improvement during induction in favour of the MP arm. During thalidomide maintenance, the scores for the QLQ-MY24 paraesthesia became significantly higher in the MPT arm (P<0.001). The QLQ-C30 subscales pain (P=0.12), insomnia (P=0.068), appetite loss (P=0.074) and the QLQ-MY24 item sick (P=0.086) scored marginally better during thalidomide maintenance. The overall QoL-scale QLQ-C30-HRQoL showed a significant time trend towards more favourable mean values during protocol treatment without differences between MP and MPT. For the QLQ-C30 subscales emotional function and future perspectives, difference in favour of the MPT arm from the start of treatment was observed (P=0.018 and P=0.045, respectively) with no significant 'time × arm' interaction, indicating a persistent better patient perspective with MPT treatment. This study shows that the higher frequency of toxicity associated with MPT does not translate into a negative effect on HRQoL and that MPT holds a better patient perspective.

CHOP compared with CHOP plus granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin's lymphoma.

PURPOSE: To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle. RESULTS: In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P =.01) and doxorubicin (median, 95.4% v 93.3%; P =.04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P =.63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P =.76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P =.006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. CONCLUSION: In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.

Lactic acidosis in a patient with B-cell non-Hodgkin's lymphoma.

A patient with an intermediate grade B-cell non-Hodgkin's lymphoma who presented with severe dyspnea caused by lymphoma-related lactic acidosis is described. The serum lactate and pyruvate levels paralleled the disease activity. Although oncologists are familiar with the relationship between bulky solid tumors and lactic acidosis, well-documented lymphoma cases are extremely rare.

Generation of B-cell chronic lymphocytic leukemia (B-CLL)-reactive T-cell lines and clones from HLA class I-matched donors using modified B-CLL cells as stimulators: implications for adoptive immunotherapy.

Allogeneic stem cell transplantation following reduced-intensity conditioning is being evaluated in patients with advanced B-cell chronic lymphocytic leukemia (B-CLL). The curative potential of this procedure is mediated by donor-derived alloreactive T cells, resulting in a graft-versus-leukemia effect. However, B-CLL may escape T-cell-mediated immune reactivity since these cells lack expression of costimulatory molecules. We examined the most optimal method to transform B-CLL cells into efficient antigen-presenting cells (APC) using activating cytokines, by triggering toll-like receptors (TLRs) using microbial pathogens and by CD40 stimulation with CD40L-transfected fibroblasts. CD40 activation in the presence of IL-4 induced strongest upregulation of costimulatory and adhesion molecules on B-CLL cells and induced the production of high amounts of IL-12 by the leukemic cells. In contrast to primary B-CLL cells as stimulator cells, these malignant APCs were capable of inducing the generation of B-CLL-reactive CD8(+) CTL lines and clones from HLA class I-matched donors. These CTL lines and clones recognized and killed primary B-CLL as well as patient-derived lymphoblasts, but not donor cells. These results show the feasibility of ex vivo generation of B-CLL-reactive CD8(+) CTLs. This opens new perspectives for adoptive immunotherapy, following allogeneic stem cell transplantation in patients with advanced B-CLL.

Human interleukin for DA cells (HILDA) does not affect the proliferation and differentiation of hematopoietic progenitor cells in human long-term bone marrow cultures.

Human Interleukin for DA cells (HILDA), a cytokine also known as leukemia inhibitory factor (LIF), induces proliferation without concurrent differentiation of murine embryonic stem cells. Therefore, we investigated the effects of recombinant HILDA/LIF on the proliferation and differentiation of human hematopoietic progenitor cells (HPC) grown in long-term bone marrow cultures (LTBMC). Pre-established stromal cell layers were reinoculated with autologous cryopreserved mononuclear phagocyte- and T-lymphocyte-depleted bone marrow cells in the presence or absence of HILDA/LIF (200 U/ml). At weekly intervals cultures were sacrificed, and the cells in the adherent and the nonadherent cell fractions were counted. The numbers of HPC were determined by culturing these cells in semisolid medium stimulated with phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM), and LTBMC supernatants were assayed in semisolid cultures for the presence of colony-stimulating activity (CSA). The total number of cells, their differential counts, the number of HPC, and the concentrations of CSA in culture supernatants were similar for long-term cultures containing HILDA/LIF and for controls. These data suggest that HILDA/LIF may not play a role in the proliferation and differentiation of normal human (early) HPC in LTBMC. Moreover, HILDA/LIF did not stimulate the proliferation of relatively mature progenitor cells in semisolid cultures, not did it influence the colony formation induced by other colony-stimulating factors (CSF). Finally, using a [3H]thymidine suicide test we could not find an effect of HILDA/LIF on the cell-cycle status of HPC.

Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40-60 years.

The preferred type of post-remission therapy (PRT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1) is a subject of continued debate, especially in patients at higher risk of nonrelapse mortality (NRM), including patients >40 years of age. We report results of a time-dependent multivariable analysis of allogenic hematopoietic stem cell transplantation (alloHSCT) (n=337) versus chemotherapy (n=271) or autologous HSCT (autoHSCT) (n=152) in 760 patients aged 40-60 years with AML in CR1. Patients receiving alloHSCT showed improved overall survival (OS) as compared with chemotherapy (respectively, 57±3% vs 40±3% at 5 years, P<0.001). Comparable OS was observed following alloHSCT and autoHSCT in patients with intermediate-risk AML (60±4 vs 54±5%). However, alloHSCT was associated with less relapse (hazard ratio (HR) 0.51, P<0.001) and better relapse-free survival (RFS) (HR 0.74, P=0.029) as compared with autoHSCT in intermediate-risk AMLs. AlloHSCT was applied following myeloablative conditioning (n=157) or reduced intensity conditioning (n=180), resulting in less NRM, but comparable outcome with respect to OS, RFS and relapse. Collectively, these results show that alloHSCT is to be preferred over chemotherapy as PRT in patients with intermediate- and poor-risk AML aged 40-60 years, whereas autoHSCT remains a treatment option to be considered in patients with intermediate-risk AML.

Recovery of hematopoiesis after blood-group-incompatible bone marrow transplantation with red-blood-cell-depleted grafts.

Severe hemolytic transfusion reactions may complicate major blood-group-incompatible bone marrow transplantations (BMT). Probably the most appropriate way to avoid this complication is removal of the incompatible red blood cells (RBC) from the bone marrow graft. In this report we describe a method to eliminate incompatible RBCs that is based on repeated dilution of the graft with donor-and-recipient--compatible third-party erythrocytes. Four patients with ABO incompatibility and one patient with Rh-C incompatibility were transplanted using this technique. After the procedure 86 +/- 8% (mean +/- SD) of the nucleated cells, 95 +/- 14% of CFU-GM, 88 +/- 14% of BFU-e, and 103 +/- 30% of CFU-e were recovered, but only +/- 1% of the incompatible RBCs was left in the transfusate (1-3 ml). No signs of hemolysis were observed. All patients engrafted promptly. The patients with low titers of antibody had normal reticulocyte recoveries. Maturation of erythropoiesis was suppressed only when high titers of antibody were present. However, despite high antibody titers, erythroid progenitor cells (CFU-GEMM, BFU-e, and CFU-e) could be cultured from the bone marrow of the recipient after BMT. Thus, anti-A and anti-Rh-C antibodies give little, if any, inhibition of stem-cell proliferation. The method described to remove incompatible RBCs appears to be simple, safe, and--in most cases--sufficient.

Highly purified CD34+ cells isolated using magnetically activated cell selection provide rapid engraftment following high-dose chemotherapy in breast cancer patients.

The primary objective of this study was to evaluate the safety of infusion of CD34+ cells, selected using a clinical scale magnetically activated cell sorting device, assessed by time to hematological engraftment and incidence of adverse events. Secondary objectives included evaluation of device performance in terms of purity and recovery of the CD34+ cell product. Breast cancer patients suitable for transplantation received cyclophosphamide and filgrastim for mobilisation, followed by three leukaphereses. The products of the first two leukaphereses underwent CD34+ cell selection. The product of the third leukapheresis was cryopreserved unmanipulated. Following high-dose cyclophosphamide, thiotepa and carboplatin, selected CD34+ cells were infused. In 54 patients who received selected cells only, the median time to platelet recovery and neutrophil recovery was 11 days (range 5-51) and 9 days (range 5-51), respectively. There were no adverse events associated with infusion of selected cells. A total of 126 leukapheresis samples was available before and after selection for central CD34+ analysis. The median purity was 96.1% (27.4-99.4) and the median recovery was 52. 3% (15.2-146.3). These data show that cells selected using magnetically activated cell selection provide safe and rapid engraftment after high-dose therapy. Bone Marrow Transplantation (2000) 25, 243-249.

[Thalidomide in the treatment of refractory multiple myeloma: a Dutch study of 72 patients: an antitumor effect in 45%]. / Thalidomide als behandeling voor refractair multipel myeloom in een Nederlandse studie onder 72 patiënten: een antitumoreffect bij 45%.

OBJECTIVE: To determine the efficacy and side effects of thalidomide in the treatment of refractory multiple myeloma. DESIGN: Retrospective, descriptive. METHOD: Data were obtained by means of case research on patients with refractory multiple myeloma who were treated with thalidomide at four regional hematological centres in the period from 1 May 1999 to 31 May 2001. The patients had previously been treated with one, two or three schedules of chemotherapy. The starting dose of thalidomide was 200 mg per day and the dose was increased gradually to a maximum of 800 mg per day depending on the tolerance. RESULTS: The 72 patients included 43 men and 29 women with an average age of 62 years (range: 38-82 years). The median follow-up was 13 months (range: 2-25). Thalidomide as a single agent was prescribed for 64 patients, of whom 29 (45%) responded; a complete response was achieved in 3 patients, a partial response in 18, and a minor response in 8. In 4 of 11 patients with an extramedullary plasmacytoma a decrease in size was observed. The median duration of the response was 9 months (range: from 2 till > 24). The median overall survival from the start of thalidomide treatment was 9 months. Thalidomide plus dexamethasone was given to 9 patients who did not respond to thalidomide alone, and in 6 of them a reduction of M-protein was then observed. The most frequent adverse effects were constipation, drowsiness, somnolence, dizziness, venous thrombosis and polyneuropathy. Doses of up to 400 mg per day were generally well tolerated. CONCLUSION: Thalidomide has antitumour activity in refractory multiple myeloma.

Hepatocellular carcinoma after danazol treatment for hereditary angio-oedema.

Hereditary angio-oedema is characterised by recurrent episodes of laryngeal, intra-abdominal, facial or peripheral oedema. Danazol can be used as prophylaxis for recurrent attacks. Hepatotoxicity is a recognised adverse effect of danazol. We report an exceptional case of a danazol-induced hepatocellular carcinoma in a 75-year-old patient with hereditary angio-oedema.

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.

Clinical and toxicological aspects of the antineoplastic drug cladribine: a review.

Cladribine (2-chlorodeoxyadenosine, 2-CdA) is a new antineoplastic drug which exerts its antilymphoproliferative activity by its resistance to the enzyme adenosine deaminase. Cladribine is mostly administered as a 7-day continuous infusion and in a dose of 0.1 mg/kg/day. However, preliminary data show that the subcutaneous and oral routes of administration might be feasible. The drug is well tolerated, and myelosuppression was found to be the dose-limiting toxicity. Nonhematological toxicity, such as alopecia, nausea, vomiting, stomatitis, diarrhea, and organ toxicity is mild or absent. Cladribine has shown efficacy in phase-II studies in hairy cell leukemia [response rate (RR) = 75-100% and complete response rate (CR) = 46-92%], chronic lymphocytic leukemia (RR = 37-67% and CR = 4-39%), and lymphocytic lymphoma (RR = 43-52% and CR = 14-20%). Furthermore, there is preliminary evidence that cladribine might be effective in the treatment of cutaneous T cell lymphoma (RR = 47% and CR = 20%), acute myeloid leukemia in children (RR = 59% and CR = 47%), acute lymphoid leukemia in children (RR = 14% and CR = 14%) and Waldenström macroglobulinemia (RR = 58% and CR = 3.5%). In multiple myeloma cladribine was not effective. Comparative randomized studies with established first-line and second-line therapeutic regimens are warranted and will define the ultimate place of cladribine in the therapy of malignant hematological disorders.

The biological activities of interleukin-1.

Interleukin-1 (IL-1) refers to a hormone-like polypeptide that mediates a broad spectrum of activities in host defence as well as a variety of disease processes. Originally described as a substance produced by activated macrophages, IL-1 is now recognized as a polypeptide produced by many other cell types. Two distinct genes have been identified that code for two structurally related forms of the molecule, termed IL-1 alpha and beta. IL-1 is the primary mediator of the acute phase response and is responsible for many of the changes associated with the onset of infection. It is involved in the immune response to antigenic challenge. IL-1 induces fever and has profound endocrinologic, neurologic, metabolic and hematologic effects. Both forms of IL-1 bind to a common receptor that has been identified on a variety of cell types including lymphocytes, hepatocytes, endothelial cells and fibroblasts. Many of the activities of IL-1 are mediated by the induction of other cytokines like IL-2, IL-6, interferons, tumor necrosis factor, and colony-stimulating factors. In animals IL-1 protects against the effects of radiation, it enhances natural resistance of infection, and it stimulates bone marrow recovery after myelosuppression. These studies suggest that IL-1 may be used as a therapeutic agent.

Staging and treatment of non-Hodgkin's lymphoma of intermediate-grade malignancy: a retrospective study of 102 cases.

Since the introduction of the Working Formulation for Clinical Usage, 3 different prognostic groups are recognized among the various histological classifications of non-Hodgkin's lymphomas. We looked at the lymphomas of intermediate-grade malignancy and studied retrospectively the staging and treatment of 102 patients. Almost half of the patients with clinical stage I disease, who therefore received radiotherapy only, later appeared to have had more extended disease. For patients with stage II, III and IV disease the complete remission rate was significantly higher with CHOP than with CVP (76% versus 36%). However, once complete remission was achieved there was no difference in disease-free survival between the 2 groups (at 4 yr, 50% of the patients were in complete remission). As far as the amount of cytostatic drugs given during the initial courses of chemotherapy is concerned, no difference was found between patients who achieved complete remission and those who did not. Most patients did not receive the full dosage. For those patients who did not respond well to initial therapy, or who suffered a relapse, second line therapy was disappointing.

Simultaneous production of interleukin 6, interferon-beta and colony-stimulating activity by fibroblasts after viral and bacterial infection.

Different viruses were compared with the double-stranded RNA poly(rI).poly(rC) and interleukin (IL) 1 for their IL 6-inducing potential in several human and animal cell types. The laboratory viruses Sendai, Mengo and Newcastle disease virus were found to dose dependently stimulate IL 6 production in diploid fibroblasts. A similar effect was obtained with the human pathogens, measles and rubella virus. Concomitantly with IL 6, two other cytokine activities, i.e., interferon-beta and colony-stimulating activity for granulocytes and monocytes, were induced. In addition, these three activities were also produced by fibroblasts in response to Escherichia coli, whereas lipopolysaccharide was only marginally active. The specificity of the induction phenomenon was confirmed by the lack of IL 6 induction with inactivated infectious agents and by the complete neutralization of produced IL 6 by specific antibodies. This study indicates that the coordinate production of hemopoietic growth factors and interferon, originating from cells that do not classically belong to the immune system, can influence the local and systemic reactions observed during host defence against various infectious agents.

Apoptosis and secondary necrosis of lymphocytes in culture.

It has been reported that cultured peripheral B lymphocytes of chronic lymphocytic leukemia (B-CLL) patients show a high degree of apoptosis (programmed cell death). Till now, no data exist about the occurrence of in vitro apoptosis of normal B and T cells. We measured the amount of apoptosis and secondary necrosis (type 2 necrosis) in B-CLL lymphocytes and in normal peripheral B and T lymphocytes in culture. Observations were made on B-CLL lymphocytes and on normal B and T cells purified by immunomagnetic cell sorting. Apoptosis and secondary necrosis were measured using a recently described sensitive flow-cytometric assay, probing simultaneously for cell surface exposure of phosphatidylserine with the use of FITC-labeled annexin-V and for cell membrane integrity as demonstrated by the exclusion of propidium iodide. The degree of in vitro apoptosis and secondary necrosis of normal B cells appears to be higher than that of normal T cells, and even higher than that of B-CLL cells. The results indicate that cultured mature circulating normal B lymphocytes exhibit a higher cell death rate than normal T cells and B-CLL lymphocytes.

Vulvar paraneoplastic amyloidosis with the appearance of a vulvar carcinoma.

Nodular cutaneous amyloidosis of the vulva is a rare phenomenon. We describe a patient with localized nodular lesions on the vulva that mimicked kissing ulcers such as are seen with vulvar carcinoma. These lesions were a result of multiple myeloma with subsequent primary systemic amyloidosis. The patient died of cardiac and renal decompensation 2 months after diagnosis.

Ex vivo evidence of lymphocyte apoptosis in hairy cell leukemia, induced by 2-chlorodeoxyadenosine treatment.

In all living cells phosphatidylserine (PS) is located at the cytosol side of the membrane and becomes exposed at the cell surface only during necrosis or apoptosis. This phenomenon allows measurement of cell death on a cell-by-cell basis, using labeled Annexin V, which has a strong affinity to PS. Two patients with hairy cell leukemia (HCL) who had relapsed after splenectomy and alpha-interferon therapy were treated with 2-chlorodeoxyadenosine (2-CdA) for 7 days. Blood samples were taken from the start of therapy until day 22. Percentages of HCL cells, T cells, B cells, and NK cells were measured with PE-labeled monoclonal antibodies by flow cytometry (FCM). The absolute lymphocyte count dropped rapidly to almost zero in both patients within 7 days. The disappearance rate of lymphocyte subfractions did not show a specific pattern. The percentage of apoptosis in lymphocyte subfractions was measured in freshly prepared cell samples by FCM with FITC-labeled Annexin V in the propidium iodide-negative (non-necrotic) cell fraction. Percentages of PS-positive cells increased gradually till a nadir of Annexin V positivity was reached at 14 and 16 days. Because during the first week the absolute cell counts became almost zero, the absolute numbers of PS-positive cells were still extremely low, i.e., less than 0.1x10(9)/l. Nevertheless, we observed apoptotic cells in circulation after 2-CdA therapy. To our knowledge, this is the first report of the occurrence of apoptosis ex vivo in circulating blood cells after cytotoxic therapy.