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 the interval between high dose 1-beta-D-arabinofuranosylcytosine injections on leukemic cell load, intestinal toxicity, and normal hematopoietic stem cells in a rat model for acute myelogenous leukemia.

One injection of 1-beta-D-arabinofuranosylcytosine (ara-C) in BN rats bearing myelocytic leukemia induces recruitment and synchronization of the leukemic cells. A second ara-C injection, given when the largest fraction of cells is in S phase, causes the largest reduction in leukemic clonogenic cells. The relevance of recruitment and synchronization of leukemic cells after high dose ara-C (200 mg/kg) by rapid i.v. injection (comparable with 1 g/m2 in patients) has been tested in rats with respect to survival time and toxicity. Several groups of leukemic rats have been treated with seven injections of ara-C; the intervals between the injections per group were 4, 6, 9, 12, 15, 18, and 24 h, respectively. The longest mean survival time is observed in the group treated every 9 h which is 70.8 days compared to 22.6 days in nontreated leukemic controls. This 9-h interval of ara-C administration corresponds with the moment when DNA synthesis of the leukemic cells resumes after its inhibition by the ara-C. The most severe toxic side effects on the gastrointestinal system are observed in the group that received ara-C every 6 h; no toxic death has occurred in the animals treated with 15-h or longer intervals. The effect of the increasing interval between two ara-C injections on the normal hematopoietic stem cells has been measured with the colony forming unit spleen assay. This study showed that the reduction of normal stem cells due to ara-C is independent of the interval of administration. This differential effect of ara-C on leukemic and normal hematopoietic stem cell kinetics might in part explain the mechanisms of achieving a complete remission in acute leukemia.

Independent prognostic effect of co-morbidity in lymphoma patients: results of the population-based Eindhoven Cancer Registry.

The prevalence of co-morbidity among elderly lymphoma patients is associated with a decrease in the use of chemotherapy. This study assessed the independent prognostic effect of co-morbidity in 1551 unselected lymphoma patients, diagnosed between 1995 and 2001 in the area of the population-based Eindhoven Cancer Registry. The prevalence of serious co-morbidity was 58% for patients with Hodgkin's disease (HD) who were over 60 years of age and 66% for patients with non-Hodgkin's lymphoma (NHL) who were over 60 years of age. The administration of chemotherapy declined in the presence of co-morbidity for elderly patients with early-stage HD and elderly patients with aggressive NHL. Co-morbidity was associated with a 10-20% decline in 5-year survival. Whether less frequent application of chemotherapy in the presence of co-morbidity is justified as far as complications, prognosis and quality of life are concerned requires further investigation.

The standardised mortality ratio: the proper quality indicator in acute leukaemia?

BACKGROUND: The standardised mortality ratio (SMR) is a quality indicator used to measure quality of care in the Netherlands. It is subject to much criticism, which was the reason to study the value of the SMR as a quality indicator for the treatment of acute leukaemia. METHODS: A retrospective analysis was performed in patients with acute leukaemia admitted to a Santeon hospital during the period 2005-2009. SMR values were calculated and compared with the overall survival (OS). RESULTS: During the study period, 455 unique patients were admitted with acute leukaemia. SMR calculation was based on 992 admissions. SMR analysis yielded a high mortality ratio in hospital 1, 2, 3 and 4 in comparison with the national average (100), significant for hospital 1 and 4 (180 [CI 95% 126-257] and 187 [CI 95% 134-261], respectively) OS analysis also showed a significantly different outcome between hospitals. However, using OS as outcome parameter, hospital 2 and 6 showed the lowest performance as compared with hospital 1 and 4 using SMR as parameter. After multivariate analysis, age (HR 1.04; CI 95% 1.03-1.05; p < 0.001) and hospital (hospital 5 compared with 6: HR 0.54; CI 95% 0.30- .98; p = 0.043; hospital 2 compared with 1: HR 1.51; CI 95% 1.02-2.23; p = 0.039) were the only significant variables that influenced OS. CONCLUSION: Outcome according to SMR is not equivalent to outcome according to OS. This study shows that the use of the SMR as a quality indicator for the treatment of acute leukaemia does not appear to be justified.

Deoxycytidine kinase and deoxycytidine deaminase values correspond closely to clinical response to cytosine arabinoside remission induction therapy in patients with acute myelogenous leukemia.

In this study, it has been shown that in 21 patients with AML the dCyd kinase and dCyd deaminase activities correspond closely to the clinical response to ara-C remission induction therapy. Patients with primary disease were treated with a conventional-dose ara-C regimen whereas nonresponders and relapsed patients followed an ID ara-C regimen (1 g/m2 X 12). Of these 21 patients (11 with primary disease and ten relapsed), seven had ara-C resistant disease (three primary and four relapsed patients). Five of the seven patients had a very low dCyd kinase and normal dCyd deaminase activity, whereas the other two had a normal dCyd kinase and an increased dCyd deaminase activity.

Percentage of S-phase cells in bone marrow aspirates, biopsy specimens and bone marrow aspirates corrected for blood dilution from patients with acute leukemia.

For 14 patients with acute leukemia flow cytometry was used to determine the percentage of cells in S-phase flushed out of a bone marrow biopsy compared with the percentage in a bone marrow aspirate; there was a statistically significant difference (p less than 0.01) between the two. The percentage dilution of the bone marrow aspirate by peripheral blood was then calculated, according to Holdrinet et al. [1], in order to correct the percentage S-phase cells in the aspirate. The data presented show that when the percentage S-phase cells in the aspirate is corrected for blood dilution, it closely approaches the percentage S-phase cells in the biopsy (p greater than 0.10).

Amyloid and peripheral nervous system disease.

The peripheral nervous system can be involved in the following amyloid deposition diseases. (1) Amyloid deposition composed of beta 2-microglobulin in patients on long term hemodialysis causing a carpal tunnel syndrome; (2) deposition of light chain immunoglobulin derived amyloid leading to polyneuropathy, carpal tunnel syndrome and autonomic nervous system involvement in patients with primary amyloidosis, or amyloidosis secondary to or associated with multiple myeloma, Waldenström's macroglobulinemia, non-Hodgkin's lymphoma, and solid neoplasms like hypernephroma; and (3) several types of heredofamilial amyloid polyneuropathies, which are mainly caused by a point-mutation in the transthyretin gene on chromosome 18. The clinical and biochemical features of these three groups will be discussed, with special attention for recently developed therapy. In clinical practice, amyloid polyneuropathy should be considered in case of familial occurrence of a polyneuropathy and when a patient presents with a polyneuropathy and a monoclonal gammopathy.

Cutaneous leukocytoclastic vasculitis in relation to streptokinase.

The case history is presented of a patient who developed a cutaneous leukocytoclastic vasculitis after he had been treated with intravenous streptokinase because of an acute myocardial infarction. Leukocytoclastic vasculitis is a seldom reported side effect of streptokinase and may be caused by a type III-hypersensitivity reaction.

Compassionate use programme of irinotecan in colorectal cancer patients in The Netherlands.

BACKGROUND: Irinotecan is an effective treatment for metastatic colorectal cancer. However, its use may be associated with troublesome adverse effects such as delayed diarrhoea, acute cholinergic syndrome and neutropenic infection. The manufacturer decided to release irinotecan for compassionate use in The Netherlands prior to its regulatory approval (June 1998) and first introduction for second-line treatment of metastatic colorectal cancer. In view of the drug's adverse effect profile this was done in a carefully controlled manner. METHODS: Irinotecan was made available to patients with colorectal cancer with elaborate precautions. Treating physicians requesting irinotecan for compassionate use received a protocol, providing recommendations for the proper use and the prevention/management of potentially troublesome adverse events. Limited demographic, toxicity and efficacy data were collected. RESULTS: Between June 1997 and September 1998, 112 patients were registered for this programme, 103 of whom actually received irinotecan. The percentage of patients experiencing grade 3-4 adverse effects was relatively low: delayed diarrhoea in 17%, nausea and vomiting 17%, acute cholinergic syndrome 6%, febrile neutropenia 4% and neutropenic infection 2%. Five partial tumour responses and a high proportion of patients with 'no change' were noted. CONCLUSIONS: The carefully controlled release of irinotecan for compassionate use with a very detailed protocol for guidance and advice on safety precautions seems to have contributed to the relatively safe use of the drug outside the setting of a formal clinical trial.

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.