Jørgen Ellegaard

The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload

Long‐term follow‐up data are presented on changes in peripheral blood counts and Hb requirements of 11 patients with myelodysplastic syndromes (MDS) during iron chelation treatment with desferrioxamine for up to 60 months. The erythroid marrow activity was indirectly evaluated by repeated determinations of the serum transferrin receptor concentration. The efficacy of iron chelation was evaluated by repeated quantitative determination of the liver iron concentration by magnetic resonance imaging.

In B-cell chronic lymphocytic leukaemia chromosome 17 abnormalities and not trisomy 12 are the single most important cytogenetic abnormalities for the prognosis: A cytogenetic and immunophenotypic study of 480 unselected newly diagnosed patients

Of 560 consecutive, newly diagnosed untreated patients with B CLL submitted for chromosome study, G-banded karyotypes could be obtained in 480 cases (86%). Of these, 345 (72%) had normal karyotypes and 135 (28%) had clonal chromosome abnormalities: trisomy 12 (+12) was found in 40 cases, 20 as +12 alone (+12single), 20 as +12 with additional abnormalities (+12complex). Other frequent findings included abnormalities of 14q, chromosome 17, 13q and 6q. The immunophenotype was typical for CLL in 358 patients (CD5+, Slg(weak), mainly FMC7-) and atypical for CLL in 122 patients (25%) (CD5-, or Slg(strong) or FMC7+). Chromosome abnormalities were found significantly more often in patients with atypical (48%) than in patients with typical CLL phenotype (22%) (P < 0.00005). Also +12complex, 14q+, del6q, and abnormalities of chromosome 17 were significantly more frequent in patients with atypical CLL phenotype, whereas +12single was found equally often in patients with typical and atypical CLL phenotype. The cytomorphology of most of the +12 patients was that of classical CLL irrespective of phenotype. In univariate survival analysis the following cytogenetic findings were significantly correlated to a poor prognosis: chromosome 17 abnormalities, 14q+, an abnormal karyotype, +12complex, more than one cytogenetic event, and the relative number of abnormal mitoses. In multivariate survival analysis chromosome 17 abnormalities were the only cytogenetic findings with independent prognostic value irrespective of immunophenotype. We conclude that in patients with typical CLL immunophenotype, chromosome abnormalities are somewhat less frequent at the time of diagnosis than hitherto believed. +12single is compatible with classical CLL, and has no prognostic influence whereas chromosome 17 abnormalities signify a poor prognosis. In patients with an atypical CLL immunophenotype, chromosome abnormalities including +12complex, 14q+, del 6q and chromosome 17 are found in about 50% of the patients, and in particular chromosome 17 abnormalities suggest a poor prognosis.

No effect of vitamin B-12 treatment on cognitive function and depression: a randomized placebo controlled study

BACKGROUNDnAssociations between vitamin B-12 deficiency and impaired cognitive function and depression have been reported.nnnMETHODSnA randomized placebo controlled study including 140 individuals with an increased plasma methylmalonic acid (0.40-2.00 micromol/l) not previously treated with vitamin B-12. Cognitive function was assessed by the Cambridge Cognitive Examination (CAMCOG), Mini-Mental State Examination (MMSE), and a 12-words learning test. Symptoms of depression were evaluated by the Major Depression Inventory. The main outcome measure was change in cognitive function and depression score from baseline to follow-up 3 months later.nnnRESULTSnAt baseline 78 (56%) individuals had cognitive impairment judged from the CAMCOG score and 40 (29%) according to the MMSE; 18 (13%) individuals had symptoms of depression. No improvement was found in cognitive function comparing the treatment and placebo group (total CAMCOG score: P = 0.43), nor among individuals with only slightly impaired cognitive function (n = 44, total CAMCOG score: P = 0.42). The treatment group did not improve in depression score as compared to the placebo group (P = 0.18).nnnLIMITATIONSnThe duration of impaired cognitive function was unknown.nnnCONCLUSIONSnA high proportion of individuals with an increased plasma methylmalonic acid had impaired cognitive function, and a rather high prevalence of depression was observed. However, vitamin B-12 treatment did not improve cognitive function or symptoms of depression within the 3-months study period.

Low levels of mannose-binding lectin do not affect occurrence of severe infections or duration of fever in acute myeloid leukaemia during remission induction therapy.

Abstract: Purpose: To estimate the clinical significance of low serum concentrations of mannose‐binding lectin (MBL) in patients with acute myeloid leukaemia (AML) during initial cancer chemotherapy. Patients and methods: 80 consecutive, newly diagnosed, and unselected AML patients (age 18–77 yr) undergoing remission induction chemotherapy. The patients were examined for 28 d. Main findings: Low levels of serum MBL (<1000 μg/L) were found in 16/80 patients at diagnosis. This frequency is similar to what is found in the general population. In the remaining 64 patients, MBL concentrations were significantly higher than in controls and showed only a slight rise during the period of antineoplastic chemotherapy with its associated infectious complications. Low levels of MBL did not affect overall survival or morbidity in terms of incidence or duration of fever, or occurrence of septicaemia or pneumonia. Long‐term survival was likewise independent of MBL concentration. Conclusion: MBL levels have no discernible influence on the occurrence or course of infections in AML patients during the initial hospitalisation. The predominant immunodeficiency during this phase is the profound granulocytopenia, which also compromises important effector functions of MBL. The finding in most AML patients of elevated MBL concentrations on admission is most likely because of the role of MBL as an acute phase reactant.

Non‐invasive assessment of tissue iron overload in the liver by magnetic resonance imaging

Summary. We investigated the clinical usefulness of a standard magnetic resonance imaging (MRI) system for non‐invasive determination of the liver iron concentration in 38 patients with iron overload and 15 normal controls by measurement of the signal intensity ratio between liver and skeletal muscle (SIR). However, SIR was found dependent on the applied repetition time (TR) of the MRI system, which led us to investigate this relationship in autopsy material of liver and muscle tissue specimens with various iron content. Based on these results, adjustment of SIR measurements to a constant value of TR was achieved. By use of this technique we found a close correlation between MRI and chemically determined liver iron concentration (r2= 0.98) as well as the serum ferritin concentration (r2= 0.86). The reproducibility was sufficiently good for the use of MRI in the follow‐up of iron reductive treatment. The use of iron store parameters in serum was found insufficient as indicators of endpoint for venesection therapy, if 20 μmol Fe/g dry weight was applied as the upper reference limit of the liver iron concentration.

Natural killer (NK)-cell activity and antibody-dependent cellular cytotoxicity (ADCC) in primary preleukemic syndrome☆

In 13 patients with a multi-parameter based diagnosis of primary acquired preleukemic syndrome (PPS), natural killer (NK) cell activity and antibody-dependent cellular cytotoxicity (ADCC) were investigated on peripheral blood mononuclear cell (MNC) fractions. In all but two patients a defective NK activity was found. Lymphocyte-monocyte mixture experiments demonstrated that this was not due to suppressor monocytes. Furthermore, NK activity was defective when both myeloid and non-myeloid target cell lines were used. Addition of human leukocyte interferon to the NK cultures augmented the cytotoxicity, which exhibited the same kinetics as that of normal controls, but NK activity levels remained subnormal. These data strongly indicate that the decreased NK activity seen in the patients is due to a decreased number of circulating NK cells. In contrast ADCC was within the normal range both when MNC suspensions as well as when purified peripheral blood lymphocytes were used as effector cells thus ruling out subnormal lymphocyte ADCC masked by the presence of monocyte ADCC. These results demonstrate that PPS patients have a selective NK defect with an intact lymphocyte ADCC function. Whether this defect will prove to be valuable in the assessment of a malignant transformation in a given patient will await further longitudinal NK studies and clinical follow-up of the patients.

EFFECT OF PSYCHOLOGICAL INTERVENTION IN THE FORM OF RELAXATION AND GUIDED IMAGERY ON CELLULAR IMMUNE FUNCTION IN NORMAL HEALTHY SUBJECTS : AN OVERVIEW

The present study measured the effects of relaxation and guided imagery on cellular immune function. During a period of 10 days 10 healthy subjects were given one 1-hour relaxation procedure and one combined relaxation and guided imagery procedure, instructing the subjects to imagine their immune system becoming very effective. Even though no major changes in the composition of the major mononuclear leukocyte subsets could be demonstrated a significant increase in natural killer function was demonstrated. These data suggest that relaxation and guided imagery might have a beneficial effect on the immune defense and could form the basis of further studies on psychological intervention and immunological status.

DESFERRIOXAMINE TREATMENT REDUCES BLOOD TRANSFUSION REQUIREMENTS IN PATIENTS WITH MYELODYSPLASTIC SYNDROME

The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by clonal haematopoietic proliferation and the production of end-stage cells with abnormalities of maturation and function (Hassan & Rees, 1989). Apart from eventual progress to acute leukaemia and complications related to thrombocytopenia and neutropenia, dependency on regular blood transfusions can be a major clinical problem. Development of transfusional iron overload in these patients with a heavy transfusion requirement and a long duration of the underlying disease adds another therapeutic problem. Severe manifestations of transfusional iron overload are well documented in patients with thalassaemia (Hofirand & Wonke, 1989), and patients with myelodysplastic syndromes may suffer from similar problems. In thalassaemia it has been proved that treatment with the iron chelating agent desferrioxamine (DFO) can induce a negative iron balance (Maurer et al, 1988: Hofirand et al, 1979), may normalize serum concentration of ferritin (Maurer et al, 1988; Hoarand et al, 1979), and reduce liver iron concentration (Maurer et a / , 1988: Barry et at, 1974). leading to an improved liver function (Maurer et nl, 1988: HofPorand et al. 1979), and thus possibly prolong the life of the patient (Modell et al, 1982). DFO treatment in patients with MDS is especially indicated in younger patients with a stable disease, but is not always performed, in many cases due to difficulties in the administration of daily subcutaneous infusions, or due to the high costs. The aim of the present investigation was to review retrospectively during DFO treatment the need for blood transfusion and changes in some haematological parameters in MDS patients with a permanent blood transfusion requirement. The study includes all MDS patients in our department, who had been in UFO treatment for more than 6 months, at the time of investigation. All patients were classified according to the FAB criteria (Bennett et a / , 1982). including five patients with refractory anaemia (RA), and one patient (no. 5 ) with refractory anaemia with excess of blasts in transformation (RAEB-t). All six patients, aged 36-66 years (mean 5 1.7), had a continuous blood transfusion requirement, and were without any evidence of chronic blood loss. The number of blood transfusions given at the beginning of DFO treatment varied from 59 to 264. The duration of the disease varied from 14 to 36 months for patients 2-6 to 236 months for patient 1. DFO treatment was given subcutaneously in the abdominal wall 5 d/week either by continuous infusions over 12 h, or by bolus injections twice a day. Continuous infusion was given to the two youngest patients (no. 1 and 2) accomplished by a portable computer-assisted infusion pump. The DFO dose was dissolved in sterile water and diluted to 50 ml in isotonic saline. The older patients found it difficult to handle the pump. Therefore they were given bolus injections twice a day, usually at 8 a.m. and 7 p.m. The daily dose of DFO was 2 g for patients 2, 3 , 4 and 6, and 2 .5 g for patient 1. The treatment was administered on an outpatient basis, after careful instruction of the patients. No practical problems were encountered, and the patient compliance was high. No ascorbic acid supplement was given in any case. The effect of DFO treatment on iron excretion was monitored by measuring the urinary excretion of iron (Zettner & Mansbach, 1965) and by measuring the serum concentration of ferritin (Amerlite ferritin assay). The Hb concentration, white cell count (WBC), platelet count (PLC). mean cell volume (MCV) and mean cell haemoglobin content (MCHC), was measured just before each transfusion episode by Coulter count analysis until May 1989. and later by autoanalyser H-1 (Technicon). The change of analysis technique did not have any significant influence on the values of the haematological variables of interest. Data were collected retrospectively for a time period up to 2 years before start of DFO treatment and up to the time of investigation (Table I). The mean value of these data was calculated, and compared with the similar mean values during DFO treatment for statistical comparison (Student’s ttest). A calculation of the transfusion requirements expressed in g Hb/month was done every time the patient was transfused according to the following formula:

Acyclovir given as prophylaxis against oral ulcers in acute myeloid leukaemia: randomised, double blind, placebo controlled trial.

Abstract Objectives: To evaluate (a) the prophylactic effect of the antiherpetic drug acyclovir on oral ulcers in patients with acute myeloid leukaemia receiving remission induction chemotherapy and thus (b), indirectly, the role of herpes simplex virus in the aetiology of these ulcers. Design: Randomised, double blind, placebo controlled trial. Subjects: 74 herpes simplex virus seropositive patients aged 18-84. Thirty seven patients received acyclovir (800 mg by mouth daily) and 37 placebo. The patients were examined daily for 28 days. Main outcome measures: Occurrence of herpes labialis, intraoral ulcers, and acute necrotising ulcerative gingivitis. Results: The two populations were comparable in age, sex, type of antineoplastic treatment, and history of herpes labialis. Acute oral infections occurred in 25 of the acyclovir treated patients and 36 of the placebo treated patients (relative risk 0.69 (95% confidence interval 0.55 to 0.87)). This difference was due to a reduction in the incidence of herpes labialis (one case versus eight cases; relative risk 0.13 (0.02 to 0.95)), intraoral ulcers excluding the soft palate (one case versus 13 cases; relative risk 0.08 (0.01 to 0.56)), and acute necrotising ulcerative gingivitis (one case versus eight cases; relative risk 0.13 (0.02 to 0.95)). However, ulcers on the soft palate were diagnosed with similar frequency in the two groups. Isolation of herpes simplex virus type 1 in saliva was reduced from 15 cases in the placebo group to one case in the acyclovir group (relative risk 0.07 (0.01 to 0.48)). Conclusion: Intraoral ulcers excluding the soft palate are most often due to infection with herpes simplex virus, whereas ulcers on the soft palate have a non-herpetic aetiology. The findings suggest that acute necrotising ulcerative gingivitis may also be due to herpes simplex virus. Prophylaxis with acyclovir should be considered for patients with acute myeloid leukaemia during remission induction therapy. Key messages Key messages Oral ulcers were found in more than half of patients with acute myeloid leukaemia during remission induction therapy The incidence of herpes labialis, intraoral ulcers outside the soft palate, and acute necrotising ulcerative gingivitis was greatly reduced by prophylaxis with oral acyclovir (800 mg by mouth daily) during remission induction therapy Intraoral ulcers on the soft palate were not associated with herpes virus infection

Evaluation of transfusional iron overload before and during iron chelation by magnetic resonance imaging of the liver and determination of serum ferritin in adult non-thalassaemic patients.

The ability to quantitate transfusional iron overload is crucial for determining the need for and the efficacy of chelation therapy in patients with long‐standing transfusion‐dependent anaemias. We evaluated the usefulness of some indirect measures of iron overload in estimating the iron concentration in the liver ‐ the most important iron storage organ ‐ in 26 non‐chelated adult non‐thalassaemic patients. Liver Iron concentration was determined noninvasively by magnetic resonance imaging (MRI). The standard error of the estimated liver iron concentration was 80 μmol Fe/g dried liver tissue when using the number of transfused blood units, and 93 μmolFe/g when using a serum ferritin assay. Follow‐up in 11 patients (1248 months) revealed that serum ferritin is a poor measure of the liver iron concentration during iron chelation. However, this discrepancy was individually different and seemed to be dependent on the erythropoietic marrow activity. By monitoring the liver iron concentration by MRI. we compared the efficacy of chelation with desferrioxamine given either by subcutaneous continuous infusions or by bolus injections. Depletion of liver iron stores could be achieved efficiently by both regimens.