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Portal hypertension with varices developed in 18/675 patients with chronic myeloid leukaemia (CML) in a randomized trial comparing busulphan with busulphan and thioguanine. All 18 had received the drug combination and none busulphan alone (P less than 0.0001). Ascites was also seen significantly more often in the combination arm (P less than 0.05). These results strongly suggest that the addition of thioguanine was responsible for the development of portal hypertension. The histological features were predominantly those of non-cirrhotic portal hypertension--either idiopathic portal hypertension with minimal morphological abnormalities, nodular regenerative hyperplasia or in two cases leukaemic infiltration only was noted. Cirrhosis was present in 3/16 cases studied. Both treatment groups developed abnormal liver function tests during the chronic phase, but particularly with progression of the disease. During chronic phase abnormalities were significantly more frequent in those receiving busulphan and thioguanine-alkaline phosphatase (P less than 0.02), transaminases (P less than 0.04), bilirubin (P less than 0.05), multiple abnormalities (P less than 0.01). The development of portal hypertension was often associated with abnormalities of these tests; however, lack of specificity precludes their use as a predictor of subsequent clinical problems. Thioguanine confers no survival advantage in this disease. In view of its hepatotoxicity it should not be used routinely for maintenance of control in chronic phase CML.

Item does not contain fulltext The optimal dose of interferon-alfa (IFN) for chronic myeloid leukemia (CML) is unknown. Retrospective analyses suggest that low doses are as effective as high doses, with less toxicity and fewer patients abandoning the drug. The Dutch Hemato-Oncology Association (HOVON) and British Medical Research Council (MRC) cooperative groups jointly performed randomized trials in newly diagnosed CML patients, comparing high-dose IFN (5 MIU/m(2) daily) with low-dose (3 MIU, 5 times a week). Both arms allowed additional hydroxyurea to keep the white blood cell count lower than 5 x 10(9)/L. Quality of life data were collected in a subset of patients. Between 1993 and 2001, 407 patients were randomized. At a median follow-up of 53 months, there were no significant differences in overall survival (odds ratio = 1.09, 95% confidence interval, 0.81-1.46), progression-free survival, and complete hematologic or major cytogenetic responses. Fewer patients in the low-dose group abandoned IFN for reasons other than transplant or progressive disease (P =.002, 58% vs 72% at 5 years). Quality of life data showed comparable results in both arms for most factors. There is no evidence of benefit for high-dose IFN compared with low-dose for the treatment of CML. Therefore, when IFN is combined with other drugs, low-dose IFN is advised, to minimize toxicity and costs.

Chronic myelogenous leukemia (CML) is characterized by the presence of a Bcr-Abl fusion protein with deregulated tyrosine kinase activity that is required for maintaining the malignant phenotype. Imatinib, a selective inhibitor ofBcr-Abl, induces major cytogenetic remission (MCR) or complete cytogenetic remission (CCR) in the majority of patients with CML in first chronic phase. However, thorough re-evaluation of cytogenetics in a cohort of patients in MCR or CCR demonstrated clonal karyotypic abnormalities in more than 10% of cases, some of which were clinically associated with a myelodysplastic syndrome (MDS). Further analysis identified previous exposure to cytarabine and idarubicin as significant risk factors for the subsequent occurrence of abnormalities in Philadelphia chromosome–negative (Ph−) cells. To investigate if cytogenetically normal but clonal hematopoiesis might be present in other patients in cytogenetic remission, we studied X-chromosome inactivation as a marker of clonality by polymerase chain reaction analysis of the human androgen receptor (HUMARA). We find that imatinib restores a polyclonal pattern in most patients in CCR and MCR. Nonetheless, our results are consistent with the notion that targeted therapy of CML with imatinib favors the manifestation of Ph− clonal disorders in some patients. They indicate that patients on imatinib should be followed with conventional cytogenetics, even after induction of CCR.

Chronic lymphocytic leukaemia (CLL) is a B-cell disorder, which has a median survival of over 10 years from diagnosis for stage A disease. The natural history of stage A disease is generally indolent or only slowly progressive. It is less well known that CLL may undergo spontaneous regression. We report a series of 10 such cases (eight stage A and two stage B) followed at our institutions.

Chronic myeloid leukemia (CML) is characterized by formation of the BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Large deletions on the derivative chromosome 9 have recently been reported, but it was unclear whether deletions arose during disease progression or at the time of the Ph translocation. Fluorescence in situ hybridization (FISH) analysis was used to assess the deletion status of 253 patients with CML. The strength of deletion status as a prognostic indicator was then compared to the Sokal and Hasford scoring systems. The frequency of deletions was similar at diagnosis and after disease progression but was significantly increased in patients with variant Ph translocations. In patients with a deletion, all Ph+ metaphases carried the deletion. The median survival of patients with and without deletions was 38 months and 88 months, respectively (P = .0001). By contrast the survival difference between Sokal or Hasford high-risk and non-high-risk patients was of only borderline significance (P = .057 and P = .034). The results indicate that deletions occur at the time of the Ph translocation. An apparently simple reciprocal translocation may therefore result in considerable genetic heterogeneity ab initio, a concept that is likely to apply to other malignancies associated with translocations. Deletion status is also a powerful and independent prognostic factor for patients with CML. The prognostic significance of deletion status should now be studied prospectively and, if confirmed, should be incorporated into management decisions and the analysis of clinical trials. (C) 2001 by The American Society of Hematology.

Telomere shortening is associated with disease evolution in chronic myelogenous leukemia (CML). We have examined the relationship between diagnostic telomere length and outcome in 59 patients with CML who entered into the MRC CMLIII Trial by Southern blot hybridization using the (TTAGGG)4 probe. Age-adjusted telomere repeat array (TRA) reduction was found to significantly correlate with time from diagnosis to acceleration, such that patients with a larger TRA reduction entered the accelerated phase more rapidly (r = −0.50; P = .008). Cox-regression analysis for this group was suggestive of a relationship between a greater TRA-reduction and a shorter time to acceleration (P = .054). Age-adjusted TRA reduction did not significantly affect either the time to blast crisis or overall survival. Our results show that telomere shortening observed at the time of diagnosis in CML significantly influences the time to progress to the accelerated phase. The measurement of diagnostic TRA may prove to be clinically important in the selection of patients at high risk of disease transformation in CML.

We studied telomere length in the peripheral blood leukocyte samples of a large group of patients with chronic myelogenous leukemia (CML) by Southern blot hybridization using the (TTAGGG)4 probe. The average telomere length expressed as the peak telomere repeat array (TRA) of the peripheral blood samples obtained from a group of 34 healthy age-matched controls ranged between 7.6 and 10.0 kb and the mean peak TRA was 8.7 kb. Forty-one patients in the chronic phase of CML were studied; 32/41 (78%) showed telomere reduction (

Interferon-alpha may be better than cytotoxic drugs in the long-term management of patients with chronic myeloid leukaemia (CML) in chronic phase. To test this possibility 587 patients with CML in chronic phase were randomly allocated to receive lymphoblastoid cell-line interferon-alpha n1 (IFN-alpha, n = 293) or chemotherapy with busulphan or hydroxyurea (no IFN-alpha, n = 294) as maintenance after initial induction treatment with cytotoxic drugs. There was a significant survival benefit for patients in the IFN-alpha arm when analysed on the basis of intention to treat (2p = 0.0009). The median survival for those allocated IFN-alpha was 61 months and no IFN-alpha was 41 months. Out of 269 patients with Philadelphia-positive CML in the IFN-alpha arm with at least 6 months follow-up, 211 were evaluable for haematological response: 145 (68%) achieved good responses (A+ or A type), 37 (18%) had partial responses (B type) and 29 (14%) had poor responses (C type). Patients with types A and B responses had a better survival than those in the no IFN-alpha arm; patients with type C responses had survival equivalent to the no IFN-alpha arm. Of these 269 patients, 26 of whom had not started IFN-alpha, 59 (22%) achieved a significant degree of cytogenetic response but 210 (78%) did not have a response. Cytogenetic responders survived significantly longer than non-responders and even non-responders survived longer than patients in the no IFN-alpha arm. Since cytogenetic non-responders had worse than average prognostic features, they may also benefit from IFN-alpha therapy. We conclude that treatment with IFN-alpha prolongs the survival of patients with CML; benefits of IFN-alpha are not confined to cytogenetic responders but may extend to most, if not all patients receiving IFN-alpha treatment; and cytogenetic response to IFN-alpha treatment identifies patients with a relatively good prognosis.

Two hundred and nineteen cases of Ph+ve CML and 15 Ph-ve, BCR+ve CML cases have been analysed to determine the breakpoint site and its relationship to clinical features, cytogenetic response, duration of chronic phase and survival. 119 cases have had RNA analysis performed to determine the type of BCR/ABL transcript and have also been analysed in a similar way. Presenting features at diagnosis including age, sex, white-cell count and platelet count showed no significant difference for those with 5' and 3' breakpoints and those with either b2a2 or b3a2 BCR/ABL transcripts. However, in a subgroup of patients whose presenting white-cell count was < 100 x 10(9)/l, those with b3a2 transcript did have a significantly higher platelet count. Analysis by Sokal risk grouping showed no difference for 5' or 3' breakpoints but a trend for lower stage among those with b2a2 transcripts. No correlation was found either for genomic breakpoint site or BCR/ABL RNA transcript in terms of duration of chronic phase or survival. When stratified by randomized therapy, either interferon-alpha or standard chemotherapy, no difference was noted in relation to genomic breakpoint site or BCR/ABL transcript. Cytogenetic response was not related to the molecular findings.

We describe four patients who developed severe thrombocytopenia which progressed to aplasia after the use of alpha-interferon in maintenance therapy of chronic phase CML after busulphan induction. On reviewing over 400 patients in the MRC CML III trial we found that there is a risk of cytopenia developing after busulphan therapy and a lesser risk of cytopenias developing after alpha-interferon therapy. If the therapies are given in a sequential fashion the risk of cytopenia developing appears to be additive, may be pronounced, and may lead to clinically significant problems. Hydroxyurea alone does not lead to sustained cytopenia. Care should be taken to ensure that counts are stable after the use of busulphan before starting alpha-interferon as maintenance therapy.

Summary This paper explores the evolving nature of an understanding of culture through attendance on an Intensive Programme (IP) funded by ERASMUS–SOCRATES. Aims The purpose of this paper is to report a journey of learning about culture through attendance on a ERASMUS–SOCRATES funded Intensive Programme (IP) for nurses in Hasselt, Belgium. Method This paper seeks to describe the process and experience of our involvement through an examination of the authors’ participation as teachers and students. This was undertaken using serial taped group and individual interviews. The metaphor of the IP as a journey is described and used as the vehicle for data collection and analysis. Findings The key findings were the development of key themes relating to: Personal Values and Culture, Engagement and Culture, Personality and Culture and Physicality and Culture. Discussion of these findings raises issues of language and language skill, communication and listening skills, stereotyping, personal awareness, cultural awareness, sensitivity and competence. Conclusions It is proposed that direct engagement through programmes, such as the reported IP, with other nurses and nurse educationalists in Europe is an essential part of any modern nursing curriculum and aids the development of internationalisation. Without such direct engagement there is potential for a narrower, limited view of culture and a lack of sensitivity in understanding our own and other cultures.

Chronic lymphocytic leukaemia (CLL) is a B-cell disorder, which has a median survival of over 10 years from diagnosis for stage A disease. The natural history of stage A disease is generally indolent or only slowly progressive. It is less well known that CLL may undergo spontaneous regression. We report a series of 10 such cases (eight stage A and two stage B) followed at our institutions.

A substantial minority of patients with chronic myeloid leukaemia (CML) achieve a complete response to treatment with interferon-alpha (IFN-alpha), defined as the disappearance of Philadelphia chromosome positive metaphases or, for patients who are Philadelphia chromosome negative but BCR-ABL positive, the disappearance of the leukaemic clone as assayed by Southern blot. We have measured the levels of BCR-ABL transcripts in 20 such patients by quantitative PCR. Results were standardized for both quality and quantity of cDNA by quantification of ABL as an internal control. All 20 patients had evidence of residual disease; the median number of transcripts was 750/micrograms RNA (range 10-22,000) and the median BCR-ABL/ABL ratio was 0.17% (range 0.0008-3.6%). Our findings show that CML has not been eradicated in any patient and that the quantity of residual disease in complete responders may vary by as much as four orders of magnitude.

Stem cell transplantation (SCT) remains the only proven curative therapy for chronic myeloid leukemia (CML) but is limited by significant procedure related morbidity. Imatinib is the first of a new generation of specifically targeted drugs for this disorder based on the ubiquitous presence of the BCR-ABL kinase. The success of Imatinib therapy to induce a cytogenetic remission (CCyR) raises questions over the suitability and timing of SCT as a treatment for CML. Of importance is the degree of protection CCyR infers from developing a blast crisis. We report a total of 68 patients from five centres all of whom started Imatinib within six months of diagnosis of 1st chronic phase CML and subsequently achieved a complete cytogenetic remission. In this group, five cases spontaneously developed blast crisis despite achieving a CCyR. In the affected patients CCyR was achieved between 97 and 254 days (mean 148 days) and BC developed between 177 and 875 days (mean 446 days). The BC was myeloid in three cases and lymphoid in the remaining two. Statistical analysis of this group predicts a 91% freedom from blast crisis at two years (figure 1). The development of acute leukemia is assumed to derive from further mutations within the BCR-ABL expressing stem cell pool. The success of SCT therapy in curing CML drops significantly if the patient has previously progressed to a blast crisis. The finding that cytogenetic remission is no guarantee of protection from developing a blast crisis suggests that for young patients with a sibling match, stem cell transplantation may be considered as an early therapy in the management of CML. Download : Download high-res image (135KB) Download : Download full-size image