Summary. In order to evaluate the natural history of essential thrombocythaemia (ET), clinical data and prognostic factors of 143 patients with ET were retrospectively analysed (mean observation time 6·1 Ϯ 4·6 years). In 42 patients the early phase of the disease with initial platelet counts between 250 and 600 × 10 9 /l was assessed. In most early cases, ET was suggested by clinical symptoms (79%) and increased megakaryopoiesis (95%) with abnormal megakaryocytes in bone marrow histology (n ¼ 34) and cytology (n ¼ 5). Other myeloproliferative disorders and reactive thrombocytosis were excluded according to the diagnostic criteria of the Polycythemia Vera Study Group. During follow-up of the 38 early cases not treated cytoreductively at diagnosis, the platelet counts increased to >600 × 10 9 /l in 28 patients (74%) and remained between 450 and 600 × 10 9 /l in 10 patients (26%). In primarily asymptomatic patients (n ¼ 46) with initial platelet counts above (n ¼ 37) and below 600 × 10 9 /l (n ¼ 9) the rates of increase of symptomatic patients were similar at about 7% per year. No influence of the initial platelet count on survival was seen in multivariate analysis of prognostic factors which included all 143 cases. Survival was mainly influenced by the rate of ET-related complications during follow-up (P ¼ 0·002). Analysing the influence of cytoreductive therapy on symptom-free survival, platelet reduction benefited patients under 60 years (19 cytoreductively treated v 65 untreated patients, P ¼ 0·075). The results demonstrate the possible clinical relevance of the early stages of ET and suggest that the features of pathologic megakaryopoiesis in the bone marrow are a more reliable diagnostic criterion than a definite platelet limit. Therefore, further therapeutic studies should include all stages of the disease and all age groups.Keywords: myeloproliferative disorder, early essential thrombocythaemia, prognostic factors, diagnostic criteria, bone marrow histology.Due to the lack of a specific diagnostic marker, the diagnostic criteria of essential thrombocythaemia (ET) established by the Polycythemia Vera Study Group (PVSG) were directed primarily at the exclusion of other myeloproliferative disorders and of reactive thrombocytosis. For diagnosis of ET, a platelet count of 600 × 10 9 /l was considered as an absolute requirement (Murphy et al, 1986). For protocols involving myelosuppressive agents a platelet count of 1000 × 10 9 /l was determined to restrict the erroneous inclusion of cases with reactive thrombocytosis and to avoid possible overtreatment of cases with a mild course of ET (Murphy et al, 1986(Murphy et al, , 1997. In most of the following studies, patients with lower platelet counts were excluded according to the criteria of the PVSG. Such selectivity is acceptable for therapeutic studies. But in the evaluation of the natural course of ET the exclusion of early stages with moderate thrombocytosis below the limit of 600 × 10 9 /l may lead to incomplete recognition of characteristic features of the di...

Early allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as primary treatment modality for patients with chronic myeloid leukemia (CML). This concept has been challenged by transplantation mortality and improved drug therapy. In a randomized study, primary HSCT and best available drug treatment (IFN based) were compared in newly diagnosed chronic phase CML patients. Assignment to treatment strategy was by genetic randomization according to availability of a matched related donor. Evaluation followed the intention-to-treat principle. Six hundred and twenty one patients with chronic phase CML were stratified for eligibility for HSCT. Three hundred and fifty four patients (62% male; median age, 40 years; range, 11-59 years) were eligible and randomized. One hundred and thirty five patients (38%) had a matched related donor, of whom 123 (91%) received a transplant within a median of 10 months (range, 2-106 months) from diagnosis. Two hundred and nineteen patients (62%) had no related donor and received best available drug treatment.

As curative bone marrow transplantation is available only to a minority of patients with chronic myelogenous leukemia (CML), drug therapy remains of central interest. Several nonrandomized studies have suggested that interferon-alpha (IFN) may prolong survival in CML. In a randomized multicenter study the influence of IFN versus busulfan or hydroxyurea (HU) on survival of Philadelphia-positive (Ph+) CML was examined. A total of 513 Ph+ patients were randomized for treatment as follows: 133 for IFN, 186 for busulfan, and 194 for HU. IFN-treated CML patients have a significant survival advantage over busulfan-treated (P = .008), but not over HU-treated patients (P = .44). The longer survival is due to slower progression to blast crisis. Median survival of IFN-treated patients is 5.5 years [5-year survival, 59%; 95% confidence interval (CI), 48%-70%], of busulfan-treated patients, 3.8 years (5-year survival, 32%; CI, 24%-40%), and of HU-treated patients, 4.7 years (5-year survival, 44%; CI, 36%-53%). Patients who continue on IFN survive longer than those in whom IFN is discontinued before blast crisis (P = .007). Complete hematologic IFN-responders have a survival advantage over partial responders or nonresponders (P = .02). Cytogenetic IFN-responders have no significant survival advantage over nonresponders (P = .2). Patients who attain white blood cell (WBC) counts of 10 x 10(9)/L or less have a survival advantage in the IFN (P = .007) and HU (P = .05) groups. Whereas toxicity in the IFN group was considerably higher than in the busulfan or HU groups, long-lasting cytopenias necessitating discontinuation of therapy as observed with busulfan have not been seen with IFN or HU. The problems of conventional prognostic scores (Sokal's score, Score 1) that we observed in IFN-treated patients support the idea that IFN changes the natural course of CML. We conclude that, with regard to survival of CML in the chronic phase, IFN is superior to busulfan and as effective as HU. Whether and to what extent IFN is superior to HU appears to depend, at least in part, on the degree of WBC suppression by HU-therapy and on the risk profile of the patients.

Gender-related aspects in chronic myeloid leukemia (CML) have not been studied well. We therefore analyzed 856 patients with Ph/BCR-ABL-positive CML from the German randomized CML-studies I (interferon a (IFN) vs hydroxyurea (HU) vs busulfan) and II (IFN þ HU vs HU alone). The median observation time was 8.6 years. A total of 503 patients (59%) were male. Female patients were older (51 vs 46 years; Po0.0001), presented with lower hemoglobin (11.7 vs 12.5 g/dl; Po0.0001), higher platelet counts (459 vs 355 Â 10 9 /l; Po0.0001), smaller spleen size (3 vs 4 cm below costal margin; P ¼ 0.0097), a lower rate of additional cytogenetic aberrations (9 vs 15%; P ¼ 0.018) and a less favorable risk profile (P ¼ 0.036). The transplantation rate was 14% for female (n ¼ 48) and 22% for male patients (n ¼ 113). Median survival was longer in female patients (58 vs 49 months; P ¼ 0.035) mainly attributable to better survival in the low-and intermediate-risk groups and, independent from risk groups, in the HU group. These results were confirmed by matched-pair analyses based on German population data (n ¼ 496, 59 vs 45 months; P ¼ 0.0006). This is the first analysis of gender aspects in CML using randomized trials. It demonstrates the relevance of analyses of gender differences in CML and in malignant disease at large.

The optimum treatment conditions of interferon (IFN) a therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CMLstudy I and it had been planned in advance to add the HU patients of study I (n ¼ 194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n ¼ 21), major in 14% (n ¼ 24), and at least minimal in 35% (n ¼ 59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (Po0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P ¼ 0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.