Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day ( n =400) could be optimized by doubling the dose ( n =420), adding interferon (IFN) ( n =430) or cytarabine ( n =158) or using IM after IFN-failure ( n =128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients’ and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Allogeneic bone marrow transplantations were carried out between March 1983 and July 1985 in 31 patients aged 7 to 45 years (median 18 years). Acute lymphoblastic leukaemia in 1st to 5th remission was present in 8 patients, acute myeloblastic leukaemia in 1st and 2nd remission in 4 patients, chronic myeloid leukaemia, with various remission status, in 6 patients, 3 patients had severe aplastic anaemia and there were single cases of myelodysplasia and immature cell megakaryocytic myelosis. Transplantation was carried out during relapse in 8 patients with either acute myeloid or lymphoblastic leukaemia. Phenotypic HLA-identical mothers (n = 2) as well as genotypic HLA-identical siblings (n = 27), and in two cases HLA-non-identical mothers, served as bone marrow donors. In leukaemia patients the conditioning treatment consisted of fractionated total body irradiation and high dose cyclophosphamide or etoposide. Patients with severe aplastic anaemia received cyclophosphamide (4 X 50 mg/kg) and fractionated total nodal irradiation (total dose 8 Gy). 19 patients (61%) survived 14 to 605 days after bone marrow transplantation. 15 patients (48%) continue to remain in complete remission with Karnofsky indices of greater than or equal to 90%. Causes for death were infection (n = 3), interstitial pneumonia (n = 3), relapse (n = 3) as well as single cases involving acute graft-versus-host-disease, non-engraftment of donor marrow and veno-occlusive disease of the liver.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

In myelodysplastic syndromes (MDS), the karyotype is one of the most significant prognostic markers with profound impact on differential diagnosis and therapeutic decisions. In a retrospective study, we examined karyotypes of bone marrow specimens of an oligocentric cohort comprising 529 patients with MDS to address the question how many metaphases need to be analyzed to detect even small cell clones with an appropriate expenditure. We found a statistically significant difference of the frequency of normal karyotypes in the patient group with 19 or less analyzed metaphases compared to the group with 20 or more metaphases analyzed (56% versus 47%, p=0.041). Furthermore, we demonstrate that the analysis of 25 or more metaphases can further improve the sensitivity of karyotype analysis and leads to the identification of additional clinically relevant abnormal clones or subclones in a substantial proportion of patients. In summary, our data suggest the examination of at least 20 metaphases in MDS.

PURPOSE:On the basis of cytomorphology according to the French-American-British (FAB) classification, we evaluated the prognostic impact of dysplastic features and other parameters in de novo acute myeloid leukemia (AML). We also assessed the clinical significance of the recently introduced World Health Organization (WHO) classification for AML, which proposed dysplasia as a new parameter for classification.PATIENTS AND METHODS:We analyzed prospectively 614 patients with de novo AML, all of whom were diagnosed by central morphologic analysis and treated within the German AML Cooperative Group (AMLCG)-92 or the AMLCG-acute promyalocytic leukemia study.RESULTS:Patients with AML M3, M3v, or M4eo demonstrated a better outcome compared with all other FAB subtypes (P <.001); no prognostic difference was observed among other FAB subtypes. The presence or absence of dysplasia failed to demonstrate prognostic relevance. Other prognostic markers, such as age, cytogenetics, presence of Auer rods, and lactate dehydrogenase (LDH) level at diagnosis, all showed significant impact on overall and event-free survival in univariate analyses (P <.001 for all parameters tested). However, in a multivariate analysis, only cytogenetics (unfavorable or favorable), age, and high LDH maintained their prognostic impact. Dysplasia was not found to be an independent prognostic parameter, but the detection of trilineage dysplasia correlated with unfavorable cytogenetics.CONCLUSION:Our results indicate that cytomorphology and classification according to FAB criteria are still necessary for the diagnosis of AML but have no relevance for prognosis in addition to cytogenetics. Our results suggest that the WHO classification should be further developed by using cytogenetics as the main determinant of biology. Dysplastic features, in particular, have no additional impact on predicting prognosis when cytogenetics are taken into account.

Risk assessment in acute myeloid leukemia (AML) using pretreatment characteristics may be improved by incorporating parameters of early response to therapy. In the 1992 trial of the German AML Cooperative Group (AMLCG), the amount of residual leukemic blasts in bone marrow was assessed one week after the first induction course (day 16 blasts). A total of 449 patients 16 to 76 years of age (median, 53 years) with de novo AML entered the trial and were evaluable. Treatment included TAD/HAM (thioguanine, cytosine arabinoside, and daunorubicin/high-dose cytosine arabinoside and mitoxantrone) double induction, TAD consolidation, and randomly either maintenance therapy or S-HAM consolidation. Cytogenetics were favorable, intermediate, unfavorable and not available in 10.0%, 48.3%, 13.1%, and 28.5%, respectively. Day 16 blasts ranged from 0% to 100% (median, 5%, mean +/- SD, 18.6 +/- 28.5%). Complete remission (CR) rate was 72.6%, 17.6% had persistent leukemia (PL), and 9.8% succumbed to hypoplastic death. Median overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were 18, 9, and 15 months with 28.4%, 21.6%, and 30.1% at 5 years, respectively. As a continuous variable, day 16 blasts were related to CR rate (P < 0.0001), PL rate (P < 0.0001), OS (P < 0.0001), EFS (P < 0.0001), and RFS (P = 0.0049). Multivariate analyses identified the following parameters to be associated with the respective end points. CR rate: day 16 blasts (P <.0001), age (P =.0036), and LDH (P =.0072); OS: unfavorable cytogenetics (P <.0001), day 16 blasts (P <.0001), age (P <.0001), and LDH (P =.0040); EFS: unfavorable cytogenetics (P <.0001), LDH (P <.0001), day 16 blasts (P <.0001), and age (P =.0061); RFS: unfavorable cytogenetics (P <.0001), LDH (P <.0001), and day 16 blasts (P =.0359). The prognostic significance of day 16 blasts is independent of pretherapeutic parameters and predicts outcome even in patients achieving a CR.