BACKGROUND:Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. METHODS:In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. FINDINGS:Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments. INTERPRETATION:Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.

Specific chromosomal abnormalities such as chromosome 13 deletions and some translocations affecting the immunoglobulin heavy chain (IGH) gene, namely t(4;14)(p16;q32) and t(14;16)(q32;q23) have been associated with an adverse prognosis in multiple myeloma. Conventional cytogenetic techniques fail to detect these aberrations in the majority of cases. Thus, we have developed a novel set of interphase fluorescence in situ hybridization (I-FISH) assays targeting those regions frequently lost on chromosome 13 as well as those oncogenes most recurrently involved in translocations with the IGH locus in multiple myeloma, i.e. IRTA1/2 (1q21), FGFR3/MMSET (4p16), CCND3 (6p21), IRF4 (6p25), CCND1 (11q13), MAF (16q23), and MAFB (20q12). The probes were combined in a multicolor fashion to develop novel multicolor I-FISH (MI-FISH) assays, whose validity and applicability was evaluated in negative controls and in a series of 13 plasma cell neoplasias. Additionally, a combination of the novel MI-FISH assays with staining for the plasma cell-specific antigen VS38c by means of multicolor FICTION (M-FICTION, fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms) allowed us to selectively analyze the plasma cell compartment, and thereby to increase the assay sensitivity.

BACKGROUND:This study aimed to determine the somatosensory characteristics and pain types in patients with acute oxaliplatin-induced neuropathy and to relate this profile to the hereby detected underlying pathophysiological mechanisms.PATIENTS AND METHODS:Sixteen patients treated with oxaliplatin for cancer were characterised with neurological assessment and a standardised and validated set for quantitative sensory testing (QST). Patients were allocated to two groups depending on the presence or absence of pain symptoms of acute neuropathy.RESULTS:Comparison with normative data revealed in patients with pain symptoms a characteristic somatosensory profile of cold and mechanical hyperalgesia. Group-to-group analysis revealed additional heat hyperalgesia and warm hypoesthesia.CONCLUSION:Pain symptoms of acute oxaliplatin-induced neuropathy are related to signs of sensitisation within the peripheral (cold and heat hyperalgesia) and central nervous nociceptive system (mechanical hyperalgesia). This strengthens the rationale for treatment with anticonvulsants and antidepressants and fosters research on ion channel and receptor related mechanisms.

Background: A previous CALGB trial (JCO 2002; 20:2429) showed a positive OS trend with AZA vs best supportive care (BSC) in MDS. The objective of this Phase III, international, multicenter, randomized, prospective trial was to demonstrate the superiority of AZA + BSC for prolonging OS vs CCR + BSC. Design: Higher-risk MDS patients (pts), FAB-defined as RAEB, RAEB-T, or CMML (10–29% marrow blasts) with an IPSS of Int-2 or High by central pathology/cytogenetic review, were enrolled. Before randomization, investigators preselected pts to 1 of 3 CCR: BSC only (transfusions, antibiotics, and G-CSF for neutropenic infection); low-dose ara-C (LDAC, 20 mg/m2/d x 14d, q 28d); or standard chemotherapy (Std CT: conventional induction/consolidation). Pts were stratified by FAB/IPSS and randomized to AZA (75 mg/m2/d x 7d, q 28d) or CCR. This trial did not allow erythropoietin. All analyses used the ITT population.

T-Large Granular Lymphocyte (T-LGL) leukaemia is a rare clonal disease characterized by neutropenia and/or anaemia. Because of its strong association with rheumatoid arthritis (RA), T-LGL leukaemia is an important differential diagnosis to Felty's syndrome. This differentiation might be especially difficult since, in severe RA with extraarticular manifestations, there is often an expanded memory effector T-cell population which can hardly be separated from T-LGL leukaemia cells by means of immunophenotyping. The main criterion for T-LGL leukaemia is the detection of a clonal T-cell-receptor rearrangement by PCR. First-line therapy consists of weekly low-dose methotrexate. Alternatively, other immunosuppressives or cytotoxic agents can be useful. There are very limited data from therapy studies. The German CLL study group has initiated a protocol using parenteral low-dose methotrexate as first-line therapy and fludarabine as second-line medication.

There is now evidence that the tolerability, and response to systemic chemotherapy in HIV-infected patients with AIDS-related lymphoma (ARL) is significantly improved by highly active antiretroviral therapy Here we report an severely immunocompromised AIDS patient with recurrent ARL who was successfully treated with autologous stem cell transplantation (ASCT). We also review the current literature of ASCT in HIV-infected patients.

Die T-Large Granular Lymphocyte Leukämie (T-LGL-Leukämie) ist eine seltene klonale Erkrankung, die durch Neutropenie und/oder Anämie gekennzeichnet ist. Da sie häufig mit einer Rheumatoiden Arthritis (RA) assoziiert ist, stellt sie eine wichtige Differenzialdiagnose zum Felty-Syndrom da. Da bei schwer verlaufender RA mit extraartikulären Manifestationen häufig stark expandierte Memory-Effekor-T-Zellpopulationen auftreten, die sich immunphänotypisch kaum von T-LGL-Leukämie-Zellen unterscheiden lassen, kann diese Differenzialdiagnose sehr schwierig sein. Wichtigstes Kriterium ist dann der molekulargenetische Nachweis einer monoklonalen T-Zellpopulation bei der T-LGL-Leukämie. Die Erstlinientherapie besteht in einer wöchentlichen niedrig dosierten Methotrexatgabe. Alternativ können andere Immunsuppressiva oder Zytostatika eingesetzt werden, wobei kaum Daten aus Therapiestudien vorliegen. Im Rahmen der Deutschen CLL-Studiengruppe wird eine Therapiestudie mit Erstlinien parenteraler Methotrexatgabe und Zweitlinientherapie mit Fludarabin durchgeführt.

The Follicular Lymphoma International Prognostic Index (FLIPI) is a useful predictor for the prognosis of patients with FL. It relies on a score consisting of age, stage, hemoglobin, LDH, and number of nodal sites involved at diagnosis, which defines 3 risk groups with different 5-year survival (5-y OS): Low risk (0–1 factor; 5-y OS >90%); intermediate risk (2 factors; 5-y OS 78%); and high risk (>2 factors; 5-y OS 53%). We hypothesized that SCT in first remission might improve the course of patients with advanced FL and high/intermediate risk FLIPI, thereby abrogating the prognostic impact of the FLIPI.

BACKGROUND: Trypan blue exclusion staining is probably the most frequently applied method (Method I) for assessment of viability in peripheral blood progenitor cell grafts after cryopreservation. Alternatively, a flow cytometry–based method (Method II) was established and optimized.STUDY DESIGN AND METHODS: In a first series of 22 autologous apheresis products, the influence of duration of antibody staining and red cell (RBC) lysis on viability was investigated. In a second series of 21 autologous and 1 allogeneic apheresis products, the effect of omitting the RBC lysis was evaluated. On the basis of the results of the first two series, 155 autologous and 57 allogeneic apheresis products were analyzed with Method I and the now optimized Method II.RESULTS: Halving the incubation times did not influence the viability of CD45+ or CD34+ cells. Omission of RBC lysis resulted in a significantly (p = 0.022) increased median viability of CD45+ cells (75.8% vs. 71.0%) without any influence on CD34+ cells. In the third series, the median viability of CD34+ cells (96.9%) was significantly (p < 0.0001) higher compared with the viability of CD45+ cells (76.2%) and the viability determined by Method I (86.5%).CONCLUSION: The viability of CD34+ cells was significantly higher compared with the viability of all white blood cells. The presented cytometry‐based method is superior to the standard trypan blue method regarding the number of analyzable cells and documentation, regarding observer independence and standardization; it allows the analysis of the cells of interest for transplantation after minimal sample manipulation.

The purpose of our study was (i) to evaluate the impact of all- trans retinoic acid (ATRA) given as adjunct to chemotherapy and (ii) to compare second consolidation vs maintenance therapy in elderly patients with acute myeloid leukemia (AML). A total of 242 patients aged ⩾61 years (median, 66.6 years) with AML were randomly assigned to ATRA beginning on day +3 after the initiation of chemotherapy (ATRA-arm, n =122) or no ATRA (standard-arm, n =120) in combination with induction and first consolidation therapy. A total of 61 patients in complete remission (CR) were randomly assigned to second intense consolidation ( n =31) or 1-year oral maintenance therapy ( n =30). After induction therapy the intention-to-treat analysis revealed a significant difference in CR rates between the ATRA- and the standard-arm (52 vs 39%; P =0.05). Event-free (EFS) and overall survival (OS) were significantly better in the ATRA-compared to the standard-arm ( P =0.03 and 0.01, respectively). OS after second randomization was significantly better for patients assigned to intensive consolidation therapy ( P <0.001). The multivariate model for survival revealed lactate dehydrogenase, cytogenetic risk group, age, and first and second randomization as prognostic variables. In conclusion, the addition of ATRA to induction and consolidation therapy may improve CR rate, EFS and OS in elderly patients with AML.

It is usually not possible to generalise conclusions from a therapeutic study to the whole population because of the select nature of the study population. The situation seems to be, however, different in the German Multicentre Study Group For Adult ALL on acute lymphoblastic leukaemia GMALL (Gökbuget et al. 2000), age 15-64, because more than a hundred centres are recruiting in Germany.

Due to eligibility criteria not all patients with the disease under investigation can be recruited for therapeutic studies. Thus, the external validity of study results cannot per se be taken for granted. The representativity of the admitted patients is the most relevant determinant for external validity and has to be assessed. As an example we examined the representativity of the patients recruited for the German multicenter study group for adult acute lymphoblastic leukemia (ALL) (GMALL). Lacking nationwide ALL incidence figures available in Germany, a methodology was developed to estimate incidence figures, too. All relevant study groups, hospitals, and diagnostic labs were asked to provide data about patients with ALL newly diagnosed between 1997 and 1998. A matching procedure was developed, as heterogeneous databases had to be pooled and checked for duplicates. Age- and sex-specific incidences of ALL were estimated and compared with the number of patients recruited for the GMALL in the same time period. The purpose was to develop a methodology for estimating incidence figures and evaluating the representativity of patients of the GMALL. The combination of various data sources allowed estimation of reliable incidence data for ALL in Germany. Comparisons with the incidence figures for ALL in other countries and crosschecks within Germany confirm our results. Sixty-two percent of all ALL patients in Germany were admitted to the GMALL study. The recruitment rate of more than 60% of the annual incidence of ALL to the GMALL suggests a high external validity as well as an impact of the study on the patterns of treatment and referral of ALL in adults in Germany. There is no selection bias of patients admitted to the GMALL compared to those patients not included in the study.