ALBERT

Beschreibung: Abstract 862 Rapid relapse after discontinuation of imatinib, the need for indefinite therapy and residual disease in most patients are the major challenges in management of CML. Combinations of imatinib with IFN simultaneously, or consecutively preceding imatinib, or with araC may improve treatment outcome. The German CML Study Group therefore designed a randomized trial to compare standard imatinib vs. imatinib + interferon alpha (IFN) vs. imatinib + low dose araC vs. imatinib after IFN failure (for low- and intermediate-risk patients, high risk patients received imatinib 800 mg instead). The current evaluation represents the prefinal results of the pilot phase of the trial. Inclusion criteria were newly diagnosed BCR/ABL positive CML in chronic phase (CP). Primary aims are: prolongation of survival (overall, OS, and progression free, PFS), determination of rates of hematologic, cytogenetic and molecular remissions, adverse events (AE) and role of allografting. By the end of 2005, 670 patients were randomized, 13 had to be excluded (no CML (n=3), pregnancy, no CP (n=1 each), imatinib 800 mg (n=8)). Analysis was according to intention to treat. 657 patients were evaluable (174 with imatinib 400 mg, 196 with imatinib+IFN, 158 with imatinib+araC and 129 with imatinib after IFN-failure). 656 patients were evaluable for hematologic, 611 for cytogenetic, and 618 for molecular responses. Patient characteristics of treatment arms were similar for age (median 53 years), sex (40% female), median values for Hb (12.6 g/dl), WBC (66.2/μl), platelets (383/μl) and for Euro risk score (low 35%, intermediate 54%, high 10%). The median dose of imatinib was 400mg/die in all arms, of araC 10 mg per treatment day and of IFN 4.2 Mio I.U./die in the imatinib after IFN arm and 1.8 Mio I.U./die in the imatinib+IFN arm. Median observation time was 57.3 months. 55 patients died, 73 patients were transplanted in 1st CP, 81 patients progressed, 59 patients were switched to second generation TKIs. After 3 years 126 patients (72%) of the imatinib 400mg arm still received the initial therapy as well as 60 patients (30%) of the imatinib+IFN arm and 53 patients (34%) of the imatinib+araC arm. 9 patients (7%) of the imatinib after IFN arm are still on IFN. 5-year OS of all patients is 91%. 5-year PFS of all patients (no death, patient still in first chronic phase) is 87%. 5-year-OS and PFS according to treatment arm are shown in the Table. At 5 years, the cumulative incidences of achieving complete cytogenetic remission or major molecular remission (MMR) as determined by competing risks (death, progression) are not different (Table). Type and severity of adverse events (AE) over a 5-years period did not differ from those reported previously (Table). Hematologic AEs grade III/IV were similar in all therapy arms except leukopenia grade III/IV, which was more frequently observed in the imatinib after IFN arm (14%). Non hematologic AEs were mainly fluid retention, neurological and gastrointestinal symptoms and fatigue. Neurologic symptoms and fatigue were more often reported for the therapy arms with IFN. Imatinib 400mgImatinib+IFNImatinib+AraCImatinib after IFN5-Year Survival and Response RatesOS87%93%92%92% PFS84%91%88%84% CCR92%92 %89%83% MMR83%78%80%70% Adverse Events, WHO Grade III/IVAnemia7%1%3%3% Leukopenia4%5%2%14% Thrombocytopenia5%6%6%6% WHO Grade I-IVEdema15%13%5%0% Neurological5%15%5%22% Gastrointestinal17%27%21%15% Fatigue8%13%9%23% This analysis shows excellent survival and durable response rates in all arms. Currently, survival in all treatment arms is equal to, or better than in IRIS. To verify possible differences in survival, e.g. imatinib 400 mg vs. imatinib + IFN, longer observation is planned. Although cytogenetic and molecular responses in the imatinib after IFN failure arm at 5 years are inferior to that in the other treatment arms, the question of whether the consecutive therapy with IFN first and imatinib after IFN-failure provides a survival advantage requires long term follow-up. Imatinib in combination with, or after IFN, or with low dose araC are feasible and safe treatment modalities. We expect that the study will optimize and improve therapy outcome in CML. Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; German Competence Net : Research Funding; European LeukemiaNet: Research Funding; Roche: Research Funding; Essex: Research Funding.

Beschreibung: The N-myc down-regulated gene 1 (NDRG1) is a stressed induced protein whose expression is associated with growth arrest and differentiation of tumor cells. Although the exact function of NDRG1 protein remains unknown, various studies support its role as a suppressor of tumor metastasis. In prostate, colon and breast cancer its expression is associated with a better disease prognosis and patient survival. In hematopoietic cells, NDRG1 was identified in a differential display screen for differentiation-related genes in human myelomonocytic U937 cells. In the present study, we sought to investigate the role of NDRG1 in myeloid differentiation. To this end we first evaluated NDRG1 mRNA expression in acute myeloid leukemia (AML; n=82) patient samples as well as in CD34+ progenitor cells (n=5) and neutrophils (n=6) of healthy donors using quantitative real-time RT-PCR. We found significantly higher NDRG1 mRNA levels in granulocytes as compared to CD34+ (p=0.0043) or AML blast cells (p

Beschreibung: Introduction Even mild renal dysfunction (e.g. creatinine 100 to 140 μmol/l) can be related to inadequate erythropoietin (EPO) response in patients with refractory anemia and bone marrow features compatible with dysplasia (Korte, Cogliatti et al. 2000). Overall, this seems not an infrequent mechanism (Fehr, Ammann et al. 2004) Therefore, patients with MDS bone marrow morphology and secondary bone marrow dysfunction due to EPO deficiency may be diagnosed as having a myelodysplatic syndrome (refracory anemia [RA] or even refractory anemia with ringed sideroblasts [RARS]). Patients and Methods We performed a single center, prospective, non-randomized pilot study to evaluate the potential benefit of EPO therapy in patients with refractory anemia, mild renal insufficiency and low EPO levels. Eligibility criteria were: hemoglobin (hb) concentrations

Beschreibung: The advent of imatinib has considerably changed treatment in chronic myeloid leukemia (CML). Although response rate and duration of response with imatinib monotherapy continue to be impressive, the majority of patients (pts) in complete cytogenetic remission (CCR) retain BCR-ABL transcripts as markers of residual disease and potential cause of relapse. In addition rapid evolvement of blast crises from CCR has been reported. Therefore, we designed an investigator-initiated phase IV prospective trial aiming to address the role of imatinib in combination with interferon alpha (IFN) or Ara-C and treatment intensification with high dose imatinib. In July 2002, the German CML-Study Group has activated the four-armed randomized controlled trial comparing imatinib 400 mg/d with imatinib+IFN, imatinib+Ara-C and imatinib after IFN failure in newly diagnosed pts with chronic phase CML. Randomization is stratified according to prognostic risk groups and not biased by consecutive allogeneic stem cell transplantation (SCT). High risk pts are randomly assigned to primary imatinib-based therapies including a 4th treatment arm with imatinib 800 mg/d. The treatment arm imatinib after IFN failure retains the chance of an IFN-induced CCR with 10 year-survival rates of 70–80%. In case of IFN failure pts are crossed over to imatinib. Allogeneic SCT is recommended for all pts with high risk, imatinib failure and EBMT-score 0–1. By August 2004, 429 pts were randomized: imatinib 400 mg/d (n=103), imatinib+IFN (n=130), imatinib+Ara-C (n=108), imatinib after IFN failure (n=84), and imatinib 800 mg/d (n=4). According to the New CML score, 34% of patients were low risk, 56% intermediate risk, and 10% high risk. At baseline, median WBC count was 63/nl (3.5–513), median platelet count was 385/nl (49–2,799) and median hemoglobin was 12.7 g/dl (6.1–16.6). We sought to evaluate results of the first cohort of pts (n=217) with a 〉12 months follow-up, recruited between 7/2002 and 5/2003 (imatinib 400 mg/d, n=52; imatinib+IFN, n=70; imatinib+Ara-C, n=49; imatinib after IFN failure, n=46). Median age was 56 yrs (16–82), 62% of pts were male. Cytogenetic data are available from 117 pts (68%) randomized to primary imatinib-based therapies. At 12 months, 104 pts (89%) achieved a major cytogenetic remission (Ph+

Beschreibung: In spite of favorable response and survival results for the majority of CML patients on imatinib therapy, in a substantial minority imatinib fails or shows suboptimal responses. A treatment optimization study was therefore designed to compare in a randomized fashion standard imatinib vs. imatinib + interferon alpha (IFN) vs. imatinib + low dose araC vs. imatinib after IFN (for low- and intermediate-risk patients) or vs. imatinib 800 mg (for high-risk patients). Inclusion criteria were newly diagnosed BCR/ABL positive CML in chronic phase. In July 2005, randomization to the arms imatinib + araC and imatinib after IFN was discontinued and recruitment for imatinib 800 mg was expanded to low- and intermediate-risk patients. Primary goals are: rates of hematologic, cytogenetic and molecular remissions, duration of chronic phase, overall survival, adverse events and analysis of subsequent allografting. Since its activation in 7/2002, 1203 patients have been randomized. The current evaluation represents the first of three designed, statistically adjusted interim analyses of 710 patients randomized by the end of 2005 with a followup of at least 2 years. Analysis was according to intention to treat. 666 patients (545 with primary imatinib, 121 with primary IFN) were evaluable for hematologic, 621 for cytogenetic, and 631 for molecular responses. Median age was 53 years, 60% were male, median values were for Hb 12.5 g/dl, WBC 71.2/nl and platelets 384/nl, 35% had low, 53% intermediate and 12% high risk (Euro score). Median observation time was 3.5 years. Median duration of IFN pretreatment was

Beschreibung: Abstract 3281 Poster Board III-1 Introduction: In the two consecutive German CML studies III and IIIA (recruitment periods from 1995 to 2001 and 1997 to 2004), eligible patients were assigned to early HSCT by genetic randomization according to availability of a matched related donor. After randomization, 113 patients of study III (84% of 135) and 144 of study IIIA (87% of 166) were eventually transplanted in first chronic phase (CP) using a related donor. Despite comparable transplantation protocols and most centers participating in both studies, survival probabilities in study IIIA were significantly better, even when adjusted for the established EBMT risk score (Gratwohl et al., Lancet 1998 [1]), p + 0.0097. For further explanation, the German Registry for Stem Cell Transplantation (DRST) and the Swiss Transplant Working Group for Blood and Marrow Transplantation (STABMT) were asked for data support. Patients and Methods: The main sample characteristics of the 257 transplanted CML study patients were also applied to the registry patients: diagnosis of CML between 1994 and 2004, first HSCT with a related donor performed in first CP between 1995 and 2004 at an age between 12 and 65 years, and blood or bone marrow as stem cell sources. Thus, additional data of 582 HSCT patients were retrieved from the two registries. Age, recipient sex, donor sex, time between diagnosis and HSCT, calendar year of HSCT, stem cell source, and HLA matching were investigated as potential predictive factors for survival. Then, a sample of patients with the same risk distribution as the 113 patients of study III was randomly drawn from the registry patients. By application of repeated resampling to this new patient group, bootstrap confidence intervals for survival probabilities at various times after HSCT were extractable. This provided the basis to judge whether the survival in study III could be seen as a typical random representation of a sample with an equivalent risk structure or not. The same method was applied to the 144 patients of study IIIA. Results: The 5-year survival probability of all 839 patients resulted in 73% (229 died). Median follow-up time of living patients was 6.7 years. Due to the characteristic plateau of post-transplant survival probabilities, the predictive influence was judged by the Kaplan-Meier method and the log rank statistic. Also consideration of age and time between diagnosis and HSCT as continuous variables seemed less appropriate than working with categorizations. Furthermore, the previously published cut-points “1 year” for time from diagnosis to HSCT ([1]) and “44 years” for age at HSCT (Maywald et al., Leukemia 2006) were independently confirmed to be the best. Cox model and logistic regression with survival status after 3 years both indicated that age at HSCT, HLA matching, time between diagnosis and HSCT, and calendar year of HSCT had independent statistically significant predictive influence on survival (p 〈 0.05). The first two factors had the strongest effects. Calendar year was only influential when distinction was made between HSCT until and after 1999. All possible combinations of the 4 factors could be summarized in 4 risk groups with significantly different survival probabilities (at 5 years: 87%, 76%, 63%, and 24%). Matched for the risk group distribution of study III [study IIIA], a maximum of 290 [428] registry patients could be drawn. For the 290 [428] patients, 5-year survival was 69% [77%] with a 95% bootstrap confidence interval from 63% to 74% [72% to 81%]. Thus, as for all yearly intervals within the first 5 years, the 5-year survival probabilities of studies III: 65% and IIIA: 79% lied within the corresponding confidence intervals. Conclusions: Along with the registry patients, the study data enabled the identification of age at HSCT, HLA matching, time between diagnosis and HSCT, and calendar year of HSCT as factors with independent predictive impact on survival which led to 4 risk groups with statistically significantly different survival probabilities. More favorable-risk patients in study IIIA stood for a better transplantation strategy. In consideration of these different risks, the survival probabilities in both studies did not significantly vary from those of registry samples with matched risk structures. Accordingly, an improved transplantation strategy along with random variation could be considered as an explanation of the significantly different survival probabilities between the two studies. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, Bristol-Myers Squibb: Research Funding. Hasford:Novartis: Research Funding. Gratwohl:AMGEN, Roche, Bristol-Myers Squibb, Novartis, Pfizer: Research Funding; Novartis: Consultancy. German CML Study Group:Kompetenznetz Leukämie, European Leukemia Net, Roche, Essex, AMGEN: Research Funding.

Beschreibung: Abstract 339 Initial reports that high dose imatinib results in better responses more rapidly than standard dose imatinib remain controversial. The German CML Study Group therefore compared imatinib 800 mg (IM 800) with standard dose imatinib +/- IFN (IM 400, IM 400 + IFN) in newly diagnosed, not pretreated CML with regard to molecular response at 12 months and survival in a randomized clinical trial. By April 30, 2009, 1026 chronic phase CML patients have been randomized (326 for IM 400, 338 for IM 800, 351 for imatinib + IFN). Comparison was for molecular and cytogenetic remissions, overall (OS) and progression free (PFS) survival and toxicity. 1015 patients were evaluable at baseline, 904 for survival analysis (294 for IM 400, 286 for IM 800, 324 for IM 400+IFN), 790 for cytogenetic (analysis of at least 20 metaphases required) and 823 for molecular response. The three treatment groups were similar regarding median age, sex, median values of Hb, WBC, platelets and distribution according to the EURO score. Median follow-up was 25 months in the imatinib 800 mg arm and 42 months in the imatinib 400 mg +/-IFN arms. The difference is due to the fact that at first the IM 800 arm was designed for high risk patients only and opened up to all risk groups in July 2005. The median daily doses of imatinib were 626 mg (209- 800 mg) in the IM 800 arm and 400 mg (184- 720 mg) in the IM 400 +/- IFN arms. Of 218 patients receiving imatinib 800 mg and evaluable for dosage at 12 months, 100 (45.9%) received more than 700 mg/day, 27 (12.4%) 601-700 mg, 37 (17.0%) 501-600 mg, 48 (22.0%) 401-500 mg and only 6 (2.8%) 400 mg/day or less. The cumulative incidences at 12 months of complete cytogenetic remission (CCR) were 52.3%, 64.9% and 50.6%, and of major molecular remission (MMR) 30.2%, 54.3% and 34.6% with IM 400, IM 800 and IM 400 +IFN, respectively. The cumulative incidences of achieving CCR and MMR with IM 400, IM 800 and IM 400+IFN at 6, 12, 18 and 24 months after start of treatment are summarized in the table. MMR at 12 months was reached faster with IM 800 than with IM 400 (p=0.0003) or IM400+IFN (p=0.0131). Optimal molecular response (OMR=

Beschreibung: The most frequent chromosomal aberrations in B-cell chronic lymphocytic leukemia (B-CLL) are deletions on 13q, 11q, and 17p, and trisomy 12, all of which are of prognostic significance. Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) are used for their detection, but cytogenetic analysis is hampered by the low mitotic index of B-CLL cells, and FISH depends on accurate information about candidate regions. We used a set of 400 highly informative microsatellite markers covering all chromosomal arms (allelotyping) and automated polymerase chain reaction (PCR) protocols to screen 46 patients with typical B-CLL for chromosomal aberrations. For validation, we compared data with our conventional karyotype results and fine mapping with conventional single-site PCR. All clonal cytogenetic abnormalities potentially detectable by our microsatellite PCR (eg, del13q14 and trisomy 12) were picked up. Allelotyping revealed additional complex aberrations in patients with both normal and abnormal B-CLL karyotypes. Aberrations detectable in the samples with our microsatellite panel were found on almost all chromosomal arms. We detected new aberrant loci in typical B-CLL, such as allelic losses on 1q, 9q, and 22q in up to 25% of our patients, and allelic imbalances mirroring chromosomal duplications, amplifications, or aneuploidies on 2q, 10p, and 22q in up to 27% of our patients. We conclude that allelotyping with our battery of informative microsatellites is suitable for molecular screening of B-CLL. The technique is well suited for analyses in clinical trials, it provides a comprehensive view of genetic alterations, and it may identify new loci with candidate genes relevant in the molecular biology of B-CLL.

Beschreibung: Targeted therapy with the BCR-ABL tyrosine kinase inhibitor imatinib induces high response rates in chronic myeloid leukemia (CML) patients (pts). Nevertheless, residual disease remains in virtually all pts on imatinib monotherapy as a potential cause of relapse. In July 2002, the German CML-Study Group activated the four-armed randomized controlled trial comparing imatinib 400mg/d with imatinib+IFN, imatinib+Ara-C, and imatinib after IFN failure in newly diagnosed pts with chronic phase CML. Randomization is stratified according to prognostic risk groups and not biased by consecutive allogeneic stem cell transplantation (SCT). High-risk pts are randomly assigned to primary imatinib-based therapies including a treatment arm with 800mg/d imatinib. By 7/05, 632 pts were randomized: imatinib 400mg/d (n=129), imatinib+IFN (n=179), imatinib+Ara-C (n=156), imatinib after IFN failure (n=157), and imatinib 800mg/d (n=11). According to the Hasford score, 35% of pts were low risk, 54% intermediate risk, and 11% high risk. At baseline, median WBC count was 67/nl (3–529), median platelet count 391/nl (34–2,799) and median hemoglobin 12.6 g/dl (6.1–16.6). We sought to evaluate results of pts with a 〉12 months follow-up (n=416), recruited between 7/02 and 6/04 (imatinib 400mg/d, n=102; imatinib+IFN, n=126; imatinib+Ara-C, n=104; imatinib after IFN failure, n=81; imatinib 800mg/d, n=3) and of pts with a 〉24 months follow-up (n=232), recruited between 7/02 and 6/03 (imatinib 400mg/d, n=55; imatinib+IFN, n=74; imatinib+Ara-C, n=54; imatinib after IFN failure, n=49) with respect to response, resistance, and progression. After 12 months of treatment cytogenetic data are available from 238/335 pts (71%) randomized to primary imatinib based therapies. 209 pts (63%) achieved a major cytogenetic remission (MCR; Ph+