ALBERT

Beschreibung: An increased annual incidence of thromboembolic events (TE) of up to 11% has been observed in patients with solid tumors, whereas there exists little data on TE in hematologic malignancies. A previous study found a 6,6% incidence of TE in patients with high grade Non Hodgkin’s lymphoma (HG-NHL) mostly occuring during the first three months of therapy. Little is known about pathogenesis and risk factors in this patient group. We retrospectively evaluated the medical records of all patients with malignant lymphoma treated at our institution between 1991 and 2004. In a seperate effort laboratory analysis for detection of acquired and hereditary thrombophilia was performed at diagnosis and during treatment in 44 patients with various hematologic malignancies: HG-NHL (n = 22), Low grade- NHL (LG-NHL) (n = 7), Hodgkin’s disease (HD) (n = 6), CNS-lymphoma (n = 1) and acute myeloid leukemia (AML) (n = 8). A total of 96 TE occurred in 80 of 1048 patients (7,6%) with malignant lymphoma: DVT (n = 51), pulmonary embolism (n = 19), central venous catheter thrombosis (n = 11), upper extremity thrombosis due to tumor compression (n = 9), central nervous system thrombosis (n = 3), arterial thrombosis (n = 2) and portal vein thrombosis (n = 1). 69 TE (72%) occurred during treatment, whereas 27 (28%) were diagnosed prior to (n = 16) (17%) or after completion of therapy (n = 11) (11%). 9 patients (9%) had comorbid solid tumors. In 12 patients (15%) results of thrombophilia screening were available and FVIII levels were high (〉 150%) in 7 (58%). In the prospectively analyzed patient cohort 30 (68%) had high FVIII levels, 22 (50%) showing very high levels (〉 180%). High FVIII was associated with high von Willebrand factor (vWF) and increased collagen binding activity, but not with elevated IL 6 or TNF-a. 4 patients (9%) had heterozygous factor V Leiden mutation, one had the G20210A mutation of the prothrombin gene. Fibrinolysis was normal in all patients as were protein C, S and AT-III. No anticardiolipin antibodies or lupus anticoagulants were detected. However only 2 patients (4,4%) in this cohort developed TE, one of whom also had heterozygous protein C resistance. Patients with malignant lymphoma are at substantial risk for TE, especially during treatment, thus prophylactic anticoagulation seems warranted. Our study shows sustained strikingly high factor VIII levels in patients with malignant lymphoma even months or years after a TE as well as in a prospectively analyzed, yet mostly asymptomatic cohort with lymphoma and acute leukemia. Infection as a cause of secondary F VIII elevation in these patients was ruled out by absence of fever and normal IL 6 and TNF-a. Increased FVIII activity (〉 150%) has been recognized as an independent risk factor for TE, however the pathogenesis is unclear so far and high FVIII and vWF levels have previously also been found in Multiple Myeloma patients. Ongoing investigations will focus on the implication of these findings in the pathophysiology of hematologic disease.

Beschreibung: Abstract 1971 Introduction: While the role of lenalidomide monotherapy in the treatment of relapsed/refractory patients with multiple myeloma (MM) is established, combination therapies with Lenalinomide are still under investigation. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective in combination with steroids, thalidomide and bortezomib for the treatment of patients with MM. In the current trial, combination therapy of bendamustine, lenalinomide and prednisolone (RBP) was tested for feasibility and safety in patients with relapsed or refractory MM. Patients and Methods: This is a phase I trial examining dosing of lenalidomide in combination with bendamustine and prednisolone. The first cohort of patients received a starting dose of 10mg/d d1-21 lenalidomide, 60mg/m2/d d1-2 bendamustine and 100mg/d d1-4 prednisolone. Escalation steps in the next cohorts included 15, 20 and 25mg of lenalidomide followed by an escalation step of 75 mg/m2 bendamustine. Three patients were enrolled at each dose level and the first two cycles were evaluated for maximum tolerable dose. Patients received RBP in 4-week cycles for a maximum of 8 cycles in order to evaluate efficacy. Patients with stable or responding disease following 8 cycles of RBP received single-agent oral lenalidomide 10 mg once daily on days 1–21 of each 28-day cycle as maintenance. Results: : Nine patients (3 at each dose level of 10 mg, 15 mg or 20 mg lenalidomide) have been enrolled to date and 9 patients have completed at least 2 cycles. Response was assessed using modified EBMT criteria to include near complete remission (nCR) and very good partial remission (VGPR). 8 of 9 patients responded after at least 2 cycles with 2 VGPR, 4 PR, 1 MR and 1 stable disease. One patient experienced progressive disease. None of the 9 patients developed dose-limiting hematoxicity as defined by an ANC 〈 1,0 × 109/l with fever for 〉 3 days or an ANC 7 days or platelet count 〈 25 × 109/l for 〉 3 days. Neutropenia was reported in 4 patients (CTC grade ≥ 3) but no thrombocytopenia (CTC grade ≥ 3) was observed. No grade 3 or 4 non hematological toxicity was encountered and no dose modification was required. Conclusions: RBP with a dose of 20 mg lenalidomide d 1–21 and 60 mg/m2 bendamustine d 1–2 is well tolerated in patients with relapsed or refractory MM. Maximum tolerable dose was not reached. Further dose increase according to the protocol is in progress. Disclosures: Niederwieser: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

Beschreibung: Abstract 1855 Introduction: Bortezomib and bendamustine have turned out to be effective, rapid action drugs in the treatment of multiple myeloma (MM). Bortezomib is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination with other cytostatic agents in MM. Bendamustine is a bifunctional alkylating agent with low toxicity that produces both single- and double-strand breaks in DNA, and shows only partial cross resistance with other alkylating drugs. The combination of bendamustine and prednisone with bortezomib (BPV) was assessed to determine the efficacy and toxicity of this regimen in patients with relapsed or refractory MM. Methods: Between January 2005 and December 2011, 78 patients (median age 62; range 31–81 years) with relapsed or refractory MM were treated with bendamustine 60 (–120) mg/qm on day 1 and 2, bortezomib 1.3 mg/qm on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11. Cycles were repeated every 21 days until maximum response or progressive disease. Maximum response was achieved if three weeks of therapy did not further reduce myeloma protein by more than 10 %. The median number of prior therapies was 2 (range 1–9). Previous therapies included 31 × thalidomide, 10 × lenalidomide, 14 × bortezomib, 24 × autologous PBSCT, and 19 × autologous-allogeneic PBSCT. In contrast to other clinical studies, patients with pronounced pancytopenia due to stem-cell toxic pre-treatment or advanced disease were also included. Patients were divided into two groups: group A (n = 45) comprised patients with normal bone marrow function and group B (n = 33) patients with pre-existing restricted bone marrow function and pronounced pancytopenia (CTC-Criteria grade III and IV). Patients were excluded from this retrospective analysis if they had other secondary malignancies. To exclude myelodysplastic syndroma or secondary acute myeloid leukemia cytological and cytogenetic examination of bone marrow was performed in patients with pre-existent severe pancytopenia. Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR). Results: The median number of BPV-treatment cycles was 2 (1–7). 54 patients (69 %) responded after at least one cycle of chemotherapy with 3 CR, 10 nCR, 10 VGPR, and 31 PR. Nine patients had MR, 9 patient's stable disease and 6 patients underwent progression. A follow up of surviving patients at a median of 34 months revealed median PFS and OS for patients without preexisting severe haematological toxicities (group A) of 11 months and 50 months respectively. Outcome was significantly better than that of patients with pre-existing severe haematological toxicities (group B) who had a median PFS, and OS of 3 months and 5 months, respectively (p 〈 0.001). The regimen was well-tolerated with few significant side effects in patients without preexisting severe haematological toxicities. New cytopenias occured infrequently with thrombocytopenia grade 3 in 11 patients, grade 4 in 8 patients and neutropenia grade 3 in 7 patients. Six patients experienced a moderate new polyneuropathy (grade 2). Summary: BPV therapy was well tolerated in patients with relapsed/refractory MM, with a response rate of approximately 70 %. The high efficacy and the favourable toxicity profile of BPV warrant further evaluation in clinical trials. Disclosures: Poenisch: Mundipharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Beschreibung: Introduction: Rituximab plus chemotherapy has been proved to be the standard in treating advanced follicular lymphoma. However in mantle cell lymphoma (MCL) the results are still controversial. Methods: In a prospective randomised trial (OSHO#39) we compared the efficacy and toxicity of MCP chemotherapy(mitoxantrone 8 mg/m2 d 1+2, chlormabucil 3x3 mg/m2 d 1–5 and prednisolone 25 mg/m2 d q 4 weeks)versus MCP plus rituximab (375 mg/m2 d -1) in advanced indolent lymphoma and mantle cell lymphoma. Here we present the results of the MCL subgroup (n=90) among the 358 randomised patients (FL, MCL, LPL). Study endpoints included overall and complete response rate (RR + CR), progression free survival (PFS), event free survival (EFS), overall survival (OS) and toxicities. Results: with a median follow-up of 43 months for the MCL subgroup we can provide relatively mature data. Concerning toxicities there was no striking difference between the treatment groups. The treatment results for the MCL patients are as follows: Conclusions: Concerning all end-points R-MCP is not superior to MCP chemotherapy alone in advanced mantle cell lymphoma. Immunochemotherapy is obviously not the solution for this poor prognosis lymphoma entity. Results R-MCP n=44 MCP n=46 p-value Response Rate 70,5% 63% .5074 Complete Responses 31,8% 15,2% .0822 PFS median 20,5 months 19 months .2482 PFS 42 months 31% 14% EFS median 19 months 14 months .1369 EFS 42 months 27% 11,5% OS median 56 months 50 months .4862 OS 42 months 60% 61%

Beschreibung: Abstract 494 Several randomised pediatric trials have demonstrated that intensification of Asparaginase (ASP) treatment in ALL can contribute to improved outcome. In adult ALL few data are availabe and optimal ASP preparation, schedule and intensity with respect to efficacy and tolerability have to be defined. The optimisation of ASP treatment is therefore an essential aim of the GMALL. Treatment: Induction treatment of the ongoing study 07/2003 consists of dexamethasone, vincristine, daunorubicine, pegylated asparaginase (PEG-ASP) (phase I), mercaptopurine, cyclophosphamide and cytarabine (phase II) as previously described (Brueggemann et al, Blood 2006: 107; 1116). During the study the dose for PEG-ASP was increased from 1000 to 2000 U/m2 in induction and from 500 to 2000 U/m2 in consolidation (combined with HDMTX and MP) for pts aged between 15 and 55 years. 1 application for high risk and 7 applications for standard risk (SR) were scheduled during the first year and the aim was improvement of overall survival (OS) and remission duration (RD). Patients: From more than 100 centers in Germany 1226 pts with a median age of 35 (15-55) yrs were evaluable. 826 pts were treated with 1000 U/m2 (cohort 1) and 400 pts with 2000 U/m2 (cohort 2) and both groups were comparable regarding major entry criteria. The analysis was restricted to pts who received one of the scheduled PEG-ASP doses during induction. Outcome: CR rate after induction was 91% vs 91% in cohort 1 and 2 resp., with comparable rates for early death (4% vs 5%) and failure (5% vs 4%). Data on molecular response (MRD below 10−4) after induction are available in a subset and showed no difference between both cohorts after induction (79% vs 82%). OS after 3 years was improved in cohort 2 (60% vs 67%; p〉.05). The positive effect was specifically evident in SR patients (N=407 vs 190) with respect to OS (68% vs 80%; p=.02) and RD (61% vs 74%; p=.02). It was demonstrated in younger pts (15-45 yrs) (71% vs 82%; p=.02) and older pt (45-55 yrs) (56% vs 74%; p〉.05). Excellent results were achieved in young adults (15-25 years) with respect to OS (77% vs 86%; p〉.05) and RD (60% vs 78%; p〉.05). Toxicity: The analysis of toxicity was focused on grade III-IV events during induction with potential correlation to PEG-ASP (764/382 pts in cohort 1/cohort 2)). Incidences are as follows: GOT or GPT (30%/30%), bilirubine (10%/16%), thrombosis (5%/5%) and hypersensitivity (

Beschreibung: Background: While the CHOP regimen is widely accepted standard chemotherapy regimen of care for aggressive lymphomas, the optimal number of chemotherapy cycles for the treatment of aggressive lymphomas has not been determined. Since RICOVER-60 is the first randomized comparison between 6 and 8 cycles of chemotherapy, it allowed to analyze whether 8 cycles are better than 6 in patients with poor prognosis and/or those achieving less than a complete response after 4 cycles of chemotherapy. Methods: In the RICOVER-60 trial, 1222 elderly patients (61–80 years, stages I–IV) were randomized to receive 6 or 8 cycles of CHOP-14 with or without rituximab given on days 1, 15, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. Results: In a multivariate analysis adjusted for prognostic factors using 6xCHOP-14 without rituximab as the reference, all intensified regimens improved event-free survival. Compared to 6xCHOP-14, progression-free survival (PFS) improved after 6xR-CHOP-14 and 8xR-CHOP, while overall survival (OS) improved only after 6xR-CHOP-14 (Pfreundschuh et al., 2006, Blood 108: 64a, Abstract #205). Since 8 cycles of chemotherapy were not better than 6 in the overall RICOVER-60 population, we searched for subgroups who might have a benefit from the two additional cycles of chemotherapy. The outcome after 6 cycles was at least as good as 8 cycles, in any risk group according to IPI. Compared to patients in CR after 4 cycles (n=261), patients in PR after 4 cycles (n=459) had a significantly worse 3-year PFS (63% vs. 75%; p=.001) and OS (69% vs. 84%; p=0.001), while for patients in CRu (n=276) this applied to PFS (68% vs. 76%; p=0.043), but not to OS (78% vs. 84%; p=0.125). Among patients with mid-therapy CRu, the 3-year progression free rates receiving 6 cycles (6x-CHOP-14: 65%, 6xR-CHOP-14: 72%) and those receiving 8 cycles (8xCHOP-14: 63%; 8xR-CHOP-14: 71%) were not different (p=0.601 and p=0.815 without and with rituximab, respectively). The same was true with respect to overall survival (6xCHOP-14: 82%; 8xCHOP-14: 70%; 6xR-CHOP-14: 80%; 8xR-CHOP-14: 80%; p=0.422 and p=0.759 without and with rituximab, respectively). Conclusion: Patients in CR after 4 cycles of therapy have a better outcome than those in CRu and PR at mid-therapy, with no difference between patients who received 6 and 8 cycles of (R−)CHOP-14. Response-adapted assignment of 8 cycles instead of 6 does not compensate for the worse prognosis of patients achieving less than a CR after 4 cycles. Response-adapted assignment of the number of chemotherapy cycles - either with or without rituximab - is not supported by our data.

Beschreibung: The association of lymphoma with a plethora of secondary immune defects is well established. However, most investigations were performed many years ago and little is known about disease specific alterations of the immune system. The availability of new diagnostic methods and a new classification of hematologic diseases (WHO 2000) makes a newly designed study of the immuno-dysfunction in this patient group worthwhile. From January 2003 to August 2004 50 patients with newly diagnosed malignant hematologic diseases - diffuse large cell lymphoma (DLCL) (n = 15), acute myeloid leukemia (AML) (n = 11), mantle cell lymphoma (n = 6), follicular lymphoma (FL) (n = 5), Hodgkin’s disease (HD) (n = 8) and chronic lymphocytic leukemia (CLL) (n = 5) - were analyzed. Parameters of cellular and humoral immunity, including CBC, FACS analysis of lymphocyte subpopulations, cytokines sIL2-R, IL-6, IL-10, TNF-a, serum complement components C3, C4, CH50 and total concentrations of serum immunoglobulin IgG, IgM, IgA were measured. At diagnosis patients with AML had severe cellular immunodeficiency (neutro-, monocyte- and lymphopenia). Infectious complications occurred in 8 of 11 AML patients (73%). Patients with DLCL and MCL had predominantly increased CD3+/CD8+ lymphocyte subsets (median 0,26/m l) with an infection rate from 30%. However, the rate was significantly higher if CD4+ depletion (43%) or CD19+ depletion (40%) were additionally present. High IL-2, IL-6, IL-10 and TNF-a levels were mostly observed in FL and MCL. Elevated TNF-a levels were also associated with infections (43%) and advanced stage or B-symptoms. IL-10 was found to correlate with mortality and relapse risk in all patients (overall: 18% and 20% respectively, increased IL 10 level: 39% and 33% respectively). Serum complement levels were normal to slightly elevated in all patients. Very high levels (CH50 〉 160) were found in patients with Hodgkin’s disease (5/8 patients, 63%) and decreased immunoglobulin levels occurred in CLL patients only, none of whom had infections during follow up. These results indicate that untreated patients with DLCL and MCL have a significant lower CD8+T-lymphocyte cell count. In contrast to previous studies we did not found a predominant depletion of CD4+T-lymphocyte. A combination of CD4+/CD8+ T-cell deficiency or T-/B-cell deficiency was strongly associated with infections, thus antibiotic prophylaxis seems warranted in this patient group. Additionally IL-10 may serve as prognostic marker particularly in MCL and FL.

Beschreibung: The association of lymphoma with a plethora of secondary immune defects is well established. However, most investigations were performed many years ago and little is known about disease specific alterations of the immune system. From January 2003 to August 2004 50 patients with newly diagnosed malignant lymphoma were analyzed and compared with 50 healthy volunteers Corresponding in age and gender. Parameters of cellular and humoral immunity, including CBC, FACS analysis of lymphocyte subpopulations, cytokines (sIL2-R, IL-6, IL-10, TNF-a), serum complement components C3c, C4, CH50 and total concentrations of serum immunoglobulin IgG, IgM, IgA were measured. The median number of CD3+ and CD4+ lymphocyte subsets (p≤0.01) were significantly lower in lymphoma patients compared with matched healthy volunteers. The number of CD8+ T-cells was decreased in patients with bulky disease (p≤0.01). High-intermediate/high risk lymphoma (IPI 3-4 or aaIPI 2-3) had significantly higher CH50 (p=0,02), C3c (p≤0,01), sIL2-R (p≤0,01) and TNF-a levels (p=0,05) than patients with low/low-intermediate risk lymphoma. Infectious complications after chemotherapy (n=14) occurred frequently in patients with high initial LDH (p=0,04), low number of CD4+ (p=0,02) or CD8+ T-cells (p=0,04) and high levels of sIL2-R (p=0,02) or TNF-a (p=0,03). Relapse (n=6) was also observed in patients with decreased CD8+ T-cells (p=0,04) and in patients with high C4 levels (p=0,02). These results indicate that tumor burden in lymphoma patients significantly influenced the number of lymphocyte subsets, serum cytokine levels (sIL2R, TNF- a) and complement components (CH50, C3c). IPI-score and clinical course (infections and relapse) were related to the immunodeficiency. We conclude that measurement of peripheral blood lymphocyte subsets, cytokines and complement factors can be expected to improve existing methods of risk assignment in lymphoma.

Beschreibung: Introduction: Patients with solid tumors have an increased risk for venous thromboembolisms (VTE) associated with substantial morbidity and mortality, but so far there exists little data on hematologic malignancies. We have recently found a VTE rate of 7,7% in patients with malignant lymphoma. However, information on patients with acute leukemia (AL) is very limited so far. Patients and methods: Medical records of all patients with AL treated in our institution between january 1992 and april 2005 were reviewed and data was collected and analyzed in a microsoft excel data base. P-values to show correlation of VTE with leukemia type, patient age and gender were calculated using Fisher’s exact test. All reported p-values are two-sided. Results: Of a total of 455 patients 310 (68%) had AML, 108 (24%) had ALL and 37 (8%) had blast crisis. 248 patients (55%) were male and 207 (45%) were female, median age was 60 years. 55 patients with AL (12,1%) had at least one VTE, occuring during therapy in 82% of events. 27 patients (5,9%) had central venous catheter associated VTE, whereas 28 patients (6,2%) had deep vein thrombosis and/or pulmonary embolism. Neither leukemia lineage - myeloid versus lymphocytic - (p=1,0) nor patient gender (p=.193) had an impact on the VTE risk. However, central venous catheter associated VTE more likely occured in younger patients (〈 60 years) than in patients ≥ 60 years (p=.003). There was no statistically significant difference in the incidence of non-central venous catheter associated VTE between both age groups (p=.563). Discussion: Patients with acute leukemia have a substantial risk for VTE, half of which occur with the use of central venous catheters. A recently published study analysed the incidence of VTE in close temporal relationship to onset of disease and found a VTE rate of 2,09% with equal risk in ALL and AML. Our study included VTE occuring prior to diagnosis of AL as well as during chemotherapy and follow up, revealing a VTE rate that is 6-fold higher and showing a considerable association with central venous catheters. Conclusions: The risk of VTE is surprisingly high in patients with acute leukemia, thus improvement of prophylactic measures, especially in regard to central venous catheter use is warranted.

Beschreibung: Asparaginase (ASP) has a unique role in the treatment of ALL, and several pediatric studies have demonstrated that modifications of schedule, preparation and dose of ASP may have an impact on overall outcome. The optimisation of ASP treatment is therefore an important aim of the German Multicenter Study Group for Adult ALL (GMALL). In 1999 a pilot trial for adult ALL was started (GMALL 06/99), followed by the ongoing main trial 07/2003. Induction comprised dexamethasone, vincristine, daunorubicine and i.th. methotrexate. One dose of pegylated ASP (PEG-ASP) 1000 U/m2 (500 U/m² if 〉 55yrs) was given instead of 7 doses of 5000 U/m2 native E.coli asparaginase (ASP) given over 14 days in previous GMALL studies. In consolidation one dose PEG-ASP (500 U/m2) replaced one dose of E.coli ASP (10000 U/m2) in combination with high-dose methotrexate (1500 U/m²) and mercaptopurine. ASP activity was above 100 U/l at day 10 in 80% of the pts after 1000U/m2 and in only 42% after 500 U/m2. Based on this correlation between dose and duration of activity in study 07/2003 (amendment II in 12/2006) the dose for PEG-ASP was increased to 2000 U/m2 in induction and consolidation for pts 〈 55 yrs and to 1000 U/m2 for pts 〉 55 yrs in order to improve treatment efficacy. Details of the protocol have been reported (Brüggemann, Blood2006: 107;1116). Patients: 959 pts with a median age of 36 yrs are evaluable. 8% (N=82) were older than 55 yrs. Clinical characteristics were representative for adult ALL and similar in the cohorts. 766 pts were treated before the amendment with 1000 U/m2 (cohort 1) and 117 pts after the amendment with 2000 U/m2 (cohort 2), with the respective reductions for pts 〉 55yrs. 76 pts did not receive ASP in induction due to various reasons (cohort 3). Efficacy: In cohort 1 and 2 91% and 90% achieved CR after induction (80% in cohort 3). Data on molecular response, defined as MRD below 10 −4,after induction are available in a subset of both cohorts. There is a trend towards earlier and higher molecular CR rate in cohort 2 (82% after induction) compared to cohort 1 (70%). Survival after 1 yr is similar in cohort 1 (79%) compared to cohort 2 (77%) and inferior in cohort 3 (66%). Probability of continuous CR after 1 year shows a trend to improvement with 87% in cohort 2 vs 77% in cohort 1. Toxicity in induction: Toxicity reported here is focused on potentially ASP related oIII–IV (WHO scale) events. 676 pts are evaluable for cohort 1 and 107 pts for cohort 2. Incidences for both cohorts are as follows: GOT or GPT (30%/27%), bilirubine (12%/14%), thrombosis (5%/2%), bleeding (2%/0%) and hypersensitivity (1%/1%). Details on adverse events of all degrees are available in a subset of pts showing an increase of any WHO grade in 81% for bilirubine, 80% for GPT, 52% for amylase, 29% for lipase and 51% for glucose. Data on substitution of clotting factors were available in 84 and 61 pts: 73% vs 93% required substitution (25%/12% FFP, 37%/46% ATIII concentrate and 37%/42% both). Conclusions: This is the largest cohort of adult ALL pts treated with PEG-ASP so far. Overall intensified PEG-ASP was feasible in the context of intensive multidrug induction. Coagulation disturbances occurred frequently and substitution was extensive, but bleeding or thrombosis were rare events. Although substitution of clotting factors was clinically effective it remains open whether it is clinically necessary. The rate of severe hepatotoxicity was stable after dose escalation however lead to significant treatment delays in individual pts. Lab value changes e.g. liver occured in a large proportion of pts; it remains open to what extent they are clinically relevant and require interruption of further chemotherapy. It would be an important goal to identify parameters to predict severe ASP related toxicities e.g. by pharmacogenomics. The molecular CR rates after dose escalation are promising and will hopefully turn out into an improved overall survival. Supported by supported by Deutsche Krebshilfe 70-2657-Ho2 and partly BMBF 01GI 9971 and Medac GmbH