ALBERT

Description: Abstract 324 Introduction and classification: This is the largest adult T-ALL cohort treated according to immunologic subtypes. All patients were immunophenotyped in one central lab (Berlin). T-ALL (cyCD3+, CD7+) were subclassified into early T-ALL (sCD3-, CD1a-), thymic T-ALL (sCD3-/+, CD1a+) and mature T-ALL (sCD3+, CD1a-). T-ALL constitutes in 3 consecutive GMALL-studies 24% of ALL patients. Patients and methods: A total of 744 T-ALL pts (15 to 55 yrs) were accrued in 102 hospitals in the GMALL studies 05/93, 06/99 and 07/2003. In GMALL 05/93 239 adult T-ALL patients, were treated according to a multi-agent chemoprotocol. Stem cell transplantation (SCT) was not recommended in CR1. In GMALL studies 06/99 and 07/03 505 T-ALL pts received intensified chemotherapy; particularly with introduction of PEG-asparaginase in induction as well as HDMTX/PEG-Asp consolidation cycles. Based on study 05/93 results, SCT from sibling (Sib) as well as matched unrelated (MUD) donor in CR1 was recommended for all patients with early T-ALL, mature T-ALL and for high-risk (HR) pts with thymic T-ALL (defined as late CR, complex karyotype or MRD positivity (MRD+)). Results: T-ALL subtype distribution in the total cohort of 744 adult T-ALL was early-T 23% (N=170), thymic-T 56% (N=420), mature-T 21% (N=154), without any differences between the studies. GMALL Study 05/93: The overall CR rate was 86% (early-T 72%, thymic-T 93%, mature-T 84%. The lower CR rate in early T-ALL was mainly due to early death (19%). The overall CCR rate was 47% (early-T 45%, thymic-T 54%, mature-T 30%). The overall survival rate at 10 yrs for all pts was 47% (early-T 47%, thymic-T 55%, mature-T 25%). GMALL Study 06/99 and 07/03: Of the 505 patients, 87% achieved CR (early-T 84%, thymic-T 92%, mature-T 77%). PR/Failure was higher in early-T (13%) and mature-T (17%) compared to thymic-T (5%). Early death was 4% and equally distributed. 267 pts (64%) received chemotherapy only and the majority were 229 pts (86%) with thymic T-ALL, not considered for SCT in CR1. The CCR rate was 61%. The few early (n = 15) and mature (n = 23) T-ALL pts, which could not have a transplant in CR1, are a negative selection (e.g. early relapse, comorbidity, no donor) and their CCR rate was 33% and 22% respectively. This was due to a high relapse rate in early T-ALL (60%) and mature-T (74%) compared to 33% in thymic-T. Overall survival rate at 8 yrs for thymic T-ALL with chemotherapy was 68%, for the 77 adolescent pts (15 to 25 yrs) even 76%. Stem cell transplantation: 153 T-ALL pts in studies 06/99 and 07/03 received a SCT in first remission. SCT realisation rate in early T-ALL was 84%, in mature-T 68%. Overall CCR rate was 58% (early-T 47%, HR thymic-T 79%, mature-T 61%). Relapse rate after SCT was in early-T 33% and in mature-T 22%. The overall TRM rate was 18% despite more than half MUD SCT, without any TRM difference between the immunological subtypes. Overall survival rate after SCT in CR1 at 8 yrs was 53%, early-T 44%, thymic-T 67%, mature-T 59%. SCT modalit: 49% received alloSib, 55% alloMUD and 20% auto-SCT. Overall CCR rate after alloSib for the total cohort was 65% (early-T 60%, thymic-T 73% and mature-T 69%); for alloMUD total 55% (early-T 45%, thymic-T 77%, mature-T 61%) and for the small cohort of 20 pts with auto-SCT CCR was 35%. Conclusion: The strategy in three consecutive GMALL studies to stratify and treat adult T-ALL pts according to the immunologic T-subtypes was successful. Overall survival at 5 yrs could be improved to 56% from 44%. There was a particular improvement for mature T-ALL (49% vs. 30%) and early-T (40% vs. 33%). This was mainly due to a high realisation rate of SCT in early T-ALL and mature T-ALL and the substantial better results of SCT. Results of alloMUD SCT were comparable to alloSib SCT. The small cohort of HR thymic T-ALL pts also had a benefit from SCT. The excellent outcome of SR thymic T-ALL (∼ 50% of all T-ALL) with the OS of 68% and 76% in adolescents due to intensified chemo, partic. PEG-Asp, does not suggest SCT in CR1. Several molecular markers, such as ERG, BAALC, WT1, had in a retrospective analysis some prognostic relevance in this pt cohort. The new GMALL study generation will however focus in thymic T-ALL on early evaluation of MRD to decide for SCT (MRD+) or not (MRD-) whereas early/mature T-ALL remain allocated to high risk groups with SCT in CR1. Supported by Deutsche Krebshilfe 702657Ho2 and BMBF 01GI9971/8 Disclosures: No relevant conflicts of interest to declare.

Description: Background: Many patients (pts) with myelodysplastic syndromes (MDS) [particularly those with Low- or Int-1-risk] are susceptible to iron overload from ongoing blood transfusions and increased dietary iron absorption. Deferasirox (Exjade®) has shown efficacy in maintaining or reducing body iron (assessed by liver iron concentration [LIC] and serum ferritin [SF]) in MDS pts. More recently, the efficacy and safety of deferasirox in pts with various underlying anemias, including MDS, was evaluated in the large EPIC study. Data for MDS pts are presented here. Methods: The EPIC study was a 1-yr, openlabel, single-arm, multicenter trial. Pts with transfusion-dependent MDS and SF ≥1000 ng/ mL, or SF 20 transfusions or 100 mL/kg of blood and an R2 MRI-confirmed LIC 〉2 mg Fe/g dry weight (dw), received an initial deferasirox dose of 10–30 mg/kg/day. SF was assessed monthly and protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 mths based on SF trends and safety markers. Primary efficacy endpoint was the change in SF from baseline at 12 mths. Safety assessments included monitoring of adverse event (AE) and laboratory parameters. Results: 341 MDS pts (204 M, 137 F; mean age 67.9 yrs, range 11–89 yrs) with median baseline SF of 2730 (range 951–9465) ng/mL were enrolled. Mean transfusion duration was 3.6 yrs, and pts received a mean of 116.4 mL/kg of blood in the previous yr. Almost half (48.4%) of all pts had not received any prior chelation therapy; 40.0% had previously received deferoxamine (DFO), 4.1% deferiprone, 7.0% combination DFO/ deferiprone, and 0.3% other therapy. Overall, mean actual dose of deferasirox over 1 yr of treatment was 19.2±5.4 mg/kg/day. At 12 mths, there was a significant reduction in median SF from baseline (by LOCF: –253.0 ng/mL; P=0.0019). Median SF (range) ng/mL values at baseline, 3, 6, 9 and 12 mths were 2729.5 (951–9465; n=336), 2358.0 (534–46569; n=263), 2209.5 (357–10066; n=230), 2076.0 (358–25839; n=197) and 1903.5 (141–10155; n=174), respectively. Overall, 48.7% of pts (n=166) discontinued therapy. Reasons for withdrawal included AEs [n=78, 23% (n=44, 13% for drug-related AEs)], consent withdrawal (n=33, 10%), unsatisfactory therapeutic effect (n=6, 2%), lost to follow-up (n=2, 33% above baseline (in normal range), 10.6% had two values above ULN, and 24.9% had both two consecutive values 〉33% and 〉ULN; 19 pts had dose decreases and 10 dose interruptions due to abnormal creatinine; there were no progressive increases. One patient (10xULN on two consecutive visits. Conclusions: In this large cohort of MDS pts with iron overload, deferasirox provided significant reduction in SF levels over 1-yr treatment with appropriate dose adjustments every 3 mths based on SF trends and safety markers. The AE profile in this study is consistent with previously reported deferasirox data in MDS pts. The discontinuation rate was higher in this subgroup. Investigations are ongoing to assess possible contributing factors including associated comorbidities, age of pts, and others.

Description: In the recent years T-ALL/LBL has turned to a favourable subtype of adult ALL due to intensive chemotherapy and/or SCT in first CR. At relapse, however, the disease is highly refractory and rapidly progressive. In the GMALL study 05/93 in ‘early’ relapse during therapy the CR rate with HD regimens was 29% and the survival 8%. The major problem was achievement of CR in order to proceed to SCT. Therefore the T-cell specific purine analogue compound GW506U78 (NSC 686673, Nelarabine) was evaluated. The compound was provided by the National Cancer Institute and administered as single drug (1.5 g/m2 day 1,3,5) in 53 adult pts. The median age was 31 (19–81) yrs. 47 (89%) had T-ALL and 6 T-LBL. 44 presented BM and 9 only extramedullary involvement. All pts had heavily pretreated, refractory disease. 36 (68%) were included in 1st ‘early’, 7 (13%) in 2nd relapse, 7 (13%) in relapse after SCT. 3 (6%) had never obtained CR. 32/36 pts in 1st relapse were refractory to 〉= one HD salvage therapy (FLAG-IDA 5, Cladribine/VP16/HDAC 18, other HDAC/HDMTX based 9). 25/53 evaluable pts (47%) achieved CR, 7 PR (13%) and 21 (40%) were refractory. The highest CR rate was achieved in pts with thymic T-ALL (76%). 19/25 CR pts (76%) were rapidly transferred to SCT (4 sibling, 14 MUD, 1 auto). Median time to SCT was 41 (20–83) d. 7/25 CR pts are in continuous CR at median 13 (1–36) mo. 4 pts died in CR (1 sepsis/liver failure, 3 transplant related). 14 pts relapsed, 10 after SCT. Time to relapse was median 5 (1–8) mo. 2 pts developed AML in relapse after SCT. 10 pts were included in the programme a second time, 8 in relapse after SCT. 4 CRs, 1 subjective improvement and 5 failures were observed. The probability of survival in the whole cohort is 16%, but significantly higher in pts who achieved CR (27%). Moderate bone marrow suppression and elevated liver enzymes were the most frequent toxicities. Neurotoxicity was encountered in only two pts (reversible psychosyndrome with agitation and somnolence). We conclude that the compound has a impressive single drug activity in highly resistant relapsed T-ALL and is well tolerated even in heavily pretreated pts. Exploration in earlier stages e.g. molecular relapse, in front-line therapy and in combination is warranted. Since a durable remission cannot be expected with chemotherapy a high proportion of CR pts was transferred to SCT. Importantly no unexpected mortality or morbidity was observed after SCT. Long-term relapse free survival was achieved in some pts. The major problem were relapses. Therefore a better remission quality and lower tumor load before SCT should be obtained e.g. by consolidation cycles with the compound. After SCT close monitoring should aim for early detection of beginning relapse by MRD analysis in order to decide on interventions e.g. reduction of GvHD prophylaxis, donor lymphocyte infusions or additional cycles with the compound.Partly supported by Deutsche Krebshilfe (M84/92Ho1), NCI/CTEP and GlaxoSmithKline

Description: In 1999 the German Multicenter Study Group for Adult ALL (GMALL) activated a pilot study (GMALL 06/99). One major aim was to develop a new, shortened and intensified induction regimen based on the following new principles compared to previous GMALL trials: 1) Dexamethasone (DEXA) instead of prednisone to improve antileukemic activity and prophylaxis of CNS relapse 2) prephase with cyclophosphamide (CYCLO) 3) G-CSF parallel to chemo 4) intensified daunorubicin with two 2day cycles (DNR) vs 4 wkly applications 5)1 dose PEG-L-Asparaginase (ASP) instead of 14 d conventional ASP Induction I was followed by GMALL induction phase II as previously reported and a uniform consolidation I. Remission control took place on d24 and d44. Thereafter treatment was risk adapted. Induction I consisted of DEXA, CYCLO and G-CSF. In addition pts received PEG-ASP 1000 U/m2 (d13), vincristin 2 mg (d4,11,18) and DNR 45 mg/m2 (d4+5,11+12). The regimen was modified by 3 amendments which separated the study to 4 pilot phases. The major modifications referred to reduction of DEXA/CYCLO and earlier application of G-CSF. Table 1: Major modifications of induction phase I Drug Pilot 1 Pilot 2 Pilot 3 DEXA 40 mg/m2 (d1–3) 10 mg/m2 (d4–17) 10 mg/m2 (d 1–6,11–16) 10 mg/m2 (d 1–5,11–14) CYCLO 200 mg/m2 (d1–3) none none G-CSF from d13 from d4 from d4 Overall 843 pts were included between 4/99 and 10/03. The median age was 36 (15–65) yrs. Subtypes distribution was c-/pre B 65%, pro B 8%, early T 8%, thymic 14%, mature T 6%. 23% had Ph/BCR-ABL+ ALL. The overall CR rate was 83%, with 12% failure/PR and 7% early death (ED). Significant differences were detected for the pilot phases (p=.0008). The high mortality in pilot I was mainly due to infections. With lower doses of DEXA the rate of ED (p=.0002) and severe infections decreased significantly whereas the failure rate increased slightly. The earlier application of G-CSF contributed to a significant decrease of grade III/IV granulocytopenias and probably also mucositis. Table 2: Results and major toxicities (grade III/IV) of induction therapy Pilot 1 Pilot 2 Pilot3 P Evaluable 103 100 605 CR 76% 83% 82% .0008 PR/Failure 9% 9% 14% ED 16% 8% 5% Survival (3y) 45% 47% 47% 〉.05 Granulopenia 84% 72% 69% .008 Median duration 17d 15d 12d

Description: Introduction: In older patients with AML in whom conventional chemotherapy is not indicated (comorbidities, performance status, poor cytogenetics etc.), treatment with low-dose azanucleoside DNA demethylating agents may be a less intensive alternative. In MDS, these drugs need to be administered over a prolonged time period in order to gain full benefit, since delayed responses are common, and thus occur not infrequently after more than 6 months of treatment. In a phase II multicenter trial (00331) of low-dose decitabine (DAC, 135 mg/m2 administered over 3 days in 9 intravenous 3-hour infusions, with 15 mg/m2/infusion, repeated every 6 weeks) patients benefiting from this treatment were offered an outpatient maintenance with the drug given at an even lower dose and as one-hour infusions on 3 consecutive days. Patients and Methods: Patients having completed 4 courses of DAC according to the study protocol and being in complete or partial remission (CR, PR), having achieved an antileukemic affect or stable disease were offered continued DAC treatment with 20 mg/m2 given intravenously over one hour on 3 consecutive days, repeated every 6 to 8 weeks. Maintenance treatment was continued until relapse or progression. Results: Of the 235 patients included in the 00331 study, 57 (25%) received the 3-day DAC maintenance. Median age of these 57 patients before study inclusion was 71 years (range 60 – 81), the median white blood count 4200/μl (range 0.2–285,000/μl), 59% had preceding MDS, with a median of 16 months duration. Performance status before initial treatment with DAC: ECOG 0, 1 and 2 in 29%, 58% and 13% of the patients, respectively. 60% had intermediate-risk cytogenetics, 28 % poor-risk cytogenetics, no metaphases were obtained or cytogenetics not done in 12 %. Remission status at maintenance start, i.e. response to 4 courses of DAC, was CR+PR in 71 % of the patients. A median number of 4 maintenance courses was administered (range, 1–16), with 24 patients (42 %) receiving 5 or more courses. Treatment was overall very well tolerated, with dose reductions because of cytopenia necessary in

Description: Several conflicting options regarding management of adult ALL are currently discussed. One major issue is the indication for SCT depending on risk factors and age, and the other is the recommendation to use unmodified pediatric protocols for “young” adults. Decision making on SCT is generally based on conventional risk factors – mainly disease characteristics – available at diagnosis, and decision making for “pediatric” chemotherapy on age. It is essential to develop more sophisticated criteria – also to reduce the risk of selection in clinical trials. In order to enhance prognostic models and to better address individual patient characteristics and the course of disease we reanalysed conventional prognostic factors together with new patient specific factors in a large cohort of adult ALL patients. A total of 1657 well characterised pts (15–55 yrs) included in the risk stratified protocols of the German Multicenter Study Group (GMALL) 06/99 and 07/03 was analysed. Treatment and risk stratification have been described (Brüggemann, Blood2006: 107;1116). Age remained a highly significant factor for CR, survival (OS) and disease free survival (DFS). OS ranged from 58% for 15–25 yrs, 52% for 26–35 yrs, 43% for 36–45 yrs to 32% for 45–55 yrs (p=.0001). Poorer outcome with increasing age was mainly due to early death (ED) and death in CR. CR, OS (45% c/pre-B, 45% pro-B, 38% early T, 47% mature T and 64% thymic T;p

Description: Differentiation arrest in acute myeloid leukemia (AML) results in part from dysregulation of histone acetylation and deacetylation, leading to transcriptional repression of differentiation-inducing genes. Transcriptional repression can be returned by histon deacetylation inhibitors, such as valproic acid (VPA). In September 2004, we initiated two randomized trials [AMLSG 07-04 (age 18–60 yrs), AMLSG 06-04 (age 〉60yrs)] to evaluate the impact of VPA as adjunct to standard induction therapy (idarubicin and cytarabine; additional etoposide in pts.

Description: Abstract 2185 Background: Secondary (s)AML from MDS is more frequent in older AML patients, and associated with an overall worse outcome with standard chemotherapy than de novo AML, particularly after MDS of longer duration (1). The azanucleoside hypomethylating agents 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine (Decitabine, DAC) are active in MDS and, as recently shown, also AML. Compared to other predictors of response to these drugs, MDS duration prior to treatment thus far has received only limited attention, with two recent publications reporting conflicting results (2, 3). To independently validate our finding that shorter duration of MDS prior to DAC treatment may be a novel predictor of poor outcome (2, 4), we now applied this parameter to a large trial of low-dose DAC in AML pts (aged 〉60 years and judged ineligible for standard induction chemotherapy), about half of them with sAML from MDS with variable disease duration. Patients and Methods: Comparisons of response rate (RR, i.e. CR or PR) and overall survival (OS) from start of treatment according to MDS duration (pre-specified categorization according to quartiles) were performed post-hoc in 109 patients (pts) with previously untreated sAML (median age 72 years) treated with DAC (given over 72 hours, every 6 weeks, for up to 4 courses, followed by “maintenance” with 3 daily 1-hour infusions of DAC 20 mg/m2 every 4–6-weeks). Median WBC prior to treatment was 5.200/μl, median serum LDH 279U/l, 31.2% of pts had adverse cytogenetics, 82.6% had a performance status 〉 1, and 80.7% had a comorbidity index (HCT-CI) 〉=1. Comparisons by logistic regression and Cox regression (univariate and multivariate, adjusted for other prognostic factors showing an effect in this population of sAML pts) were performed. Results: Of the 227 AML patients treated within the 00331 trial, 109 (48%) had prior MDS with known MDS duration, with a median duration of 8 (25% quartile 3, 75% quartile 25, range 1–101) mths. The overall RR in these pts was 26/109 (24%), the overall 1 yr OS rate was 31% (94 deaths). A comparison of RR according to MDS duration revealed a trend to an increase in RR with longer duration of MDS [=25 mths: 10/28 (36%), test for heterogeneity p=0.29, test for trend p=0.06]. Similarly, when OS from start of DAC was analyzed according to this parameter, for pts with previous MDS of longer duration there was a trend to better outcome [=25 mths: 46%, test for heterogeneity p=0.17, test for trend p=0.16]. When these analyses were adjusted for other prognostic factors showing an effect in this population of sAML pts (comorbidity index, sLDH with respect to RR, and performance status, comorbidity index, and white blood count with respect to OS), the results were similar (effect of MDS duration with respect to RR: test for heterogeneity p=0.35, test for trend p=0.06, and effect of MDS duration with respect to OS: test for heterogeneity p=0.04, test for trend p=0.11). Conclusion: In this large cohort of uniformly treated pts with sAML, MDS of longer duration appeared to be associated with a better outcome, even after adjusting for important other prognostic factors. These results are supported by a similar analysis of MDS pts randomized in the 06011 EORTC intergroup trial (which compares DAC to Best Supportive Care), where MDS patients with longer (〉=3 mths) disease duration prior to treatment also had better outcome (4). They warrant application of this discriminator in the evaluation also of other non-intensive AML treatment modalities. References 1. Estey et al., Blood 90:2969-77, 1997 2. Wijermans et al., Ann. Hematol. 84 Suppl 1:9-14, 2005 3. Kantarjian et al., Cancer 109:265-73, 2007 4. Lübbert, Suciu et al., Abstract submitted, ASH 2010 Disclosures: Off Label Use: decitabine is FDA-approved for treatment of MDS and AML with up to 30% blasts. In the present study, patients with AML and higher blast percentage were treated. Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Döhner: Pfizer: Research Funding.

Description: Inhibitors of histone deacetylases (HDACIs) like valproic acid (VPA) display activity in murine leukemia models, and induce tumor-selective cytoxicity against blasts from patients with acute myeloid leukemia (AML). However, despite of the existing knowledge of the potential function of HDACIs, there remain many unsolved questions especially regarding the factors that determine whether a cancer cell undergoes cell cycle arrest, differentiation, or death in response to HDACIs. Furthermore, there is still limited data on HDACIs effects in vivo, as well as HDACIs function in combination with standard induction chemotherapy, as most studies evaluated HDACIs as single agent in vitro. Thus, our first goal was to determine a VPA response signature in different myeloid leukemia cell lines in vitro, followed by an in vivo analysis of VPA effects in blasts from adult de novo AML patients entered within two randomized multicenter treatment trials of the German-Austrian AML Study Group. To define an VPA in vitro “response signature” we profiled gene expression in myeloid leukemia cell lines (HL-60, NB-4, HEL-1, CMK and K-562) following 48 hours of VPA treatment by using DNA Microarray technology. In accordance with previous studies in vitro VPA treatment of myeloid cell lines induced the expression of the cyclin-dependent kinase inhibitors CDKN1A and CDKN2D coding for p21 and p19, respectively. Supervised analyses revealed many genes known to be associated with a G1 arrest. In all cell lines except for CMK we examined an up-regulation of TNFSF10 coding for TRAIL, as well as differential regulation of other genes involved in apoptosis. Furthermore, gene set enrichment analyses showed a significant down-regulation of genes involved in DNA metabolism and DNA repair. Next, we evaluated the VPA effects on gene expression in AML samples collected within the AMLSG 07-04 trial for younger (age60yrs), in which patients are randomized to receive standard induction chemotherapy (idarubicine, cytarabine, and etoposide = ICE) with or without concomitant VPA. We profiled gene expression in diagnostic AML blasts and following 48 hours of treatment with ICE or ICE/VPA. First results from our ongoing analysis of in vivo VPA treated samples are in accordance with our cell line experiments as e.g. we also see an induction of CDKN1A expression. However, the picture observed is less homogenous as concomitant administration of ICE, as well as other factors, like e.g. VPA serum levels, might substantially influence the in vivo VPA response. Nevertheless, our data are likely to provide new insights into the VPA effect in vivo, and this study may proof to be useful to predict AML patients likely to benefit from VPA treatment. To achieve this goal, we are currently analyzing additional samples, and we are planning to correlate gene expression findings with histone acetylation status, VPA serum levels, cytogenetic, and molecular genetic data.

Description: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 25% of adult ALL and is characterised by specific clinical and biologic features such as phenotype with early (cyCD3+,CD7+) (E-T), thymic (CD1a+) ) (Thy-T) and mature T-ALL (M-T) (sCD3+). The formerly poor prognosis of T-ALL was more recently improved in some studies albeit not in all, even not in childhood ALL. Patients: To improve outcome of T-ALL the German Multicenter Study Group for Adult ALL initiated two consecutive studies with subtype adapted therapies. 503 T-ALL pts were recruited between 4/93 and 10/03. The median age was 30 (15–55)yrs, 75% were male, 66% had mediastinal tumor (MedTu), 24% WBC 〉 100.000 and 7% CNS involvement with subtypes as follows: 53% Thy-T, 26% E-T and 21% M-T. Study Design: In Study 05/93 all T-ALL pts were treated uniformly with 8drug induction incl. prophylactic CNS (24 Gy) (CNSRAD) and proph. mediastinal (24 Gy) irradiation (MEDRAD) followed by 7x consolidation (HDAC/MITOX, HDMTX/ASP, reinduction, 2xVM26/AC, 2xCYCLO/AC) and maintenance (6MP/MTX). In Study 06/99 treatment of T-ALL was risk adapted with a shortened, intensified 8drug induction (CNSRAD in all but MEDRAD only in pts with residual MedTu after induction) followed by consolidation I (HDAC/HDMTX/VP16). Thy-T was then treated as standard risk with 6x consolidation (3xHDMTX/ASP,reinduction,VM26/AC,CYCLO/AC). E-T and M-T were considered as high risk and scheduled for stem cell transplantation (SCT) in CR1. Results: In Study 05/93 the CR rate in 291 pts was 89% (94%, 73% and 90% for Thy-T, E-T and M-T; p=.0006) and even 97% for Thy-T in adolescents (15–25 yrs) . Overall 4% failed to achieve CR and 7% died in induction. The probability of continuous CR (CCR) at 5 yrs was overall 53% and 64% for Thy-T, but only 30% (p