Several groups have reported results from smaller series of AYAs with ALL. Outcomes with so-called protocols for adults were generally inferior compared to so-called pediatric protocols. The GMALL protocols were originally based on pediatric BFM protocols and have been consecutively optimized for adults since 1981. We report the results of two recent protocols 05/93 (Goekbuget et al, Blood 98(11):802a, 2001) and 07/03 (Goekbuget et al, Blood 110(11):12a, 2007). In study 07 high risk (HR) pts were identified by one of the factors: B-lin with WBC>30.000, late CR (>3 wks), pro-B, early T, mature T, MLL1/AF4/t(4;11). Pts without risk factors were standard risk (SR) and those with BCR-ABL/t(9;22) very high risk (VHR). HR/VHR pts were candidates for SCT in CR1. The major innovations in study 07 were: intensified, shortened induction with dexamethasone instead of prednisone, PEG-asparaginase (ASP) instead of native ASP, intensified first consolidation, 6x HDMTX/ASP during consolidation, matched unrelated SCT for HR/VHR pts without sibling donor and SCT indication in pts with persistent MRD. After amendments in trial 07 pts partly also received intensified PEG-ASP, rituximab in CD20+ ALL and imatinib in Ph+ ALL. Overall, 1529 of 3060 (50%) pts recruited into both trials were aged between 15-35 yrs. 642 pts from 94 centres were recruited to study 05 and 887 pts from 130 centres to study 07. Patient characteristics were similar for both trials. 70% had B-Lin and 30% T-ALL (61% c/preB, 9% proB, 7% early T, 6% mature T, 17% thy T) with no significant differences across age subgroups (15-17,18-25 and 26-35 yrs). Allocation to SR, HR and VHR was 51%, 35% and 14%. VHR incidence increased from 3%, 11% to 19% in age groups (p<.0001). The CR rate increased in studies 05 to 07 from 88% to 91% (p=.001), most prominently within the age range of 26-35 yrs (86% to 90%;p=.001) (table). The OS increased from 46% to 65% (p<.0001) (significant in all age groups). Remission duration (RD) at 5 yrs increased from 49% to 61% (p=.0001), most prominently within the age range of 26-35 yrs (46% vs 59%; p=.005). OS improved from study 05 to study 07 in B-Lin (45% vs 66%; p<.0001) and T-ALL (47% vs 63%; p=.0007) overall and in subgroups as c/pre B (50% vs 68%;p<.0001), pro B (45% vs 67%;p=.05), mature T (19% vs 61%; p=.005) and thymic T (59% vs 70%;p=.09) but to a lesser extent in early T (35% vs 48%;p>.05). OS increased in SR (58% to 74%; p<.0001), HR (24% to 58%; p<.0001) and VHR (36% vs 55%;p=.0003).Table 1Results of Induction and Overall Outcome in GMALL-Studies 05/93 and 07/0305/9307/03Total15-1718-2526-35Total15-1718-2526-35Evaluable64210625238488753458376CR88%91%88%86%91%94%91%90%ED3%1%3%3%4%0%3%6%Failure9%8%8%11%5%6%5%4%RD at 5y49%52%50%46%61%60%62%59%OS at 5y46%57%45%42%65%73%69%60% 15% vs 43% of all CR pts underwent SCT in CR1 in studies 05 and 07. The proportion of SCT increased from 22% to 68% (p<.0001) in HR and from 62% to 73% (p<.0001) in VHR in studies 05 vs 07. The OS after SCT improved from 36% to 68% (p<.0001), mainly due to a decrease of TRM from 34% to 12% (p<.0001). In trial 07 MRD in week 16 (after consolidation I) was tested in 353 pts. The proportion of molecular failure (MRD>0.01%) was 26% with no differences across age groups. OS was 90% in pts with mol. CR vs 53% in mol. failure (p<.0001). Amendments in study 07 led to further improvement with an OS of 71% in 274 pts aged between 15-35 yrs treated according to the final protocol version. We present here results of the so far largest cohort of AYA ALL pts treated according to pediatric-derived adult ALL protocols. Outcomes have significantly improved and reached a 73% OS in pts aged 15-17 yrs. Intensified treatment with ASP, MTX and targeted therapies as rituximab and imatinib and MRD based stratification have contributed to the improvement in study 07. SCT led to improved OS in HR and VHR ALL. Obviously, there is no indication for SCT in CR1 in young SR pts with an OS of 74%. Future GMALL studies will attempt to optimize further the combination of pediatric approaches and targeted therapies in adults. Supported by Deutsche Krebshilfe 70-2657-Ho2 and partly BMBF 01GI 9971. Disclosures: Off Label Use: RItuximab in ALL.

LBL is a rare subtype of NHL and mostly displays a T-cell phenotype. The WHO classification combines acute lymphoblastic leukemia (ALL) and LBL; pts with ≥ 25% bone marrow (BM) infiltration are considered as ALL. LBL pts are usually treated according to ALL protocols and sometimes reported within ALL trials. There are however specific clinical and management questions, such as role of mediastinal irradiation (MedRad), optimal remission evaluation or risk stratification and there is a lack of prospective trials in LBL. The German Multicenter Study Group for Adult (GMALL) has reported results on 45 T-LBL pts (Hoelzer et al, Blood 2002). Based on this experience a prospective T-LBL trial was activated (cohort I) followed by a prospective registry with documentation of pts treated according to an GMALL expert recommendation (cohort II). Therapy was based on the GMALL trial for ALL (07/2003) with a prephase (Dexa, Cyclo), induction I (Dexa, VCR, Dauno, PEG-Asparaginase) and induction II (Cyclo, ARAC, Mercaptopurine) together with CNS irradiation and i.th. prophylaxis. MedRad (36 Gy) was scheduled after induction and followed by consolidation (cons) I (VCR, Dexa, VP16, HDMTX, HDARAC), cons II, III, VI (HDMTX/PEG-ASP), reinduction, cons IV (HDARAC) and V (CYCLO/ARAC). Salvage therapy was recommended in pts without CR/CRu after cons I. Essential time-points (TP) for remission evaluation were after induction II (TP1), after MedRad (TP2 in cohort I only) and after cons I (TP3). For cohort II MedRad was omitted and PET analysis was recommended in CRu or PR at TP3. 149 pts (cohort I:101; cohort II: 48) from 64 hospitals were included between 9/04 and 1/13. The median age was 31 (17-62) yrs. 73% were male. 93% had mediastinal involvement, 61% pleural and 34% pericardial effusion, 18% BM and 2% CNS involvement. 59% had stage III-IV disease. 63% had a thymic subtype (N=66) and 37% had an early or mature T phenotype (N=39). Results of response evaluation according to standard procedures (excluding PET) are given in table 1. CR/CRu rates increased from 34% to 59% and 76% through TP1-3. 96% had CR,CRu or PR as best response at TP1-3. Positive PET results at TP3 were detected in 0/21 pts with CRu and 10/22 (45%) pts with PR (p=0.001). Overall survival (OS) was 65% at 5 yrs. 3 yr OS appeared superior in cohort II vs cohort I (76% vs 67%; p>0.05), due to a lower relapse rate (15% vs 31%;p=0.07) but at shorter median follow-up (1.9 vs 5.6 yrs). 2% died in CR. No difference was observed in terms of 5y OS for pts with CR, CRu or PR, 71%, 82% and 75% resp (p>0.05). In the majority of PR pts therapy was continued per protocol. 5y OS was slightly superior for pts with thymic (N=66; 78%) vs early/mature (N=39; 58%) subtype (p>0.05). Pts <> 25 yrs had 5 yr OS rates of 75% vs 60% resp. (p=.09); stage , BM involvement and aaIPI had no significant impact on OS. Pts with early achievement of CR/CRu (TP1) had a slightly better OS (N=49; 69%) compared to those with PR/Failure (N=95; 65%) (p=.09). Overall 26% of the pts relapsed (42% BM±other, 11% CNS+other, 8% CNS only, 40% lymph node or extramedullary only). The proportion of mediastinal relapses did not increase in cohort II vs cohort I (24% vs 17%). This is the largest so far reported cohort of prospectively treated adult patients with T-LBL. The response rate including PR was high (96%). Response evaluation was challenging since many patients showed persistent residual mediastinal tumors (CRu/PR) and responses formally evolved slowly. Conventional remission evaluation had limited clinical relevance as indicated by similar OS of CR, CRu and PR pts. PET evaluation yielded positive results in 45% of the PR pts and may be helpful for decision making on salvage therapies. The omission of MedRad did not impact relapse risk and may have contributed to better feasibility of dose intense chemotherapy. Whereas pts with early/mature phenotype and older pts had a trend towards poorer OS other factors did not significantly influence outcome. In the future additional prognostic factors like minimal residual disease evaluation may help to identify patients with potential benefit from salvage therapy and/or stem cell transplantation (supported by the Jose Carreras Foundation; Grant: Ho9/01f) Table 1: Results of Remission Induction TP1 (after induction) TP2*(after irradiation) TP3 (after consolidation) Best response Evaluable 148 86 138 149 CR 22% 33% 63% 60% CRu 12% 26% 13% 13% PR 62% 35% 15% 23% Failure 3% 2% 6% 1% Early death 3% 5% 3% 3% * Cohort 1 only Disclosures No relevant conflicts of interest to declare.

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BackgroundNeuronal plasticity leading to evolving reorganization of the neuronal network during entire lifespan plays an important role for brain function especially memory performance. Adult neurogenesis occurring in the dentate gyrus of the hippocampus represents the maximal way of network reorganization. Brain radio-chemotherapy strongly inhibits adult hippocampal neurogenesis in mice leading to impaired spatial memory.MethodsTo elucidate the effects of CNS radio-chemotherapy on hippocampal plasticity and function in humans, we performed a longitudinal pilot study using 3T proton magnetic resonance spectroscopy (1H-MRS) and virtual water-maze-tests in 10 de-novo patients with acute lymphoblastic leukemia undergoing preventive whole brain radio-chemotherapy. Patients were examined before, during and after treatment.ResultsCNS radio-chemotherapy did neither affect recall performance in probe trails nor flexible (reversal) relearning of a new target position over a time frame of 10 weeks measured by longitudinal virtual water-maze-testing, but provoked hippocampus-specific decrease in choline as a metabolite associated with cellular plasticity in 1H-MRS.ConclusionAlbeit this pilot study needs to be followed up to definitely resolve the question about the functional role of adult human neurogenesis, the presented data suggest that 1H-MRS allows the detection of neurogenesis-associated plasticity in the human brain.

Cytarabine is an effective drug in the treatment of haematological malignancies. The therapy is associated with various complications. Frequencies of dermatological side-effects range from 2–72% and occur most commonly after high-dose regimens. Although most cutaneous reactions are mild and resolve spontaneously within several days, they may result in an increased risk of infection and alterations in comfort. In some cases, severe life-threatening reactions have been reported. Here we describe the case of a patient with acute myeloid leukaemia, who developed severe exceptional skin toxicity in terms of auricular oedema and palmar dyshidrotic eczema after the application of low-dose cytarabine. Re-administration of the drug resulted in reduced skin toxicity during further cycles of chemotherapy. Negative epicutaneous patch-testing supported the existence of cytarabine-provoked toxicity.