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Hemophagocytic lymphohistiocytosis (HLH) is a rare but often fatal hyperinflammatory syndrome caused by an inborn or acquired error of immunity. In adults, the underlying immunodeficiency generally arises alongside severe infections, malignancies, autoimmune diseases, and immunosuppressive treatment. To analyze risk factors and outcome in adults, we conducted a multicenter retrospective study. A total of 62 adult (age ≥18 years) patients met at least one of the following inclusion criteria: (1) ≥5 of 8 HLH-2004 criteria, (2) HScore ≥ 200 plus 4 HLH-2004 criteria, or (3) mutation compatible with an HLH diagnosis. Most patients (65%) were male, and the median age at diagnosis was 53.5 years (range, 19-81 years). All patients were assigned to 4 etiologic subgroups based on their most likely HLH trigger. The survival probability of the 4 etiologic subgroups differed significantly (P = .004, log-rank test), with patients with an underlying malignancy having the worst clinical outcome (1-year survival probability of 21%). The parameters older age, malignant trigger, elevated serum levels of aspartate transferase, creatinine, international normalized ratio, lactate dehydrogenase, sCD25, and a low albumin level and platelet count at treatment initiation were significantly (P < .1) associated with worse overall survival in the univariate Cox regression model. In multivariate analysis, sCD25 remained the only significant prognostic factor (P = .005). Our results suggest that sCD25 could be a useful marker for the prognosis of patients with HLH that might help to stratify therapeutic interventions.

Aim The aim of this retrospective observational study was to determine how response times correlated to the experience of the community first responders (CFRs) using data collected from the Danish Island of Langeland via a global positioning system (GPS)-based system. Methods All medical emergency calls involving CFRs in the time period from 21st of April 2012 to 31st of December 2017 were included. Each emergency call activated 3 CFRs. Response times were calculated using the time from when the system alerted the CFRs to CFR time of arrival at the emergency site measured by GPS. CFRs response times were grouped depending on their level of experience according to ≤ 10, 11–24, 25–49, 50–99, ≥ 100 calls accepted and arrived on-site. Results A total of 7273 CFR activations were included. Median response time for the CFR arriving first on-site (n = 3004) was 4:05 min (IQR 2:42 − 6:01) and median response time for the arrival of the CFR with an automated external defibrillator (n = 2594) was 5:46 min (IQR 3:59 − 8:05). Median response times were 5:53 min (3:43 − 8:29) for ≤ 10 calls (n = 1657), 5:39 min (3:49 − 8:01) for 11–24 calls (n = 1396), 5:45 min (3:49 − 8:00) for 25–49 calls (n = 1586), 5:07 min (3:38 − 7:26) for 50–99 calls (n = 1548) and 4:46 min (3:14 − 7:32) for ≥ 100 calls (n = 1086) (p

The heterogeneity of early stage CLL challenges prognostication, and refinement of prognostic indices for risk-adapted management in this population is essential. The aim of the multicenter, prospective CLL1 trial was to explore a novel prognostic model (CLL1-PM) developed to identify risk groups, separating patients with favorable from others with dismal prognosis. A cohort of 539 clinically, biochemically, and genetically characterized Binet stage A patients were observed until progression, first-line treatment, or death. Multivariate analysis identified six independent factors associated with overall survival (OS) and time-to-first treatment (TTFT): del(17p), unmutated IGHV, del(11q), ß2-microglobulin3.5 mg/dL, lymphocyte doubling time (LDT)12 months, and age60 years. These factors were integrated into the CLL1-PM, which stratified patients into four risk groups. The CLL1-PM was prognostic for OS and TTFT, e.g., the risk of treatment at 5 years was 85.9, 51.8, 27.6, and 11.3% for very low (0-1.5), low (2-4), high (4.5-6.5), and very high-risk (7-14) scores, respectively (P 0.001). Notably, in addition to factors comprising CLL-IPI, we substantiated del(11q) and LDT as prognostic factors in early CLL. Altogether, our findings would be useful to effectively stratify Binet stage A patients, particularly within the scope of clinical trials evaluating novel agents.

Aims: To evaluate and compare survival after out-of-hospital (OHCA), where an automated external defibrillator (AED) was used, in densely, moderately and thinly populated areas. Also, to evaluate the association between AED retrieval distance and survival after OHCA. Methods: From 2014 to 2018, AEDs used during OHCA in the region of Southern Denmark were systematically collected. OHCAs were included if the OHCA address was known. OHCAs at nursing homes were excluded. To evaluate population density, a map with 1000 × 1000 meter grid cells was used with each cell color-graded according to the number of inhabitants. Densely, moderately and thinly populated areas were defined as ≥200 inhabitants, 20–199 inhabitants and 0–19 inhabitants per km 2, respectively. Primary outcome was 30-day survival. Results: A total of 423 cases of OHCA were included, of which 207 (49%) occurred in densely populated areas, while 78 (18%) and 138 (33%) occurred in moderately and thinly populated areas, respectively. AED retrieval distances were: densely populated 105 m (IQR 5–450), moderately populated 220 m (IQR 5–450) and thinly populated 350 m (IQR 5–1500) (P < 0.001). Thirty-day survival was 40%, 31% and 34%, respectively (P = 0.3). In a multivariable regression analysis, mortality increased with 10% per 100 m an AED was placed further away from the site of OHCA. Conclusion: Survival after OHCA, where an AED was used, did not seem to differ in thinly, moderately and densely populated areas. The length of the AED retrieval distance, however, was correlated with reduced survival after adjusting for other potentially explanatory variables.

Aims To evaluate 1) the relative use of automated external defibrillators (AEDs) at different types of AED locations 2) the percentage of AEDs crossing location types during OHCA before use 3) the AED coverage distance at different types of AED locations, and 4) the 30-day-survival in different subgroups. Methods From 2014–2018, AEDs used by bystanders during out-of-hospital cardiac arrest (OHCA) in the Region of Southern Denmark were collected. Data regarding registered AEDs was retrieved from the national AED-network. The OHCA site and AED placement was categorized into; 1) Residential; 2) Public; 3) Nursing home, 4) Company/workplace; 5) Institution; 6) Health clinic and 7) Sports facility/recreational. To evaluate 30-day-survival, groups 4–7 were pooled into one Mixed group. Results In total 509 OHCAs were included. There was high relative usage of AEDs from public places, nursing homes, health clinics and sports facilities, and low relative usage from companies/workplaces, residential areas and institutions. Of AEDs used during residential OHCAs 39% were collected from public places. AEDs placed in residential areas and public places had a coverage of 575 m (IQR 130–1300) and 270 m (IQR5-550), respectively. Thirty-day- survival in public, residential and mixed groups were 49%, 14% and 67%, respectively. Conclusion The relative use of AEDs from public places, nursing homes, sports facilities and health clinics was high, and AEDs used during OHCA in residential areas were most frequently collected from public places. AEDs placed in both residential areas and public places may have a wider coverage area than proposed in current literature.

Introduction: In T-ALL, in contrast to BCP-ALL, molecular subgroups are less well defined. Molecular subgroups are based on aberrant expression of oncogenes often resting upon structural aberrations (chromosomal translocation, copy number variations, point mutations). So far, comprehensive studies on molecular subgroups have been predominantly performed in pediatric patients. The clinical relevance of molecular characteristics is not taken into account for risk stratification and targeted therapeutic options for T-ALL patients are limited. Risk stratification is mainly based on immunophenotype and MRD response. Thus, in the German Multicenter Study Group for Adult ALL (GMALL) protocols early and mature T-ALL and molecular failure after first consolidation are high risk features. Whole RNA transcriptome sequencing (RNAseq) enables molecular subgroup allocation profiles with potential prognostic relevance. Herein, we investigated a large cohort of 161 adult T-ALL patients with RNAseq for molecular subgroups and their clinical implication. Patients and methods : RNAseq data (Illumina HiSeq 4000, 100 or 125 bp paired-end, average read count ~30 million reads/sample) were generated from 161 adult T-ALL patients from diagnostic bone marrow samples. For 84 of these T-ALL patients, we additionally investigated DNA methylation using Infinium 450k methylation bead arrays and mutation status using deep targeted DNA sequencing with a gene panel consisting of 206 genes (HiSeq 1500, 100 bp paired-end, average ~800 reads/bp). All patients were treated likewise within pediatric inspired protocols of the GMALL. Clinical follow up and outcome data were available for 129 patients aged between 18 and 55 years. Results: Based on oncogene expression, we could assign molecular subgroups to 160 out of the 161 T-ALL patients: HOXA: n=37 (23%), TLX1: n=37 (23%), TAL/LMO: n=33 (20%), LYL1/LMO2: n=31 (19%), TLX3: n=17 (11%) , NKX2-1: n=4 (2%), TAL2: n=1 (1%). Among others, gene fusion events incorporating TAL1 (n=16), HOXA (n=6), TLX1 (n=14), TLX3 (n=2) and NKX2 (n=2) were detected as underlying mechanisms. Age distribution revealed more TAL/LMO in the younger population (16-25 years: 35% versus >35 years: 3%; p=0.001) and more LYL1/LMO2 and HOXA in the older patients (16-25 years: 23% vs. >35 years: 40%; n.s.). DNA methylation analyses for 84 of the 161 patients support the molecular classification with four distinct subgroups demonstrating a homogenous methylation profile for the TLX1 driven subgroup (methylation cluster M3, n=30). In contrast, methylation cluster M2 (n=21) showed a hypomethylation in CpG islands and comprises the majority of TAL/LMO positive cases (19/21) including all samples with STIL-TAL1 fusions. M1 (n=25) and M4 (n=7) clusters comprised TLX3 (mainly cluster M1, 8/10), HOXA and LYL1/LMO2 cases. Mutation analysis showed a high rate of NOTCH1 (n=71%) mutations in the TLX1 subgroup and an increased rate of mutations in the JAK/STAT pathway (n=29%) and epigenetic regulators (n=50%) in HOXA and LYL1/LMO2 subgroups. Regarding clinical outcome, 126 out of 129 (98%) patients achieved a morphologically complete remission (CR), two patients failed CR, one patient died during induction therapy. Regarding MRD response, 12% of the investigated T-ALL patients showed a molecular failure after consolidation. Noteworthy, we found a molecular CR for 28/30 (93%) patients in the TLX1 subgroup, but only 11/19 (58%) respectively 2/6 (33%) in the HOXA and the LYL1/LMO2 subgroup. This finding results in exceptional five year-overall survival (5y-OS) of 93% in TLX1 patients. Together with the NKX2-1 subgroup (n=4, with 100% 5y-OS), these patients build a prognostically favourable risk group in the overall cohort (94% 5y-OS versus 76% in TAL-LMO patients versus 62% in all other subgroups, p=0.007). This result could not only be found in the overall cohort, but also within the already good risk subgroup of thymic T-ALL patients (93% vs. 75%, p=0.02). Conclusion: This is to our knowledge the largest cohort of adult T-ALL patients characterized by RNAseq on molecular level. Our findings point towards an age dependent distribution of molecular subgroups contributing to age-dependent outcome differences. Patients with TLX1 reveal a molecular subgroup with extraordinary good prognosis. Within thymic T-ALL, the subgroup of patients without TLX1 (~53%) has an inferior but still good prognosis. Disclosures Fiedler: Gilead: Other: support for meeting attendance; Jazz Pharmaceuticals: Honoraria, Other: support for meeting attendance; Abbvie: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; ARIAD/Incyte: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: support for meeting attendance, Patents & Royalties, Research Funding; Daiichi Sankyo: Other: support for meeting attendance. Alakel:Pfizer: Consultancy. Schwartz:AMGEN: Other: personal fees and non-financial support; Novartis: Other: personal fees and non-financial support; Jazz Pharmaceuticals: Other: personal fees and non-financial support; Pfizer: Other: personal fees ; BTG Intl Inc: Other: personal fees ; Gilead Sciences: Other: personal fees and non-financial support ; MSD Sharp & Dohme: Other: personal fees ; Basilea: Other: non-financial suppor. Müller-Tidow:Pfizer: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Janssen-Cilag GmbH: Speakers Bureau; BiolineRx: Research Funding. Brüggemann:Regeneron: Research Funding; Affimed: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Roche: Consultancy; Celgene: Consultancy. Goekbuget:Servier: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Gilead: Consultancy; Erytech: Consultancy; Kite: Consultancy; Jazz: Consultancy, Research Funding.

Background Data are lacking on the relative incidence of thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) caused by Shiga toxin–producing Escherichia coli (STEC) and atypical HUS (aHUS) in patients presenting with thrombotic microangiopathies (TMAs). Methods This was a prospective, cross-sectional, multicentre and non-interventional epidemiological study. Patients fulfilling criteria for TMAs (platelet consumption, microangiopathic haemolytic anaemia and organ dysfunction) were included in the study. The primary objective was to assess the relative incidence of TTP, STEC-HUS, aHUS and ‘other’ physician-defined diagnoses. The secondary objective was to develop an algorithm to predict a severe deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (≤10%) using routine laboratory parameters. A post hoc classification using the recent Kidney Disease: Improving Global Outcomes diagnostic criteria was then undertaken to further classify patient groups. Results aHUS was diagnosed with a relative incidence of 61%, whereas TTP, STEC-HUS and ‘other’ were diagnosed in 13, 6 and 20% of patients, respectively. In the post hoc analysis, 27% of patients with a TMA were classified as ‘primary aHUS’ and 53% as ‘secondary aHUS’. Multivariate analysis revealed that severe deficiency in ADAMTS13 activity (≤10%) was unlikely to underlie TMA if platelet and serum creatinine were above threshold values of 30 × 109/L and 1.8 mg/dL, respectively (negative predictive value of 92.3 and 98.1, respectively, if one or both values were above the threshold). Conclusions In this study, aHUS was the most common single diagnosis among patients presenting with a TMA. In the absence of an ADAMTS13 activity result, platelet count and serum creatinine may aid in the differential diagnosis.

Outcome of adult ALL has improved considerably during the past decades by intensive chemotherapy, which still remains a challenge in older pts. This may be partly due to comorbidities. So far there are no standards to differentiate pts who will be able to tolerate even age-adapted chemotherapy (fit vs unfit). In addition, little is known about the prevalence of comorbidities. Clinical trials with new compounds often represent a selection of pts w/o comorbidities. There is also no generally accepted tool for comorbidity scoring. The goal of this analysis is to provide reference data for pre-existing comorbidities in a large set of adult ALL pts, to compare two different tools and to evaluate the impact on early death (ED) in older pts. The German Multicenter Study Group for Adult ALL (GMALL) has collected data from trials for younger (18-55 y) and older (>55 y) pts and from a prospective registry. Trials had very limited exclusion criteria and in the registry there are no exclusion criteria. The Charlson Comorbidity Index (CCI) was assessed in the GMALL Elderly trial, whereas the Sorror Score (HCT-CI) was used in trials for younger pts and in the registry. 879 pts had a documented HCT-CI score from GMALL 08/2013 trial (N=282;group 1) and 3 groups from the registry: >55 y but eligible for intensive therapy (N=56, group 2), > 55 y in GMALL Elderly protocol (N=505, group 3) and >55 y in GMALL Frail protocol (N=36; group 4) (Table 1). In addition the CCI was documented in 333 pts treated in the GMALL Elderly Trial. HCT-CI-Score: The most frequent comorbidities were infections (17%), prior malignancies (16%), diabetes (16%), cardiac (14%) and moderate pulmonary disease (12%), obesity (11%) and mild liver disease (10%). Arrhythmias (55 y (group 2) considered eligible for intensive therapy (57%) compared to those considered for the Elderly protocol (76%) (group 3). The proportion of low risk (LR) scores decreased with age (54%, 43%, 25% and 8% resp.;p=.01), whereas high risk (HR) increased (18%, 25%, 50% and 59% resp; p=.01). CCI: The most frequent comorbidities were prior malignancy (14%), diabetes (25%) with (3%) or w/o (22%) end organ damage, cardiac (11%) and vascular disease (8%). The incidence of prior malignancy within the last 5 y was 7%. Risk classification was: LR (0) 51%, intermediate risk (IMR) (1-2) 42% and HR (≥3) 7%. HCT-CI vs CCI in pts >55 y: With HCT-CI the incidence of heart diseases (21% arrhythmias, cardiac disease or valve damage) was higher compared to CCI (9%), which differentiated better into cardiac failure (7%) and myocardial infarction (4%). Peripheral vascular disease (8% with CCI) is not assessed by HCT-CI. Liver disease was less frequent with CCI (1.5%) vs HCT-CI (14%) due to different definitions, whereas moderate pulmonary disease (12%) or infections (18%) are not assessed by CCI. The incidences of prior malignancies and diabetes were comparable. Of note, the overall incidence of distinct comorbidities e.g. cardiac was lower than the sum of subentities because some pts had several comorbidities. ED in pts >55 y: ED rates in pts >55 y in group 3 and in GMALL Elderly trial were comparable (13% vs 12% resp). In group 3 ED rates in risk groups (HCT-CI) were 7% vs 13% vs 15% (p>.05). In the GMALL Elderly trial ED in risk groups (CCI) were 9%, 12% and 35% (p=.05; p=.003 LR/IMR vs HR). Overall the analysis reveals a high incidence of comorbidities in older (57-92%) and even in younger pts (46%), which partly would represent contraindications in clinical trials with novel compounds; thus real world data in pts with comorbidities are required after marketing authorisation. HCT-CI and CCI have a different focus and shortcomings. For ALL pts a more specific score with different organ modules would be helpful. Comorbidity is significantly correlated to ED risk. CCI allows to identify a small HR group (7%) with a mortality of 35%. HCT-CI (24% of pts) and even more CCI (51% of pts) allow to identify LR groups with Disclosures Viardot: Gilead Kite: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Fiedler:Teva: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Amgen: Other: support for meetíng attendance; Pfizer: Research Funding; Amgen: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSO: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; Daiichi Sankyo: Other: support for meeting attendance. Stelljes:JAZZ: Honoraria; MSD: Consultancy; Amgen: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Serve:Bayer: Research Funding. Goekbuget:Kite / Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Other: Travel support, Research Funding; Pfizer: Consultancy, Other: Travel support, Research Funding; Amgen: Consultancy, Other: Travel support, Research Funding.

Background: Risk stratification, detection of minimal residual disease (MRD), and implementation of novel therapeutic agents have improved outcome in acute lymphoblastic leukemia (ALL), but survival of adult patients with T-cell acute lymphoblastic leukemia (T-ALL) remains unsatisfactory. Thus, novel molecular insights and therapeutic approaches are urgently needed. Methods: We studied the impact of B-cell CLL/lymphoma 11b (BCL11b), a key regulator in normal T-cell development, in T-ALL patients enrolled into the German Multicenter Acute Lymphoblastic Leukemia Study Group trials (GMALL; n = 169). The mutational status (exon 4) of BCL11b was analyzed by Sanger sequencing and mRNA expression levels were determined by quantitative real-time PCR. In addition gene expression profiles generated on the Human Genome U133 Plus 2.0 Array (affymetrix) were used to investigate BCL11b low and high expressing T-ALL patients. Results: We demonstrate that BCL11b is aberrantly expressed in T-ALL and gene expression profiles reveal an association of low BCL11b expression with up-regulation of immature markers. T-ALL patients characterized by low BCL11b expression exhibit an adverse prognosis [5-year overall survival (OS): low 35% (n = 40) vs. high 53% (n = 129), P = 0.02]. Within the standard risk group of thymic T-ALL (n = 102), low BCL11b expression identified patients with an unexpected poor outcome compared to those with high expression (5-year OS: 20%, n = 18 versus 62%, n = 84, P

Background: IKAROS (IKZF1) is a key transcription factor for B-cell development. The IKZF1 protein exerts its functions as a dimer (homodimer or heterodimer with other IKAROS family members). Various IKZF1 intragenic deletions have been identified as recurrent aberrations in acute lymphoblastic leukemia: those resulting in the loss of transcription of one allele or at least loss of the dimerization domain ("haploinsufficient", "non-functional") and those involving only the DNA-binding domain but retaining the dimerization domain of the transcription factor, leading to so-called "dominant negative" isoforms. Several studies in pediatric ALL have confirmed the negative prognostic impact of IKZF1 alterations although there is still no consensus if they are independent risk factors in a multivariate analysis. The situation in adult ALL is less clear and few larger studies have addressed this issue, in particular the prognostic impact of different types of IKZF1 alterations. Objectives: We investigated archived patient samples obtained in the context of the German Multicenter ALL Study Group (GMALL) therapy studies for different IKZF1 alterations to assess their prognostic implications and their molecular pattern. Methods: We used RT-PCR to determine the presence of aberrant IKZF1 transcript variants and additionally investigated all patients by DNA-based PCRs for the IKZF1 aberrations D4-7, D2-7, D4-8, D2-8. Rare transcript variants, such as D2-3, D2, D5-7 were molecularly characterized on the DNA level by specific PCRs. IKZF1 aberrations were quantified using gel densitometry and/or quantitative real time PCR such that clonal and subclonal aberrations could be distinguished. All chromosomal breakpoints were molecularly characterized. Results: In total, 482 B cell precursor ALL patients aged between 15 and 65 years were included in the analysis. Samples were obtained at primary diagnosis and tested BCR-ABL -negative. Other molecular aberrations were tested according to the GMALL standards: 39 MLL-AF4-positive, 4 MLL-ENL, 1 MLL-AF9, 30 TCF3-PBX1, 3 ETV6-RUNX1. The immunophenotypes were the following: 424 pre B/common, 58 pro B. One hundred and twenty-eight out of 482 (27%) patients carried at least one IKZF1 deletion, with 37 patients carrying more than one deletion. Altogether there were 175 IKZF1 deletions, 71 cases of D4-7, 47 with D2-7, 26 with D4-8, 19 with D2-3, 10 with D2-8, and 1 with D5-7 and D2 each. Taken together 56 patients (12%) carried only non-functional mutations while 50 (10%) had dominant-negative mutations only. There was a group of 22 patients with both types of mutations (5%). Evaluating the prognostic impact, we considered the effect of non-functional and dominant-negative mutations separately. Patients with a non-functional IKZF1 mutation had a reduced overall survival (OS at 5 ys 37% vs 59% in IKZF1-unmutated patients, N=78/404, p=0.001) while dominant-negative mutations had no effect on OS (OS at 5 ys 54% compared to 56%, N=72/410, p=0.95). However, solely present subclonal non-functional mutations did not affect survival (OS at 5 ys 59% compared to 59%, N=23/404). In the dominant-negative group, clonality had no influence on OS (p=0.56, N=45/73/351). Taken together, patients with clonal non-functional IKZF1 had a significantly worse OS compared to those without (0.28 vs 0.59, N=53/427, p With regard to molecular analysis 193 chromosomal fusion sites were characterized. In the great majority (>95%) putative cryptic recombination sites were identified in the near vicinity thus underlining the causal role of the VDJ recombination machinery in the generation of these aberrations. Conclusions: We conducted a detailed and large-scale molecular analysis of intragenic IKZF1 deletions and identified clonal non-functional IKZF1 deletions as adverse prognostic factor in adult and adolescent B cell precursor ALL patients treated according to the GMALL protocols. Subclonal, or dominant negative IKZF1 mutations had no prognostic effect. It remains open for further analysis whether clonal non-functional IKZF1 deletions represent an independent prognostic factor in MRD-based risk stratification. Disclosures Wäsch: German Cancer Aid: Research Funding; Comprehensiv Cancer Center Freiburg: Research Funding; Janssen-Cilag: Research Funding; MSD: Research Funding.

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 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.05). OS increased in SR (58% to 74%; p 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 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 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.

Abstract 1493 Few older ALL pts are entered into prospective trials and data on characteristics and outcome are scarce. The GMALL started a prospective trial in older ALL (>55 yrs) in 2003. In Ph-neg ALL a prephase (Dexa, Cyclo, MTX i.th.) was followed by induction I (Dexa, VCR, Idarubicin), induction II (Cyclo, AraC), alternating consolidation with IDMTX (d 1,15) ×3, VM26/AraC ×2, reinduction (VCR, Ida, Cyclo, AraC) and maintenance (MP, MTX) up to 2 yrs. In CD20+ ALL Rituximab ×8 was added. CNS-prophylaxis consisted of i.th. triple combination (MTX, AraC, Dexa) ×4 during induction, ×8 during consolidation/maintenance. The original protocol (group 1) was amended to optimize CNS prophylaxis and consolidation (group 2). I.th. therapy was then performed with liposomal cytarabine, 3x during induction, 3x during consolidation. IDMTX dose was increased from 500 to 1000 mg/m2 and native E.coli ASP (10.000 U/m2) was added on d2 and d16 of IDMTX. VM26/AraC was replaced by IDAraC (1000 mg/m2 d1,3,5). In a further amendment the original i.th. prophylaxis was reinserted until final analysis of liposomal AraC became available. Furthermore, after induction, one cycle with pegylated ASP (500 U/m2) (PEG-ASP) was scheduled to evaluate feasibility in older pts (group 3). Results of induction were compared for groups 1–3; outcome analysis was restricted to 1–2 due to still short follow-up for group 3. 268 pts with a median age of 67 (55–85) yrs treated in 94 hospitals were evaluable (180, 43 and 45 pts in groups 1, 2 and 3 resp.). 39% were aged 55–65 yrs, 51% 66–75 yrs and 10% above 75 yrs. 67% had c/pre-B-ALL, 18% pro-B-ALL and 15% T-ALL. WBC was >30/nL in 27%. Poor ECOG status (≥2) before (ECOGb) or after (ECOGa) onset of ALL was described in 7% or 38% resp. 78% had any comorbidity and 9% had a Charlson score (ChS) ≥3. No significant differences were detected between groups 1–3. Overall 76% (N=203) achieved CR after induction, 14% experienced early death (ED) and 10% did not achieve CR. In groups 1–3 CR rates were 72%, 86% and 82% resp. and ED rates 18%, 0% and 11% resp. (p=.03). CR rates were 84%, 74% and 52% in three age groups (p=.002) with ED rates of 7%, 14% and 37% resp. (p=.0004). Immunophenotype and WBC (<> 30.000) correlated with CR but not ED rate. ECOGb 0–1 vs ≥2 correlated with CR (82% vs 33%;p Overall survival (OS) at 5 yrs was 23%; 33% at 2 yrs for group 1 and 52% for group 2 resp. (p=.01). Mortality in CR was 6% and 15% of the pts were withdrawn in CR. Probability of continuous complete remission (CCR) was 32% at 5 yrs, 42% and 43% at 2 yrs for group 1 and group 2 resp. (p=>.05). Age (42% vs 37% vs 8%;p=.0007), WBC (43% vs 15%;p With this age adapted regimen a favorable CR rate was achieved in a large patient group with a median age of 67 yrs. CR was increased (86%) and mortality was decreased (0%) significantly with liposomal cytarabine compared to triple i.th. prophylaxis during induction, since the latter probably induced more bone marrow toxicity. Reduced ED contributed considerably to improved OS. Moderate intensive consolidation was feasible and ASP, including PEG-ASP, was well tolerated. Age was correlated with outcome and 75 yrs appears to be the upper limit for this regimen. General condition was an additional highly relevant prognostic factor whereas comorbidity, measured by Charlson score was associated with ED but not with OS. These results encourage further treatment optimisation in older ALL pts, including those with comorbidities, based on comprehensive diagnostics, geriatric assessment, MRD evaluation, intensified consolidation, use of ASP, dose-reduced stem cell transplantation and integration of new, targeted drugs. Disclosures: Goekbuget: Medac: Consultancy, Research Funding, Speakers Bureau; Novartis: Research Funding; BMS: Research Funding; Genzyme: Research Funding; Mundipharma: Research Funding, Speakers Bureau; Glaxo: Research Funding, Speakers Bureau; Micromet/AMGEN: Consultancy; Sigma Tau: Consultancy. Off Label Use: Liposomal cytarabine in prophylaxsis of CNS relapse in ALL.