Despite improvements in first-line therapies, published results on the treatment of relapsed adult acute lymphoblastic leukemia (ALL) show that prognosis is still poor. The aim of the present retrospective analysis of the German Multicenter Study Group for Adult ALL was to identify prognostic factors and options for improvement. A total of 547 patients with a median age of 33 years (range, 15-55) experiencing their first relapse (406 vs 141 shorter or longer than 18 months from diagnosis) were evaluated. The aim of salvage therapy was to achieve a complete remission (CR) with subsequent a stem cell transplantation (SCT). The CR rate (assessed in Philadelphia chromosomeand BCR-ABL-negative ALL without CNS involvement) after the first salvage in relapse after chemotherapy (n ‫؍‬ 224) was 42%. After failure of first salvage (n ‫؍‬ 82), the CR rate after second salvage was 33%. In relapse after SCT (n ‫؍‬ 48) the CR rate after first salvage was 23%. The median overall survival after relapse was 8.4 months and survival was 24% at

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<.0001) and ED (7% vs 53%;p<.0001). Also ECOGa correlated with CR (85% vs 67%;p=.003) and ED (6% vs 19%;p=.003). CR and ED rates were not influenced by comorbidity itself but by ChS < vs ≥3: CR (78% vs 59%;p=.003) and ED (11% vs 33%;p=.0007). Multivariate analysis confirmed ECOGb, WBC and age for CR rate, and ECOGb, age and ChS for ED. 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<.0006), ECOGb (40% vs 14%;p=.0008) and ECOGa (42% vs 30%;p=.0023) were correlated with OS in contrast to comorbidity and ChS. Age, treatment group, WBC, ECOGb and ECOGa were confirmed in multivariate analysis. Pts younger than 75 yrs with ECOGb below 2 had an 86% CR rate with 10% ED and 36% OS at 3 yrs. WBC and MRD were significant prognostic factors for CCR. MRD results after consolidation I were available in 33 pts. CCR was 11% in molecular failure vs 68% in molecular CR. Preliminary results confirmed feasibility of PEG-ASP. 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.

No abstract

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.

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.