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The aim of our study was to analyze the factors contributing to heterogeneity of prognosis in patients with hyperdiploidy50 chromosomes (HD50), a group of B-cell precursor acute lymphoblastic leukemia with favorable outcome. The 541 HD50 patients registered prospectively in the 58951 European Organisation for Research and Treatment of Cancer (EORTC) Children's Leukemia Group (CLG) trial, identified by karyotype (446 patients) and by DNA index (DI) (490 patients), had a 6-year event-free survival (EFS) of 89.0% (standard error [SE] = 1.5%) and a 6-year overall survival (OS) of 95.9% (SE = 0.9%). The strongest prognostic factor was the modal number of chromosomes (MNC): the 6-year EFS of 51-53, 54-57, and 58-66 MNC groups were 80%, 89%, and 99%, respectively (P.0001). Ploidy assessed by DI was also a favorable factor: the higher the DI, the better the outcome. The 6-year EFS of the 3 subgroups of DI1.16/≥1.16-1.24/≥1.24 were 83%, 90%, and 95%, respectively (P = .009). All usual combinations of trisomies (chromosomes 4, 10, 17, 18) were significant favorable factors but had lower EFS when MNC was lower than 58. In multivariate analysis, MNC remained the strongest factor. Consequently, the best indicator for excellent outcome was ploidy assessed by karyotype because patients with 58-66 chromosomes stood every chance of being cured (OS of 100% at 6-year follow-up) with less-intensive therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003728. Registered: http://www.eortc.org/, http://clinicaltrials.gov/show/NCT00003728.

Introduction: Aberrant DNA methylation occurs frequently in hematologic malignancies and is associated with altered gene expression. Consequently, DNA hypomethylating agents (HMAs), e.g. 5-aza-2'-deoxycytidine (DAC), have been tested for in vivo demethylation and have become accepted as first-line treatment of older MDS and AML patients (pts). While HMAs are already routinely used for the treatment of MDS and AML, only very few outcome predictors have been established thus far. Expression of the β-like globin gene locus is tightly regulated by methylation, is HMA-sensitive in vitro, and fetal hemoglobin (HbF) expression is under study as a potential biomarker for response of MDS pts to 5-azacytidine. Here, we present the first study of serial HbF measurements in MDS and AML pts receiving DAC in order to investigate a potential clinical application of HbF as a predictor of outcome to this treatment. Methods: 16 MDS and 36 AML pts enrolled on two clinical trials, the 06011 EORTC-GMDSSG phase III trial of higher-risk MDS, and the 00331 phase II trial of older, non-fit AML pts (Lübbert M et al., Haematologica 2012), were treated with DAC. MDS pts received nine 4-hour infusions of 15 mg/m2 given over 72 hours, repeated every 6 weeks for a minimum of four courses. AML pts were treated with nine 3-hour infusions of 15 mg/m2 given over 72 hours, repeated every 6 weeks for four courses followed by maintenance treatment with DAC at 20 mg/m2 when responding (defined by CR, PR or an antileukemic effect). HbF levels were measured in peripheral blood by HPLC before treatment and sequentially, i. e. after the end of each treatment course (every 6 weeks). HbF levels >1% of total hemoglobin were considered elevated. Results: Baseline HbF was elevated (>1.0%) in 7/16 MDS and 12/36 AML pts. Clinical baseline characteristics were uniformly distributed between pts with normal and elevated HbF levels. HbF induction was observed in 81% of MDS pts after a median of 2 (range 2-6) courses of DAC and in 54% of AML pts after a median of 3 (2-11) courses. Four AML pts receiving standard cytarabine-based induction chemotherapy and four pts with pancreatic cancer receiving gemcitabine-based treatment did not show HbF induction to >1%. When analyzing clinical survival endpoints, elevated baseline HbF was associated with longer median overall survival (OS) for MDS: 26.6 vs. 8.6 months (HR 8.56, 95% CI 1.74-42.49, p=0.008). Similarly, median PFS and AMLFS was prolonged in "HbF high" MDS pts with 15.4 compared to 5.9 months (p=0.016) and 26.3 compared to 8.8 months (p=0.03), respectively. A statistically non-significant trend towards higher HbF baseline values (median 1.5%, range 0.3% to 3.9%) in MDS pts achieving a CR, PR or hematological improvement compared to non-responders (median baseline 0.4%, range 0.1% - 1.9%) was noted. Likewise, OS for AML pts with elevated pre-treatment HbF was prolonged with 10.0 vs. 2.9 months OS (HR 3.01, 95% CI 1.26-7.22, p=0.014). HbF baseline values were comparable in the group that did achieve any response (CR, PR, antileukemic effect) vs. the non-responding group. In a multivariate analysis including LDH and age, the predictive value of HbF was retained. Time-dependent Cox models revealed that the predictive value of treatment-induced HbF induction was markedly inferior to that of baseline HbF. Conclusion: We provide first evidence for in vivo induction of HbF by DAC in MDS and AML pts. Notably, HbF values elevated already prior to treatment harbor highly significant predictive value for survival benefit upon DAC whereas HbF induction is inferior to a stronger effect of pre-treatment HbF. Our findings warrant incorporation of HbF as potential predictive biomarker in larger prospective studies. Disclosures Claus: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria, Other: Travel Funding. Becker:BMS: Honoraria; Novartis: Honoraria. Lübbert:Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding.

Background: Since the last decades, pediatric ALL classification has integrated new cytogenetic and genomic data, and several genetic risk factors are identified for treatment stratification. Hyperdiploidy, which is the most common cytogenetic abnormality pattern of pediatric B-lineage ALL, is known since the early 80s and is found in 25-30% of cases. It has been recognized as an isolated good prognostic factor, especially High Hyperdiploidy (HeH), defined by a modal chromosome number higher than 50. In addition, treatment descalations were performed based on NCI criteria for low risk ALL (low leucocytosis < 10 x 109/L and/or age from 1 to ²10 years old) and/or lack of high risk features. Aim: The aim of this study was to assess whether age, under or over 10 years old, has a prognostic impact on the outcome in children presenting B-cell ALL with low risk criteria, and whether therapeutic intensification might improve the outcome within each age group. Methods: Among 2039 patients treated in EORTC 58951 (BFM backbone) from 1998 to 2008, 370 children with B-cell ALL and low risk criteria such as HeH (with classical profile of chromosome gains), low leucocytosis (< 10x109/L), a lack of CNS or gonadal involvement and a lack of very high features (poor response to prephase) were included in this study. Hyperdiploidy was determined either by cytogenetics or flow cytometry. Patients were stratified into 2 risk groups: very low risk (VLR) group or standard risk (AR1) group. VLR group was defined by the criteria indicated above. It led to a less intensive treatment, particularly lower number of injections of anthracyclines and alkylating agents. AR1 group included children with surreptitious or hemorrhagic CNS involvement, and/or HeH with mismatch between modal chromosome number and DNA index. The upper limit of age in the EORTC 58951 was less than 18 years. Main endpoints were Event-Free Survival (EFS) and Overall Survival (OS). Results: Overall patients with low risk hyperdiploid B-cell ALL features treated according to a VLR or AR1 protocol had 6-year EFS and OS rates of 90.3% and 96.2% respectively. These results were comparable to previous published studies on hyperdiploidy in childhood B-lineage ALL. All patients but one reached complete remission after the induction phase. There were 315 children aged less than 10 years old and 55 patients aged 10 to 17 years old. Among children aged 10 years and older treated in VLR or AR1 groups, 6-year EFS and OS rates were respectively 86.7% and 96.4%. In comparison, among less than 10 year old childrentreated in VLR or AR1 groups, 6-year EFS and OS rates were respectively 89.8% (p=0.42) and 95.9% (p=0.93). Age did not appear as a significant prognostic factor in the outcome. Furthermore, among children aged 10 years and older, those treated in the standard risk group (AR1) had 6-year EFS and OS rates of 90% and 100% respectively. This seemed better than for children treated in the very low risk group, with respectively 84% and 92% rates. However, no significant gain was found for children who received standard risk treatment (for EFS and OS rates: p=0.47 and p=0.12 respectively). Relapse and treatment toxicity rates were comparable in both groups. Concerning long-term cardiac toxicity, despite the fact that no significant difference was found between the two risk groups of treatment, standard treatment leads to higher dose of anthracyclines and an increased theoretical risk of cardiac toxicity. Conclusion: In conclusion, age did not appear as a significant prognostic factor in outcome of children treated for a low risk B-cell ALL. Moreover, among children aged 10 years and older, therapeutic intensification in standard risk group did not lead to a significant gain in outcome. However, results are not significant, partly due to a low number of patients, and larger studies should be performed to evaluate whether these children could benefit from a less intensive treatment. Disclosures No relevant conflicts of interest to declare.

Background. Previous studies have demonstrated that monosomal karyotype (MK) confers a particularly poor prognosis in patients with acute myeloid leukemia (AML) (Breems et al., J Clin Oncol 2008, 26:4791-7). Purpose of the study. To determine the impact of the type of remission-induction chemotherapy and the impact of having a donor on overall survival (OS) in younger ( Methods. In the EORTC/GIMEMA AML-10 trial (Mandelli et al., J Clin Oncol 2009, 27:5397-403), patients were randomized to receive either daunorubicin (DNR), mitoxantrone (MTX), or idarubicin (IDA) in addition to standard-dose cytarabine (SDAC: 10 days of 100 mg/m2 per day as continuous IV infusion) and etoposide for induction chemotherapy. In the EORTC/GIMEMA AML-12 trial, (Willemze et al., J Clin Oncol 2014, 32:219-28) patients were randomized between either SDAC or high dose cytarabine (HiDAC) (3 g/m2 every 12 hours as a 3-hour IV infusion on days 1, 3, 5, and 7) induction, both with DNR, and etoposide. In both trials, a second cycle of the same remission induction chemotherapy was administered in patients who achieved a partial remission. Patients who achieved a complete remission (CR) or a CR with incomplete counts recovery (CRi) after 1 or 2 courses of induction chemotherapy received a consolidation chemotherapy with the same anthacycline as in the induction course plus intermediate dose cytarabine. Patients in both studies were then scheduled to receive an allogeneic hematopoietic stem cell transplantation (allo-HSCT) if they had a donor or an autologous HSCT (auto-HSCT) otherwise, in first CR. For the current analyses, cytogenetics were centrally reviewed and re-classified using the European Leukemia Net (ELN) definition. MK was defined as the presence of 2 or more monosomies, or a single monosomy in the presence of structural abnormalities. Results. In the AML-10 trial, 2157 patients were randomized to receive DNR, MTX or IDA. The current analyses were performed in a subgroup of 910 patients for whom cytogenetic data were available and who did not have t(8;21), inv(16) nor t(15;17). 709 of them were classified in the ELN intermediate cytogenetic risk group and 201 in the adverse group. Out of the 910 patients, 93 had a MK. In comparison to the 817 remaining (MK-) patients, MK+ patients were less likely to achieve a CR, were more likely to have resistant disease (RD), and had worse OS and disease-free survival (DFS) (Table 1). There was no impact of the type of anthracycline on outcomes. Among the MK+ patients who achieved a CR, 5-yr OS from CR was 26% (95% CI, 10-46%) in patients with a donor (n=21, of whom, 13 received an allo-HSCT in first CR), versus 4% (95% CI, 0-18%) in those without a donor (n=24, of whom, 1 received an allo-HSCT in first CR) (P=0.07). Further, among the 10 MK+ who survived more than 1 year, 7 received an allo-HSCT in first CR (n=4) or beyond (n=3). In the AML-12 trial, 1942 patients were randomized between HiDAC or SDAC. The current analyses were performed in a subgroup of 1079 patients for whom cytogenetic data were available and who did not have t(8;21), inv(16) nor t(15;17). 893 of them were classified in the ELN intermediate cytogenetic risk group and 186 in the adverse group. Out of the 1079 patients, 98 had a MK. In comparison to the 1027 MK- patients, MK+ patients were less likely to achieve a CR, were more likely to have RD, and had worse OS and DFS (Table 1). There was a higher probability of achieving a CR and a trend for better OS in MK- patients randomized in the HiDAC arm (Table 2). In contrast, in MK+ patients, HiDAC did not increase either the CR rate as compared to SDAC, nor the 5-yr OS rate: 7% (HiDAC) vs 2% (SDAC) (Table 2). Finally, among the MK+ patients who achieved a CR, 5-yr OS from CR was 14 % (95% CI, 4-32%) in patients with a donor (n=21, of whom, 12 received an allo-HSCT in first CR), versus 4% (95% CI, 0.3-18%) in those without a donor (n=24) (P=0.60). Further, among the 4 MK+ patients who survived more than 1 year, 3 received an allo-HSCT in first CR (n=2) or beyond (n=1). Conclusions. This analysis confirms the poor prognosis of MK in younger AML patients. Shifting DNR to IDA or MTX or administration of HiDAC in the induction course failed to improve outcome of MK+ patients. Finally, there was a suggestion for a longer OS from CR in MK+ patients who had a donor, suggesting that allo-HSCT should be offered in all fit MK+ patients. FB & MSK contributed equally to this work Disclosures Thomas: Pfizer: Consultancy.

Background Cranial radiotherapy (CRT) is associated with early and late side effects. Intrathecal (IT) and systemic chemotherapy could successfully replace CRT in most protocols for standard risk ALL. However, in medium and high risk ALL patients (pts) its omission is still debatable. Aim We investigated the long-term outcome, the occurrence of second malignant neoplasms (SMN) and the incidence of late toxicities in pts randomized for receiving or not CRT in the EORTC 58832 study. Methods From 1983 to 1989, ALL children under 18 years (yrs) were included in EORTC Children Leukemia Group BFM-oriented studies, either 58831, for standard risk pts (Riehm-Langerman Risk Factor (RF) < 1.2), or 58832, for medium risk (RF 1.2-1.69) and high risk pts (RF ≥1.7). Pts with central nervous system (CNS) involvement at diagnosis were ineligible. The present report focusses on pts included in the 58832 trial (randomized for receiving or not prophylactic CRT). Prophylactic CNS therapy consisted of 4 high-dose methotrexate (HD-MTX) injections (2500 mg/m2) during consolidation and 7 IT MTX injections scheduled during the treatment period. Pts still in complete remission (CR) after the end of late intensification were randomized for receiving prophylactic CRT (standard arm) or not (experimental arm) before the start of continuation therapy. Dose of CRT was age dependent: 24 Gy (> 2 yrs), 20 Gy (1-2 yrs) and 16 Gy (< 1 yr). Endpoints were: disease-free survival (DFS) (event: relapse, death in CR), incidence of SMN, event-free survival (EFS) (event: relapse, death in CR, SMN), incidence of late toxicities, and overall survival (OS) from randomization. Results 788 pts were included in the 58831/58832 study. Among them, 189 were randomized in the 58832 study to receive CRT (n=93) or No CRT (n=96). A total of 6 pts did not meet eligibility criteria, 2 had an early relapse, 3 had an early protocol violation and 2 refused allocated treatment. Finally, 176 randomized pts were included in the analyses: 84 in the CRT group and 92 in the No CRT group. The median follow-up was 20 yrs (range 4-32 yrs). Omission of CRT did not increase the 25-yr incidence of isolated CNS relapse, any CNS relapse or non-CNS relapse (4.8 vs 6.5; 11.9 vs 8.7 and 16.7 vs 21.8 in the CRT vs No CRT arms, respectively). No relapses occurred after 10 yrs. The 25-yr DFS rates were similar in both arms: 70.2% with CRT and 67.4% without CRT; No CRT vs CRT hazard ratio (HR)=1.08, 95% CI (0.63, 1.83). CRT was associated with an increase of the 25-yr SMN incidence: 13.2% with CRT and 3.9% without CRT. In the CRT arm, 9 pts (10.7%) developed SMN: 2 acute myeloid leukemias (AML), 1 non-Hodgkin lymphoma, 1 thyroid carcinoma, 4 meningiomas and 1 malignant histiocytosis. One SMN (meningioma) occurred after a CNS combined relapse. Three pts developed second SMN (meningiomas): 1 after an AML and 2 after a first meningioma. In the No CRT arm, 3 pts (3.3%) had SMN: 1 pleomorphic xanthoastrocytoma, 1 melanoma and 1 adenocarcinoma of the ileum. One SMN occurred after a bone marrow (BM) relapse. The 25-yr EFS rates were similar in both arms: 60.3% with CRT and 63.2% without CRT, HR=0.90, 95% CI (0.55, 1.46). CRT was also associated with an increase of late CNS and endocrine toxicities. Five pts (19.2% of the pts with available data) developed leukoencephalopathy in the CRT arm, versus 2 pts (8.7%) in the No CRT arm. Noteworthy, 1 of those 2 pts received CRT for a BM relapse, while the other received total body irradiation for a CNS relapse. Stroke was observed in 2 pts (7.7%) who received CRT. In contrast, there was no clear increase of the incidence of cognitive disturbance after CRT: 33.3% in the CRT arm vs 25.0% in the No CRT arm. Regarding endocrine toxicities, GH deficiency, hypothyroidism and precocious puberty were more frequent in the CRT arm: 53.1% vs 29.6%, 27.8% vs 0% and 29.4% vs 0%, respectively. Finally, the 25-yr OS rates were similar in both arms: 78.5% with CRT and 78.1% without CRT, HR=1.00, 95% CI (0.53, 1.88). Conclusion In medium and high risk pts without CNS involvement at diagnosis and treated with HD-MTX in the EORTC trial 58832 (1983-1989), omission of CRT did not increase the risk of CNS or non-CNS relapse. On long-term evaluation, CRT was associated with a higher incidence of SMN, late CNS and endocrine toxicities. These long-term results indicate that prophylactic CRT can be safely omitted in childhood medium and high risk ALL pts receiving IT and systemic chemotherapy (including HD-MTX) as CNS prophylaxis. Table Table. Disclosures No relevant conflicts of interest to declare.

*The 2 first authors contributed equally to the work. Background. The best post-remission treatment for younger acute myeloid leukemia (AML) patients has remained controversial (Cornelissen JJ &Blaise D, Blood 2016, 127, 62-70) and there is paucity of studies comparing intensive chemotherapy to autologous (auto) or allogeneic (allo) bone marrow transplantation (BMT). Aim. The main objective of this study was to provide a long-term follow-up evaluation of patients previously enrolled in the pivotal EORTC/GIMEMA AML-8A (Zittoun et al., New England Journal of Medicine 1995, 332, 217-223). Methods. The EORTC/GIMEMA AML-8A prospectively assessed the impact of 3 post-remission treatments on disease-free survival (DFS) and overall survival (OS) in younger ( Results. In the current report, median follow-up was 11.1 (range, 0-28) years. For the whole population (n=422), the 5-, 10 and 15-year OS rates from inclusion were 35%, 32% and 31%, respectively. After the completion of ICT1, 168 patients were allocated to theallo-BMT arm, while 254 patients were randomized to auto-BMT (n=128) or ICT2 (n=126). DFS from CR was longer afterallo-BMT than auto-BMT and DFS from CR was longer after auto-BMT than ICT2, due to a lower relapse incidence (P Conclusions. This long-term follow-up of the EORTC/GIMEMA AML-8A study confirms a better DFS with allo-BMT or auto-BMT when compared to ICT2 for AML patients in first CR. Further, this long-term follow-up study revealed that the vast majority of patients alive in first CR at 5-year remains disease-free survivors 5 years later. Although indications of allogeneic hematopoietic stem cell transplantation (allo-HCT) are nowadays largely driven by cytogenetic/molecular AML profile, long-term results of AML8A study demonstrate that auto-BMT remained superior to ICT2 in younger AML patients not candidate for an allo-HSCT. Disclosures Efficace: TEVA: Consultancy, Research Funding; Seattle Genetics: Consultancy; Bristol Myers Squibb: Consultancy; Lundbeck: Research Funding. Martinelli:Celgene: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Consultancy; Roche: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy, Speakers Bureau.

Background In childhood BCP-ALL, the presence of t(12;21)/ETV6 -RUNX1 defines one of the most prevalent oncogenic subgroup and is usually associated with a favorable outcome. Nevertheless, an excellent prognosis has not been reported by all collaborative groups, suggesting that the outcome of ETV6 -RUNX1 patients (pts) could be influenced by the treatment. To address this issue, the long-term outcome of ETV6 -RUNX1 pts was investigated into the EORTC 58881 and 58951 studies, with particular attention to the effect of the randomized treatments. Methods The 58881 study (1989-1998) used a BFM backbone without cranial irradiation, and aimed to compare E-Coli (Medac®) Asparaginase (A'ase) with Erwinia A'ase and to assess the value of 6-Mercaptopurine (6-MP) i.v. (1 g/m²/month) when added to classic maintenance. The subsequent 58951 study (1999-2008) used the best arm of the trial 58881, i.e. E-Coli A'ase and classic maintenance. The aims of this study were to compare dexamethasone (Dexa) (6 mg/m²/day) with prednisone (Pred) (60 mg/m²/day) during induction and maintenance; to evaluate increased number of A'ase administrations (24 vs 12) for non-very high risk pts; and to assess the value of vincristine/corticosteroid pulses during maintenance for average risk pts. Detection of ETV6 -RUNX1 by FISH and/or RT-PCR was centralized. Pts less than 1 year (yr) or with t(9;22)/BCR-ABL were excluded from the analysis. Results An ETV6 -RUNX1 was evidenced in 104/363 (28%) and 380/1493 (27%) newly diagnosed BCP-ALL pts enrolled in the 58881 and 58951 trial respectively. A majority of ETV6-RUNX1 pts were below the age of 10 yrs (93.3% in 58881 and 91.3% in 58951). The median follow-up was 11.8 yrs for the 58881 and 6.7 yrs for the 58951. In both studies, the 10-yr event-free-survival (EFS) rate was significantly higher for ETV6 -RUNX1 pts than for all BCP-ALL pts (82.5% vs 74.9% in 58881 and 90.8% vs 82.7% in 58951), and was similar to the 10-yr EFS of hyperdiploid pts. Noteworthy, very few EFS events were observed during treatment period or after 6 yrs from diagnosis. The main prognostic factors of the ETV6-RUNX1 subgroup in both studies were the white blood cell count (WBC) and the response to prephase. As shown in the table below, the analysis of the relationship between treatment modalities and outcome revealed that the in vivo drug sensitivity of ETV6-RUNX1 ALL was distinct from that of other BCP-ALL. In this subgroup, the benefit of a more potent A'ase (58881) or of intensified A'ase administrations (58951) was less pronounced as compared to other pts, and 6-MP i.v. during maintenance was particularly deleterious. Moreover, the overall benefit of vincristine/corticosteroid pulses was not observed in ETV6-RUNX1 average risk group pts, who already had an outstanding outcome. By contrast, the use of Dexa in place of Pred significantly improved the 10-yr EFS of ETV6-RUNX1 pts (95.0% vs 87.2%, hazard ratio (HR)=0.44, 95% CI 0.20-0.96) whereas no difference was observed in the remaining population (HR=1.01, 95% CI 0.77-1.33) (test for interaction: p=0.04). Table.5888158951All (n=363)ETV6-RUNX1 (n=104)Hyperdiploid (n=102)Others1 (n=155)All (n=1493)ETV6-RUNX1 (n=380)Hyperdiploid (n=484)Others1 (n=619)10-yr EFS ratesAll pts74.9%82.5%83.3%65.2%82.7%90.8%88.4%73.2%Pred ² (n=745)81.8%87.2%88.8%73.0%Dexa ² (n=748)83.6%95.0%88.0%73.5%Medac A'ase 2,3 (n=320)76.6%83.2%88.6%65.7%Other A'ase 2,3 (n=43)62.8%78.6%50.0%60.0%10-yr disease-free-survival ratesShort A'ase 4 (n=607)83.5%91.2%90.1%72.4%Long A'ase 4 (n=622)87.0%94.8%88.2%80.7%No 6-MP iv 2,5 (n=96)85.4%100%90.9%72.5%6-MP iv 2,5 (n=94)72.3%70.6%78.6%68.8%No Pulse 5,6 (n=148)87.5%96.1%88.5%71.1%Pulse 5,6 (n=153)82.8%95.1%91.3%82.3%1Others, MLL rearrangements excluded 2All risk groups 3Pts randomized or not for A'ase 4Non-very high risk pts 5Pts who started maintenance 6Average risk pts Conclusions Within the EORTC 58881 and 58951 trials, the use of Dexa rather than Pred allowed to further improved the long-term outcome for ETV6-RUNX1 pts. Our data also show that this excellent outcome can be jeopardized by slight changes in therapy, such as the addition of 6-MP i.v. to classic maintenance. Together, these results stress the importance of analyzing homogeneous oncogenetic subgroups when comparing different therapeutic schemes, to unmask specific drug effects that could be hidden when analyzing the whole group of patients. Disclosures Bertrand: ERYTECH Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: An unmet medical need persists for elderly patients (pts) with AML who are deemed not to be fit for intensive chemotherapy. Such pts are usually treated with BSC and hydroxyurea or low-dose cytarabine, but outcomes are dismal. The immunoconjugate GO has shown single agent efficacy and tolerability in older pts with relapsed AML. The AML-19 study was designed as a sequential phase II/III trial comparing GO monotherapy to BSC (including hydroxyurea if clinically indicated) in pts age ≥ 61 yrs with previously untreated AML who were considered unfit for intensive chemotherapy (or refused it). Of the two induction schedules of GO (total dose 9 mg/m2 delivered in 2 or 3 fractions over one week) under comparison in the phase II part of the study, the 2-fraction regimen was found to have the best efficacy profile to warrant phase III comparison with BSC (BJH 2010; 149:376). We herein report the final results of the phase III part of the study. Methods: Untreated pts with de novo or secondary AML, adequate renal and hepatic function, and WBC count Results: Between 11/2004 and 03/2013, 237 pts were randomized from 35 European sites. The intention-to-treat population comprised 118 pts in the GO arm and 119 in the BSC arm. The median age was 77 years (range 62-88) with 64% of pts over 75 years. Baseline characteristics were well balanced between arms. At the final analysis (05/2014 cutoff), 228 deaths occurred: 113/118 (95.8%) in the GO arm, and 115/119 (96.6%) in the BSC arm. GO significantly improved OS (median 4.9 vs 3.6 months; 45.9% vs 29% alive at 6 months; 24.3% vs 9.7% alive at 1 year; 10.3% vs 6.9% alive at 1.5 year; HR, 0.69; 95% CI, 0.53-0.90; P=0.005) compared with BSC. Subgroup analyses based on stratification factors and other baseline characteristics showed that the OS benefit was generally consistent among subgroups, with a greater effect seen in pts with good/intermediate cytogenetics (median 7.3 vs 3.8 months; HR, 0.48; 99% CI, 0.31-0.75), in those with high CD33 expression (≥81% positive blasts; median 5.5 vs 3.8 months; HR, 0.47; 99% CI, 0.30-0.74), as well as in those with secondary AML (median 7 vs 4 months; HR, 0.55; 99% CI, 0.33-0.91). Among 111 pts who received at least the first dose of GO, the overall complete response rate was 27% (CR 15.3%, CRi 11.7%), and the overall disease control rate (including PR in 5.4% and stable disease for >30 days in 24.3%) was 56.7%. Of the 30 pts who achieved CR/CRi, 28 later relapsed or died in remission (1 infection, 2 general physical deterioration, 2 unknown cause), and the median disease-free survival (DFS) was 5.3 months with a 1-year DFS of 20%. CR/CRi pts had a median survival from remission of 8.2 months, with 40% alive at 1 year. The 30-day all-cause mortality from randomization was comparable in the GO (10.8%) and BSC (13.5%) arms. Most frequent grade 3+ non-hematologic adverse events (AEs) for GO vs BSC were infection (35.1% vs 34.3%), febrile neutropenia (18% vs 23.7%), bleeding (12.6% vs 12.3%), fatigue (11.7% vs 21%), and cardiac toxicity (6.3% vs 14%). Severe liver dysfunction occurred infrequently (2.7% vs 1.8% for GO vs BSC), and no episodes of VOD were reported. Overall, AEs led to GO discontinuation or death in 27 pts (24.3%). Conclusions: Compared with BSC including hydroxyurea as necessary, single agent GO in the dose/schedule chosen significantly improved OS in elderly AML pts not considered fit for intensive chemotherapy, with an acceptable safety profile. Of note, estimates of the benefit of GO were greater in pts presenting with better-risk cytogenetics, high CD33 expression on blast cells, or secondary disease. Disclosures Off Label Use: Gemtuzumab Ozogamicin in AML.

RW and FB are co-senior authors. Background: The prognosis of younger patients with intermediate/bad risk AML or high-risk MDS remains unsatisfactory. Although with current remission induction chemotherapy, 60-85% of patients achieves complete remission (CR), only 30-50% of them remains alive for more than 5 years. Clofarabine, a second-generation purine analog, is highly active as a single agent in AML. Willemze et al (Ann Hematol, 2014) recently reported the results of phase I of the AML-14A study and identified clofarabine at 10 mg/m2/day for 5 days as the maximum tolerated dose (given either in a 1-h infusion or as push injection) in combination with cytosine arabinoside (Ara-C) and idarubicin. We herein report the final results of the combined phase I and II parts of the AML-14A study that explored the antitumor activity of clofarabine containing induction combination regimens at the aforementioned phase I selected dosage schedules. Methods: Patients aged 18-60 years with intermediate/bad-risk AML or high-risk MDS (≥10% bone marrow blasts), adequate renal and hepatic function, and WBC count 65% or not. Using a Fleming design, the regimen was considered active if ≥ 23 out of 30 patients per arm achieved CR/CRi. Secondary endpoints included safety, CR/CRi rate after consolidation, hematopoietic recovery, ability of CD34 harvesting after consolidation, disease-free survival (DFS) and survival from CR/CRi, and overall survival (OS). Randomization was stratified by institution and by presence of poor prognostic features (WBC at diagnosis >=100 x 109/L or very high-risk cytogenetics/FLT3-ITD). Results: A total of 64 patients was randomized: 12 in the phase I part and 52 in the phase II part of the study. Two patients did not meet the inclusion criteria and were excluded. Among the remaining 62 patients, 5 had high-risk MDS. Median age was 50 yrs (range 20-60). Baseline characteristics were well balanced between the two arms. The CR/CRi rate after induction was 84% (26 of 31 patients) in each arm (95% CI: 66-95%) (Table 1). In Arm A vs Arm B, the most frequent grade >2 non-hematological and non-infectious adverse events over the induction-consolidation period were anorexia (29% vs 32%), and diarrhea (26% vs 32%). Finally, during treatment period there were 2 toxic deaths in Arm-A and 1 in Arm-B. Table 1: Patient outcomes. Median follow-up was 1.8 (range, 1 – 5.25) yrs. Arm-A (n=31) Arm-B (n=31) CR/CRi after 1-2 courses of induction, # pts (%) 23 (74) / 3 (10) 25 (81) / 1 (3) CR/CRi after 1 course of induction, # pts (%) 23 (74) / 3 (10) 24 (77) / 1 (3) OS median (95%CI), yrs 2.5 (1-NR) NR OS at 1-yr (95%CI), % 74 (55-86) 74 (55-86) # of infectious episodes with G3-4 neutropenia / # of patients with infection episodes 47 / 30 59 / 31 In patients who achieved CR/CRi Time to recovery from start of course 1 # of days with neutrophils NR= not reached. Conclusions: The 2 tested clofarabine (5x10 mg/m2) containing regimens yielded an impressive (84%) CR/CRi rate among patients with intermediate/bad-risk AML and high-risk MDS patients. Toxicity profiles in the two arms appeared relatively comparable. Disclosures Off Label Use: Clofarabine was used off label..

Introduction Decitabine has been approved for the treatment of myelodysplastic syndromes (MDS) in the United States and acute myeloid leukemia (AML) in older patients in Europe. The definitions of MDS and AML differ between the FAB and WHO classification, mainly with regards to patients with 20 to 30% blasts in blood or bone marrow having MDS according to the FAB classification (i.e. refractory anemia with excess blasts [RAEB] or RAEB in transformation), but AML according to the WHO. In the phase III trial 06011, we compared low-dose decitabine with best supportive care (BSC) in patients ≥60 years with MDS according to the FAB classification (Lübbert et al., J Clin Oncol. 2011;29:1987-96). Here, we examine trial 06011 for the efficacy and safety of decitabine in patients with AML according to WHO and low proliferation, i.e., blast counts of 20 to 30%. Patients and Methods Patients were randomly assigned to receive decitabine or BSC. Decitabine 15 mg/m2 was given intravenously over 4 hours every 8 hours for 3 consecutive days in 6-week cycles, with a maximum of 8 cycles. Results were evaluated every 2nd cycle. In case of complete remission (CR) at least 2 further courses were administered. Primary endpoint was overall survival (OS). Response rates (CR; PR, partial remission; HI, hematologic improvement; PD, progressive disease), progression-free survival (PFS; time from random assignment to PD, relapse or death), AML-free survival (AMLFS; time from random assignment to AML according to FAB [>30% bone marrow blasts] or death), and toxicity were secondary endpoints. Results Applying the WHO criteria to the 233 patients enrolled onto the trial, 164 had MDS and 50 had AML with blast counts of 20 to 30%. The remaining 19 patients were excluded from the present analyses. They comprised 14 patients with chronic myelomonocytic leukemia, 2 with AML and ≥40% blasts, and 3 with no blast counts available. Among the AML patients, 27 were in the decitabine and 23 in the BSC arm. In both arms, the median age was 70 years. Of the patients in the decitabine arm, 59% received 3 or more treatment cycles. Response rates in the decitabine and the BSC arm were as follows: CR, 11% vs 0%; PR, 11% vs 0%; HI, 11% vs 0%; and PD, 37% vs 74%. Compared with the patients receiving BSC, those receiving decitabine had longer PFS (P=0.008; Table 1). However, this did not translate into a significantly improved AMLFS or OS of the decitabine treated patients, although median OS was 9.8 months, compared to 5.9 months among patients receiving BSC only (Table 1). With regard to toxicity differences between the decitabine and BSC arms, grade 1-2 nausea was observed in 46% vs 14% and grade 3-4 febrile neutropenia in 19% vs 0%. Among the MDS patients, those receiving decitabine (n=78) had a longer PFS (P=0.07) but similar AMLFS and OS compared to the patients receiving BSC only (n=86; Table 1). The impact of decitabine on PFS, AMLFS and OS did not significantly differ between the AML and MDS patients (Table 1). Response rates among the MDS patients in the decitabine and BSC arms were as follows: CR, 14% vs 0%; PR, 4% vs 0%; HI, 18% vs 2%; and PD, 23% vs 66%. Conclusions Our data point to the clinically relevant efficacy of decitabine given in the 3-day schedule among patients with AML and low blast counts, particularly by delaying progression or relapse. No impact of decitabine, compared to BSC or low-dose cytarabine, on OS in older patients with AML and 20 to 30% marrow blasts (median, 8.0 vs 6.1 months) has been previously also reported by Kantarjian et al. (J Clin Oncol. 2012;30:2670-7). In that study, decitabine was given with 20 mg/m2/day on 5 days every 4 weeks; PFS was not presented. The prolonged PFS that we observe may be used for example as non-intensive bridge to allogeneic stem cell transplantation after reduced-toxicity conditioning. Due to the post-hoc nature of our analyses and the relatively small patient numbers, further studies appear warranted to fully establish the benefit of decitabine in AML patients with low blast counts. Disclosures: Rüter: Boehringer-Ingelheim: Employment. Platzbecker:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Giagounidis:Celgene: Consultancy, Honoraria. Selleslag:Celgene: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Baron:Genzyme: Honoraria.

Background Secondary acute myeloid leukemia (sAML) describes patients (pts) with a history of malignant or non-malignant disease or AML secondary to environmental, occupational or therapeutic exposures. They are generally associated with poor outcome despite the use of intensive treatments. The impact of clinical features and type of treatment on pts' outcome is still not well established. In the current analysis we evaluated sAML pts who were treated in 13 EORTC collaborative trials conducted between May 1986 and January 2008. sAML pts in the database were pooled to characterize clinical features of the disease and evaluate changes in survival over these years (yrs). Method Main selection criteria were AML with bone marrows blasts ≥20% and documented history of prior malignancy, non-malignant disease and/or toxic exposure. AML-M3 and MDS without confirmed diagnosis ≥2 months before AML were excluded. All pts were eligible for standard treatment. Induction regimens were anthracycline and AraC based: 7+3, including etoposide, intensified with high dose (HD)-AraC randomized to standard doses (SD) in younger (AML12) or gemtuzumab ozogamicin in elderly pts. Consolidation regimens were age adapted. In mid-1980s, autologous transplant was tested vs a 2nd consolidation cycle (AML8A) in pts ≤45 yrs and thereafter used systematically in pts ≤60 yrs without available donor. Allogeneic transplant (Allo-SCT) was offered to pts ≤46 yrs with HLA-compatible sibling since mid-1980s and expanded in the last decade to pts up to 59 yrs. Selected pts were divided into 3 sAML cohorts, cohort A after MDS, cohort B after other malignant diseases and cohort C after non-malignant conditions and/or toxic exposure. Results Of 8858 pts enrolled in the 13 evaluated studies, 962 were sAML. Median age was 63 yrs (range 16-85), 413 were young (≤60 yrs) and 549 were elderly (≥61 yrs); 54% were males. Cohort A consisted of 509 pts (median age 64 yrs), cohort B of 362 pts (median age 59 yrs) and cohort C of 91 pts (median age 61 yrs). In cohort B, breast cancer (24%) and lymphoma (14%) were the most frequent primary tumors. Autoimmune diseases represented 22% of non-malignant conditions. In young pts, complete remissions (CR/CRi) rate was 59%; 55% in SD-AraC vs 89% in HD-AraC treated pts. Allo-SCT in CR1 was performed in 21% of all pts. The Allo-SCT rate increased from 5% before 1990, 20% in 1990-1999 to 25% from 2000 (20% in SD-AraC vs 31% of HD-AraC treated pts). CR/CRi was achieved in 45% of elderly pts. Median follow-up was 6 yrs. Median overall-survival (OS) was 14.5 months in young and 9 months in elderly pts. The 5-yr OS was 28% and 7% respectively. Five-yr OS was 11% in cohort A and 22% in both cohort B and C. Treatment outcome of younger pts according to disease features and treatment type over time in cohort A and B are detailed in table 1 & 2. Using Cox model stratified by cohort age, gender, WBC, risk group, year of treatment and HD-AraC were independent prognostic factors for OS. In the AML12 study, compared to denovo pts, sAML pts ≤45 yrs had worse outcome if treated with SD-AraC whereas a better OS was seen if treated with HD-AraC. In elderly pts only the good/intermediate risk group of cohort B had a relatively better 5-yr OS (15%). Conclusions The outcome of sAML in younger pts has improved over the yrs in parallel with HD-AraC introduction in induction of remission. HD-AraC should be considered for younger pts with sAML. Disclosures: Ramadan: Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other. Suciu:Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other. Meert:Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other. de Schaetzen:Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other Other.

Background Patients with acute myeloid leukemia (AML) frequently harbor mutations in genes involved in the DNA (hydroxy)methylation pathway (DNMT3A, TET2, IDH1, and IDH2). In addition, changes in DNA methylation have been implicated in the pathogenesis of AML. Recently it was discovered that TET proteins are able to convert 5-methylcytosine into 5-hydroxymethylcytosine (5hmC), which is an important intermediate in the demethylation pathway. In this study, we measured 5-hydroxymethylcytosine levels in AML patients, and correlated these with mutational status and overall survival (OS). Patients and methods Samples from 206 clinically and molecularly well-characterized younger adult AML patients (≤60 years), included in the EORTC/GIMEMA AML-12 06991 clinical trial, were analyzed for mutations in DNMT3A, TET2, IDH1 and IDH2. 5-hydroxymethylcytosine levels were measured using HPLC-MS/MS. Results In healthy control cells, 5hmC levels were confined to a narrow range (1.5 fold difference), whereas in AML cells, a much wider range was detected (15 fold difference). In remission, 5hmC values were normalized to levels comparable to healthy bone marrow and peripheral blood, indicating that the aberrant 5hmC levels at diagnosis are intrinsic to the leukemic cells. Patients with mutations in TET2 and patients with mutations in IDH1/2 had significantly lower levels of 5hmC compared to patients without mutated TET2 and IDH1/2 (both P Conclusion Both low and very high levels of 5hmC are markers of poor prognosis in AML, lending further support for testing therapies targeting the DNA hydroxymethylation pathway. Disclosures: No relevant conflicts of interest to declare.

Abstract 134 Background: Asparaginase (ASP) is an essential component in combination chemotherapy for childhood ALL and NHL, as indicated by several randomized trials. However, the optimal number of ASP administrations is still unknown. We conducted a randomized phase III trial comparing conventional E.coli ASP regimen (short-ASP, 12 doses) with prolonged E.coli ASP therapy (long-ASP, 24 doses). Methods: The European Organization for Research and Treatment of Cancer Children's Leukemia Group (EORTC-CLG) phase III 58951 trial was open to de novo ALL or NHL patients (pts) < 18 y. This BFM-based study addressed 2 main randomized questions. The first evaluated the value of dexamethasone (DEX, 6mg/m2/d) vs prednisolone (PRED, 60mg/m2/d) in induction for all pts. In the second question all non-very high risk (VHR) pts were randomized for either short- or long-ASP. All patients had to receive 8×10000 U/m2 in induction. In the short-ASP arm pts had to receive 4×10000 U/m2 in late intensification; pts in the long-ASP arm had to receive 8×5000 U/m2E.coli ASP injections in consolidation and 8 (4×10000 U/m2 + 4×5000U/m2) in late intensification. Patients with grade ≥2 allergy to E.coli ASP had to be switched to equivalent doses of Erwinia or PEG ASP. Central randomization was stratified by the 1st randomized arm, risk group (VLR, AR1, AR2) and center. The primary endpoint of the study was disease-free survival (DFS), secondary endpoints were overall survival (OS) and toxicity. Intention-to-treat analysis was performed. Results: Between December 1998 and August 2008, 2038 patients were randomized for the 1st question and 1552 pts, ALL (n=1481) and NHL (n=71), were randomly assigned to receive long-ASP (n=775) or short-ASP (n=777). At a median follow-up of 7 years there were 97 vs 112 events in the long- vs short-ASP group (see table). The 8-year DFS rate was 87.0% in the long-ASP and 84.2% in short-ASP group (hazard ratio (HR) = 0.87, 95% CI 0.66–1.14, 2-sided logrank p=0.30). The 8-year OS rate was comparable in both treatment arms: 92.6% in the long-ASP group and 91.3% in the short-ASP group (HR = 0.89, 95% CI 0.61–1.29, 2-sided log rank p=0.53). Similar treatment differences were observed in each risk group, in randomized arm (PRED vs DEX), and B- and T-lineage ALL pts. The incidence of grade 3–4 infection was higher in the long- vs short-ASP group during consolidation (25.2% vs 14.5%) and late intensification (22.6% vs 15.9%). This difference was more pronounced in pts who were randomly assigned to DEX (see table). In the long- vs short-ASP group grade 2–4 allergy to ASP was 22.5% vs 0.3% in consolidation and 10.3% vs 21.5% in late intensification. During the whole treatment period, the incidence of grade 2–4 allergy was 30.5% in the long-ASP arm and 21.7% in the short-ASP arm. In the long- vs short-ASP arm approximately 67% vs 95% pts received at least the total number of E.coli or equivalent ASP administrations as planned according to the treatment arm. Conclusion: At long follow-up (median= 7 yrs) prolonged E.coli asparaginase therapy in consolidation and late intensification for VLR and AR pts did not improve significantly the outcome. Intensive ASP treatment did increase infection rate in consolidation and late intensification and resulted in more grade 2–4 allergic reactions. In the future, we aim to improve outcome rates by the use of PEG ASP and monitoring of asparaginase activity and antibody formation. Disclosures: No relevant conflicts of interest to declare.

Abstract 121 The genetic landscape of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in children above 10 years and adolescents remains poorly defined. Specifically, more than half of these patients have none of the cytogenetic abnormalities that define oncogenic subtypes and underlie risk stratification. To uncover new genetic abnormalities in these unassigned cases, we studied 85 BCP-ALL from patients aged 10 to 17 diagnosed at St-Louis hospital (Paris, France), for which the main classifying genetic lesions were assessed (i.e. high hyperdiploidy, t(12;21)/ETV6-RUNX1, t(1;19)/TCF3-PBX1, t(9;22)/BCR-ABL1, iAMP21, MLL translocations, low hypodiploidy, and near haploidy). Fifty of these BCP-ALL presented no classifying genetic lesions. Paired leukemic and remission samples could be analysed by high density array-CGH (Agilent 1M arrays) in 17 of these unassigned cases. We focused on acquired, focal, and recurrent copy-number abnormalities. A mono-allelic intragenic deletion of the ETS-related Gene (ERG) was found in 3 cases. ERG belongs to the ETS family of transcription factors and is implicated in chromosomal translocations associated with several cancer types including acute myeloid leukemia. The possibility of a cryptic unbalanced translocation was ruled out in the 3 cases by FISH analysis. The deletions encompassed exons 3 to 7, or 3 to 9, and the breakpoints were tightly clustered. Based on the breakpoint sequences we designed a PCR assay that allowed us to screen ERG intragenic deletions in the whole cohort. ERG deletion was identified in 9 additional cases, none of them having any of the known classifying genetic lesions, bringing up to 25% (12 out of 50) the frequency of ERG deletion in unassigned BCP-ALL of children older than 10. These results suggested that ERG deletion characterized a novel oncogenic subtype of BCP-ALL. Of note, these results were consistent with independent data of Harvey et al. (2010) that reported ERG deletions in a distinct gene-expression cluster. To confirm and extend these findings in the whole population of paediatric BCP-ALL, we used our breakpoint-specific PCR assay to screen ERG deletions in an independent cohort of 822 unselected patients aged 1 to 17, enrolled in the EORTC 58951 trial. ERG deletion was identified in 31/822 (3.7%) patients. Again, none of them had another known classifying genetic lesion, confirming that ERG deletion characterizes a distinct oncogenic subtype. Patients with ERG deletion were significantly older compared to other patients (median 7.0 vs 4.0, p=0.002), but they had similar white blood counts at diagnosis. They had a favourable outcome, with a 8-year event free survival (EFS) of 82.4% and overall survival (OS) of 96.0%, which is similar to EFS of 83.4% and OS of 91.6% obtained for patients having no very high risk initial features (i.e. no t(9;22)/BCR-ABL1, MLL rearrangement or haploidy/low hypodiploidy). IKZF1 deletion is a cooperative genetic lesion that has been recently shown to be associated with a poor outcome in BCP-ALL. Remarkably, the incidence of IKZF1 deletions in patients with ERG deletion was significantly higher than in other BCR-ABL1-negative patients, especially when considering the IKZF1 intragenic deletion Δ4-7 (10/31, 32.3% vs 34/744, 4.6%, P Altogether, we have identified a novel oncogenic subtype of BCP-ALL characterized by ERG deletion. This subtype is frequently associated with IKZF1 deletions, suggesting a preferred oncogenic cooperation. Importantly, despite having older age and frequent IKZF1 deletions, which are factors usually predictive of a poor prognosis, patients with ERG deletion have a favourable outcome. Therefore, this genetic abnormality may be systematically assessed as part of the diagnostic work-up of BCP-ALL and taken into account when considering treatment stratification. Disclosures: No relevant conflicts of interest to declare.

Abstract 133 Background: T-cell acute lymphoblastic leukemia (ALL) accounts for 15% of ALL cases in children and has been associated with a higher risk for central nervous system (CNS) relapse and a worse prognosis. In EORTC trials 58831 and 2, standard risk (SR) patients (pts) were not irradiated but received intermediate dose methotrexate (MTX) courses; for medium and high risk pts, high dose (HD) MTX was added to the treatment regimen and the administration of cranial radiotherapy (RT) was randomised. The omission of RT didn't result in an increase of CNS or systemic relapse and consequently, CNS-directed chemotherapy was substituted for RT in all following trials. The long-term outcome of T-ALL pts in the subsequent phase III trials (58881 and 58951) are presented here. Methods: The BFM backbone for ALL treatment was applied to all EORTC-CLG trials since 1983. As CNS treatment in study 58881, SR pts received 4 HD MTX courses (5 g/m2) in interval therapy and 10 IT MTX injections during the intensive treatment phases. Pts with CNS-3 status at diagnosis received 2 additional IT injections during induction, 2 during consolidation and 6 HD MTX courses + IT during maintenance. T-ALL pts with poor prephase response (PPR) at day 8 or who didn't achieve complete remission (CR) after induction were included in the very high risk (VHR) group. VHR CNS-directed chemotherapy included 10 IT MTX injections, 6 IT triple and 10 HD MTX courses during intensive treatment phases, followed by 4 IT MTX injections during maintenance (the latter for CNS-3 pts only). In the 58951 trial, all T-ALL pts had an intensified induction. The CNS-directed therapy of all average risk T-ALL pts was intensified to 11 HD MTX courses, 1 IT with MTX and 15 triple IT. MRD ≥ 1% at the end of induction was added as VHR criterium. All non-transplanted VHR pts received 1 IT MTX injection, 19 IT triple and 9 HD MTX courses. Several randomized questions were addressed in both trials of which most relevant for T-ALL pts: in study 58881 the comparison E.coli asparaginase (ASP) Medac versus (vs) “other ASP” (= Erwinia ASP or E.coli ASP Bayer); in trial 58951 1) the comparison dexamethasone (DEX 6 mg/m2/d) vs prednisolone (PRED 60 mg/m2/d) in induction and 2) conventional vs prolonged E.coli ASP for non-VHR pts. Results: 303 and 296 T-ALL pts were included in trials 58881 and 58951 resp, representing 14.5% and 15.2% of all pts. Outcome results and type of events for the entire 58881 and 58951 cohorts and according to several subgroups are presented in the table. The 8-year isolated and overall CNS relapse incidences were 6.8% and 10.9% in study 58881, 5.3% and 8.5% in study 58951. The 8-year EFS, DFS and OS improved remarkably in study 58951. In the latter trial, outcome improvement was particularly seen in pts with initial WBC100x10E9/L and for pts with PPR treated in the DEX arm (HR (99%CI): 1.52 (0.63;3.64) and 1.47 (0.64;3.35)). Prolonged ASP treatment did not improve outcome of the whole T-ALL 58951 cohort. Conclusion: Prophylactic and therapeutic RT can safely be omitted from frontline treatment of children with T-ALL. Adequate ASP therapy, intensified induction treatment and CNS directed therapy can result in a significant improvement of the outcome of at least 2/3rd of T-ALL pts, particularly those with initial WBC Disclosures: No relevant conflicts of interest to declare.

Abstract 2804 Background: The “monosomal karyotype” cytogenetic subgroup (MK+), as defined by Breems et al. (1) encompasses mostly complex karyotypes (CK, >3 abnormalities) and is associated with very poor outcome in AML (1, 2) and MDS (3). Discussions are ongoing regarding treatment response prediction, and a prognosis-modifying effect within the CK+ AML subgroup (1, 4). In a study of 227 AML pts >60 years, 38 of whom were MK+, we found that particularly pts with at least 2 monosomal autosomes (MK2+, by definition also CK+) appeared to benefit from DAC (5). We now applied this question to higher-risk MDS pts randomized to either DAC or Best supportive care (BSC) in the 06011 trial (6) which explicitly enrolled pts with IPSS poor-risk cytogenetics. Methods: Of 233 randomized pts, 206 had cytogenetics informative for MK status: 63 had normal cytogenetics (CN), 143 had cytogenetic abnormalities (CA) without MK (MK-, n=73) or with MK (MK+, n=70). This last group was further subdivided into pts with 1, 2 or at least 3 monosomal autosomes (MK1, MK2, MK3+, n=17, 22, 31, resp.). Endpoints were overall survival (OS), progression-free survival (PFS) and response rate (RR, complete and partial remissions, hematologic improvement). Analysis was based on the intent-to-treat principle. Results: As recently published (6), in the overall 233 pts, PFS was significantly improved in the DAC arm as compared to BSC (median 0.55 vs 0.25 years, hazard ratio [HR] 0.68, p=0.004), but not OS (HR 0.88), probably due to post-progression treatments, suboptimal DAC schedule and treatment duration as possible confounders. In the 206 pts with informative cytogenetics, significant improvement in outcome with DAC vs. BSC was also seen for PFS (p=0.022, HR 0.72, Table 1) but not OS (HR 0.93). The improvement of PFS with DAC vs BSC was quite pronounced in the 63 pts with CN (HR 0.55, p=0.03), but less impressive and not significant in the 143 pts with CA (HR 0.76, p=0.11). When subdividing the latter by MK categories, pts with either 2 (MK2) or more than 2 (MK3+) monosomal autosomes also had significantly prolonged PFS with DAC, reflected in RR of 67% in MK2 and 33% in MK3+ DAC-treated pts (Table 1). This effect was not obvious in the MK1 subgroup, where the PFS outcome was favorable in both treatment groups, and in the MK− subgroups, either without (“MK−/CK−”) or with complex karyotype (“MK−/CK+”), the latter having a very poor outcome in both treatment groups. With caution (considering the limited size of some subgroups), these results support our observation that AML pts with a complex karyotype harboring 2+ monosomies can gain benefit from this hypomethylating agent. Conclusions: This first randomized trial addressing the predictive value of the MK genotype in the presence of 2+ monosomies embedded in a complex karyotype demonstrates a very rapid deterioration of MDS pts receiving BSC (within Disclosures: No relevant conflicts of interest to declare.

Abstract 2615 Background: The first EORTC-CLG AML pilot study (58872) demonstrated the efficacy of Mitoxantrone (MTZ), substituted for daunorubicin, in the treatment of childhood AML. The subsequent trial (58921) aimed to compare MTZ and Idarubicin (IDA), an anthracycline with a favorable pharmacokinetic profile (such as good CSF penetration) and suggested to be more efficacious than daunorubicin in adult AML trials performed in the last two decades. Methods: Between March 1993 and December 2002, 227 eligible patients (pts) =70×10E9/L was abandoned from November 1994 on. Randomization was done centrally. The primary endpoint was EFS; secondary endpoints were OS, CR rate after induction/1st intensification, DFS and toxicity. Intention-to-treat analysis was used. Results: A total of 112 and 115 eligible pts were randomly assigned to receive IDA and MTZ, respectively. The rate of CR after two courses was 79.5% (IDA) vs 85.2% (MTZ). At an overall median follow-up of 9.9 y (range 0.25–16 y), there were 65 vs 59 events in the IDA vs MTZ group: failure to achieve CR (23 vs 17), relapse (35 vs 40), and death without relapse (7 vs 2). The 5-year EFS rate was 42.0% (SE 4.7%) in the IDA group and 48.4% (SE 4.7%) in the MTZ group (hazard ratio (HR) = 1.20, 95% CI 0.84–1.71, 2-sided log rank p=0.29). The 5-year OS rate was comparable in both treatment arms: 59.8% (SE 4.6%) in the IDA group and 57.5% (SE 4.7%) in the MTZ group (HR = 1.03, 95% CI 0.70–1.54, 2-sided log rank p=0.87). In CR patients with (N=46/187) or without (N=141/187) an HLA-identical sibling donor, the 5-year DFS rate from CR was 65.1% (SE 7.1%) and 51.5% (SE 4.2%) respectively (HR=0.65, 95% CI 0.37–1.11, 2-sided log rank p=0.11) and the 5-year OS rate 78.0% (SE 6.1%) and 60.7% (SE 4.1%) respectively (HR=0.53, 95% CI 0.28–1.01, 2-sided log rank p=0.048). This advantage for patients with a donor remained important regarding both DFS (HR=0.60, p=0.07) and OS (HR=0.49, p=0.03), even after adjustment for WBC count at diagnosis, age, cytogenetic features and randomized arm. The interval between start of induction and start of 1st intensification was similar in both arms (median 5.2 weeks). Grade 3–4 infection following the induction course was 37.5% (IDA) vs 25.4% (MTZ); incidence of fever grade 3–4 was 25% (IDA) vs 22.8% (MTZ). In this trial, the cumulative anthracycline dosage (conversion factor 5) was 380 mg/m2. Acute and late-onset cardiotoxicity was comparable in both treatment arms. Conclusion: There was no significant difference in efficacy and in toxicity between the two randomized treatment groups, IDA versus MTZ, although grade 3–4 infection rate following the induction course was slightly higher in the IDA arm. Patients who reached CR and who had a HLA compatible sibling donor had a longer DFS and OS than pts without a donor. Disclosures: No relevant conflicts of interest to declare.

Abstract 2610 Introduction: Remission induction treatment in previously untreated intermediate/bad risk AML or high risk MDS needs continuous improvement. Clofarabine is a nucleoside analog with proven activity in acute leukemias. The aim of the study was to determine the recommended/maximum tolerated dose (MTD) of Clofarabine when administered with standard remission induction regimen (Ara-C and Idarubicin) in patients suffering from AML/MDS. Methods: This open label, 2-arm, multi-center, phase I trial included adult patients (pts) with previously untreated intermediate/bad risk AML or high risk MDS. All FAB subtypes except M3 and the cytogenetic groups, t(8;21) or inv(16) with WBC 0.5 × 109/l and platelets >50 × 109/l) later than 8 weeks after start of remission induction. If 1 out of the first 3 pts experienced a DLT, 3 additional pts were added (a maximum of 6 pts per dose level) in order to ensure the safety profile of this dose level. If a second patient experienced a DLT, no further pts were entered at that particular dose level. Dose escalation stopped and additional pts included at the previous lower dose to have a minimum of 6 pts treated at the recommended dose. Results: 25 pts have been entered into this phase I part in 3 participating sites. WHO PS status was 0 (N=16), 1 (N=8) or 2 (N=1). Age range was 25–60 years (median 55 years). 20 pts had de novo AML, 3 pts had secondary AML, 2 pts had de novo MDS (WHO RAEB-2). 7 pts had high cytogenetic risk features. In arm A and in arm B 10 mg/m2/d Clofarabine, and in arm A 15 mg/m2/d Clofarabine 6 pts each have been included. In arm B 15 mg/m2/d Clofarabine 7 pts were included, as one patient was substituted since she received 60% of total dose of Clofarabine and refused further treatment with Clofarabine due to related adverse event. All 25 pts were evaluable for DLT analysis. Overall, 5 pts with DLTs were observed: 1 in Arm A 10mg/m2/d Clofarabine, 3 in Arm A 15 mg/m2/d Clofarabine, 1 in Arm B 15 mg/m2/d Clofarabine. One patient with prolonged hematological toxicity as DLT reported in Arm A 10mg/m2/d Clofarabine. Two deaths in cytopenia/aplasia and one toxic death following sepsis/multiorgan failure have been reported as DLTs in 3 patients in both Arm A and B 15 mg/m2/d Clofarabine. The 5th patient had grade 4 anorexia, diarrhea, infection, prolonged hypoplasia and grade 3 confusion which classified as DLT in Arm A 15 mg/m2/d Clofarabine. In addition, three pts in the 15 mg/m2/d Clofarabine arms needed to be withdrawn from Clofarabine due to adverse events not classified as DLT. Main toxicity was bone marrow toxicity resulting in prolonged aplasia. Out of 25 pts, complete remission (CR) following induction 1/2 has been achieved in 19 pts: in 10/12 pts using 10 mg/m2/d Clofarabine (5 pts each in Arm A and Arm B) and in 9/13 pts using 15 mg/m2/d Clofarabine (4 pts in Arm A and 5 pts in Arm B). In addition CR with incomplete blood count recovery (CRi) following induction 1/2 was observed in 2 pts: 1 in Arm A 10 mg/m2/d Clofarabine and 1 in Arm B 15 mg/m2/d Clofarabine. Conclusion: Infusion of 15 mg/m2/d Clofarabine resulted in a high rate of DLTs (4/13 pts) and early treatment withdrawals (3/13 pts). The infusion of 10 mg/m2/d Clofarabine had an acceptable rate of DLTs (1/12 pts), no early treatment withdrawals occurred, and a high CR/CRi rate (11/12 pts) was observed. Therefore the MTD of Clofarabine in combination with Ara-C and Idarubicin is defined at 10 mg/m2/d and will be the recommended dose for the phase II part of this study. Disclosures: Willemze: Genzyme: member advisory committee clofarabine. Muus:Amgen: Membership on an entity's Board of Directors or advisory committees. de Witte:Novartis: Consultancy, Honoraria, Speakers Bureau.

Abstract 565FN2 Hyperdiploidy >50 chromosomes (HD>50) has long been recognized as favorable group in childhood B-ALL but there is still debate on the factors contributing to heterogeneity of prognosis observed within this entity. Better outcome has been reported for patients (pts) presenting DNA index (DI) >1.16 (Blood 1985;10:213), ≥56 chromosomes (Leukemia 1996;10:213), triple trisomies (TT) +4,+10,+17, double trisomies +4,+10 (Leukemia 2005;19:734) and trisomy 18 (Blood 2003;102:2756) but there is no consensus between the reports and these factors are differently applied in current protocols. We studied these factors in the pts with HD>50 enrolled in the ALL 58951 trial, BFM related. HD>50 were detected by cytogenetics (karyotype/FISH) and/or flow cytometry (DI). In order to analyze the outcome of HD>50 itself, pts with recurrent unfavorable translocations t(9;22), 11q23/MLL+, with t(1;19), t(12;21) or Down Syndrome were excluded, as well as near-triploidies/duplication of hypodiploidies 30–39 chromosomes. Pts were stratified into 4 risk groups (VLR/AR1/AR2/VHR) according to DI, Modal Number of Chromosomes (MNC), WBC, CNS/gonadal involvement, presence of VHR features (unfavorable translocations, poor response to prephase, residual disease (MRD) at the end of induction >10-2). VLR was defined as: DI>1.16 or MNC>50, WBC Overall Results: Out of 1651 B-lineage pts registered in the 58951 study over a 10-year period (1998-2008), a total of 541 pts had HD>50. Median age was 3 years and median WBC was 5.6×109/L. After prephase, 3% (N=17) were poor responders; initial risk group distribution into VLR/AR1/AR2/VHR was 45%/47%/5%/3%. After induction, 540 (99.8%) reached complete remission, 455 of whom had an MRD evaluation: MRD10-3 (N=26;6%) or MRD≥10-2 (N=13;2%). At median follow-up of 6 years, 48 pts (9%) relapsed, 22 pts (4%) died and 6 (1%) died without relapse. The 6-yr EFS was 89% (SE=1.5%). MNC was assessed in 446 pts (82%) with successful karyotypes, MNC ranged from 51 to 66 chromosomes and peaked at 55–56; 87 pts had 51 to 53 chromosomes (HD51-53), 258 pts had 54 to 57 (HD54-57) and 101 pts had ≥58 chromosomes (HD≥58). In these 3 groups, VLR regimen was given to 16%, 50% and 64% respectively. Structural abnormalities were detected in 46% of pts and associated with all MNCs. DI, assessed in 460 pts was Prognostic Factors: The only significant prognostic factors for EFS were MNC, DI, TT, DT and MRD. EFS was clearly improved (p10-2 and 2 pts: MRD≥10-3) and only 1 pt (MNC=58) relapsed. No specific profile of chromosome gains was identified in HD ≥58 since all chromosomes contributed to tri/tetrasomies, except chromosome 1. Likewise, the higher the DI the better the outcome (p=0.01): 6-yr EFS was 83% (DI TT were detected in 168 out of 468 pts, and DT in 242 out of 466 pts. There was no overlap with HD ≥58 since TT and DT were distributed from 52 to 66 chromosomes. One third of TT and of DT had MNC≥58. TT and DT were also of prognostic importance for outcome: the 6-yr EFS rate was 96% (TT) vs 86% (non-TT) (p=0.005) and 94% (DT) vs 84% (non-DT) (p=0.003). A hierarchical variable based on presence of HD≥58, TT or DT showed that HD ≥58 (N=101; 6-yr EFS: 99%) group had a better outcome than TT without HD≥58 (N=115; 6-yr EFS: 93%) and DT without HD≥58 and without +17 (N=55; 6-yr EFS: 84%) groups (p=0.04). We can infer from our results that the good outcome observed for all of the TT and DT was partially due to their association with HD '58. Consequently, the best indicator for excellent outcome was a high MNC (≥58 chromosomes). From our 58951 trial, we can assume that among children with B-ALL and HD>50, those with ≥58 chromosomes, stand every chance of being cured. Our results stress the necessity of karyotype for identifying them since this is the only way to assess MNC. They can also be detected (less accurately) by DI (DI ≥1.24). Therefore, both MNC and DI should be used for stratifying pts in the very low risk groups. Disclosures: No relevant conflicts of interest to declare.

Abstract 4896 Background: Primary Cutaneous T-cell Lymphomas (CTCLs) are a heterogenous group of lymphomas, as outlined in the WHO classification. Due to the rarity of CTCL, very few prospective randomized trials have been performed for this disease. EORTC consensus recommendations for the treatment of early CTCL have been published, but treatment of advanced stage disease remains largely empirical, based on small non-randomized, uncontrolled studies with uncertain response data and limited chances to affect clinical practice. Methods: The CTCL platform has been designed by the EORTC Cutaneous Lymphoma Task Force to address critical unadressed questions to move forward the standards of care of CTCL in advanced stage disease. It was built following a sequential approach. Following a European consensus defining the key clincial questions to improve disease control in CTCL, ideas regarding the biology of the disease and all possible emerging targets which may lead to a better understanding of the disease were explored. The candidate targets were selected and prioritized by their scientific and clinical relevance. The maturity and relevance of agents in development to tackle these pathways and targets were analyzed. Methodologically and statistically robust clinical trials were designed to allow the enrollment of patients through the evolution of their disease. Endpoints and translational research programs that could address and help identify mechanisms of action and clinical efficacy were also evaluated as to feasibility and scientific relevance. This comprehensive process lead to the design of early phase randomized trials on solid scientific grounds with the use of innovative drugs. Study protocol 21081 is a multicenter, randomized, open-label, phase III study and is suitable for patients who have not previously had other intravenous chemotherapy, and are therefore relatively treatment-naïve. The accrual goal is 105 patients. The objective of this trial is to test the hypothesis that lenalidomide is able to increase progression free survival in patients achieving a complete (CR) or partial (PR) response after standardized debulking treatment. A sister protocol, 21082, is addressed to patients who have had previous chemotherapy. Patients in that study will be treated with the histone deacetylase inhibitor vorinostat, with or without the addition of the proteosome inhibitor bortezomib. The primary objective of this trial will be to determine if the combination of bortezomib plus vorinostat is more effective than a histone deacetylase inhibitor alone in terms of prolonging progression free survival. The presentation will address details of the disease biology which gave rise to these trials and the selection of innovative agents, the procedures of the strategy adopted and the challenges of designing methodologically valid trials addressing this rare disease. Disclosures: Ortiz-Romero: MSD: Consultancy; Ferrer: Honoraria.

Abstract 4024 Background: The hypomethylating agents 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine (Decitabine, DAC) are active in different MDS subtypes. Compared to other response predictors to DAC, prior MDS duration has received only limited attention (1, 2), with conflicting results. Based on our finding that long duration of MDS prior to DAC treatment may be a novel factor linked to a better outcome (1), we now assess its value in the phase III trial 06011 (DAC versus BSC [3]). Immediate enrolment after diagnosis was allowed in that trial, median MDS duration prior to randomization thus only 3 months (mths). Methods: Comparison of progression-free (PFS), AML-free (AMLFS) and overall survival (OS) according to MDS duration >= vs. Results: A better prognosis of patients with MDS duration >=3 vs =3 mths (B vs D). In both arms (n=233), Mult. indicated that MDS duration (>=3 vs Conclusion: In intermediate-2 and high-risk MDS pts, long duration from MDS diagnosis to start of DAC or BSC appeared to be associated with a better outcome. This finding is in sharp contrast to the adverse prognostic impact of antecedent disease duration in patients who received intensive chemotherapy (4). It is supported by a similar analysis of pts with AML from MDS treated on the 00331 DAC phase II multicenter trial: those with longer MDS duration prior to DAC also had better outcome (5). Application of this discriminator in the evaluation also of other DAC schedules and MDS treatments therefore appears warranted. References: 1. Wijermans et al., Ann. Hematol. 84 (suppl. 1): 9–14, 2005 2. Kantarjian et al., Cancer 109:265-73, 2007 3. Wijermans et al., Blood 112 (suppl. 1): abs. 226, 2008 4. Estey et al., Blood 90:2969-77, 1997 5. Lübbert, Schmoor et al., abstract submitted, ASH 2010 Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salih:Pfizer: Research Funding. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Abstract 791 The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) combined with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability, cytogenetics and age. A 2nd randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2 (4-8 × 106 IU s.c. for 5 days per month) during one year. A total of 577 patients were required to be randomized for the 2nd question in order to reach 255 events (relapses or deaths) which would allow to detect a 11.5% increase in the 3-year disease-free survival (DFS) from 50% to 61.5% corresponding to hazard ratio (HR) = 0.70 (2-sided alpha=5%, statistical power=80%). Randomization was performed centrally; the 2nd randomization was stratified for induction treatment, cytogenetic/molecular genetic group, number of courses to reach CR, auto-SCT planned (No/Yes) and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age Disclosures: Muus: Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: An overview of trials dating back to the ‘70s and ‘80s has shown that addition of vincristine (VCR)+prednisone/prednisolone pulses to continuation therapy of childhood ALL, i.e. 6-mercaptopurine (6-MP) + methotrexate (MTX), improved disease-free survival (DFS) (Lancet, 1996). However, a recent randomized intergroup trial (IGT) has shown that, when given to intermediate risk (age=6 yrs or WBC>20×109/L) patients (pts) treated according to the BFM protocol, VCR+dexamethasone (DEX) pulses in continuation therapy failed to improve DFS and overall survival (Lancet, 2007). Methods: In 12/1998, EORTC CLG started the randomized phase III 58951 trial addressing 3 questions: R1) the value of DEX vs PRED in induction; R2) the value of prolonged (24 injections) vs conventional (12 injections) duration of L-asparaginase (ASPA) courses during consolidation and late intensification; R3) for average risk (AR) pts only: the value of 6 (VCR+corticosteroid) pulses every 10 weeks during continuation therapy. The corticoid of the pulses was that assigned to the patient at R1: DEX (6 mg/sm/d) or prednisolone (PRED) (60 mg/sm/d) during 7 days. AR pts were defined by being neither low risk (hyperploidy > 50 or DNI>1.16, and WBC Results: Between 6.1999 and 11.2004, 411 pts, ALL (N=384) and NHL (N=27), were randomized for the pulse question. In the Pulses group, 101 vs 101 pts were randomized for PRED vs DEX. At a median follow-up of 6.3 years, there were 19 vs 34 DFS events for the Pulses vs No Pulses comparison: BM (10 vs 16), CNS only (1 vs 4), other isolated (2 vs 3), BM+CNS (2 vs 5), BM+other (4 vs 4), death in CR (0 vs 2). The 6-year DFS rate from randomization was 90.6% (SE 2.1%) in the Pulses group and 82.8% (SE 2.8%) in the No Pulses group (hazard ratio (HR) = 0.54, 95% CI 0.32–0.94, 2-sided logrank p=0.027). The impact of pulses on DFS was similar in the PRED group (HR=0.56) and the DEX group (HR=0.59). In girls the treatment difference seemed to be more pronounced (HR=0.25, 99% CI 0.04–1.25; p=0.015) than in boys (HR=0.71, 99% CI 0.30–1.66; p=0.30), and also in those having been randomized to receive conventional duration of ASPA courses (HR=0.46, 99% CI 0.18–1.19; p=0.03) than in prolonged ASPA arm (HR=0.87, 99% CI 0.23–3.29; p=0.78). Grade 3–4 hepatic toxicity was lower in the Pulses group (30% vs 40%); incidence of grade 2–3 osteonecrosis was 4.4% (Pulses) vs 2% (No Pulses) and pancreatitis rate was 4.9% (Pulses) vs 2.9% (No Pulses). Conclusion: VCR+corticosteroid pulses, at long follow-up (median=6.3 yrs), significantly improved the DFS, particularly in pts having received conventional duration of ASPA. Pulses did not increase toxic effects. In future, for AR pts treated according to the BFM protocol, pulses should become a standard component of therapy.

Treatment of AML in the elderly remains challenging. In particular, few therapeutic options exist for patients (pts) who are not considered medically fit for intensive chemotherapy. Gemtuzumab ozogamicin (GO), a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, has demonstrated single agent efficacy in older patients with relapsed AML. In a previous trial we reported a complete response rate of 17% when the licensed dose/schedule of GO was used as frontline monotherapy for older unfit pts with AML, but excess hematologic and liver toxicity suggested changes in both dosing and scheduling to improve feasibility. The AML-19 study was designed as a sequential phase II–III trial in pts of age 61 or over with untreated AML, who could not be considered candidates for, or must have declined, conventional intensive chemotherapy. The primary objective of the phase II study was to investigate whether any of two different schedules of lower dose GO monotherapy (total delivered dose 9 mg/m2 in 2 or 3 fractions over one week) is sufficiently effective and tolerable frontline therapy to continue phase III comparison with best supportive care (BSC). Pts had to have adequate renal and hepatic function, and the WBC count had to be less than 30,000/cmm at the time of registration. Two-thirds of the pts were randomly assigned to receive a single induction course of either GO 3 mg/m2 iv on days 1, 3 and 5 (arm A), or GO 6 mg/m2 iv on day 1 and 3 mg/m2 on day 8 (arm B); the remaining third was assigned to the BSC arm. Randomization was stratified by age, performance status (PS), initial WBC, CD33 expression on marrow blasts, and Institution. Pts with no evidence of objective disease progression were eligible to receive continuation treatment with monthly outpatient infusions of GO at 2 mg/m2 for a maximum of 8 months. Primary end-point of the phase II study was clinical benefit rate (CBR) defined as the number of pts either achieving a remission (CR, CRp, PR) or maintaining a stable disease (SD) in each experimental arm. The arm associated with the highest CBR would be selected for phase III assessment, providing that it is at least 48% (Simon design). Between 06/2004 and 12/2006, 56 pts were randomized in the two experimental arms (arm A 29; arm B 27). The two arms were comparable in terms of age (arm A: median 77 yrs; arm B: median 78 yrs), PS >2 (arm A: 7%; arm B: 4%), secondary AML (arm A: 45%; arm B: 37%), and CD33 expression on ≥20% marrow blasts (arm A: 86%; arm B: 85%). In arm A, 6 pts achieved CR, 2 PR, and 3 maintained SD for an overall CBR of 38% (90% CI, 23%–55%); in arm B, 5 pts achieved CR, 1 CRp, and 11 maintained SD for an overall CBR of 63% (90% CI, 45%–78%). Most toxicities were

The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after CR in pts without a donor: auto-SCT followed or not by low dose IL-2. The trial was powered to detect an 8% difference in the 5-yr survival rate; secondary endpoints were response to induction, DFS, toxicity. Randomization was performed centrally; the 1st randomization was stratified for age, performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age

Background: there is some biologic and clinical evidence that DEX is more efficient than PRED at similarly anti-inflammatory doses in the treatment of childhood ALL. Previous trials have called for PRED doses (40 mg/sm/d) lower than those of PRED traditionally used in EORTC trials. In order to check whether the claimed superiority of DEX might be dose-dependent, we conducted a randomized phase III trial comparing DEX (6 mg/sm/d) to PRED (60 mg/sm/d) (conventional dose) in induction therapy. Methods: the trial was opened in 12/1998 to all newly diagnosed children with ALL up to 18 y. of age. After the opening of the Interfant trial in 1999, children Results: between 12/1998 and 2/2008, a total of 1853 ALL pts were randomized; as of 2/2008, 1703 pts were evaluable for EFS analysis. At a median follow up of 4.3 y., the 5 y. EFS rate was 82.1% (SE 1.5%) for the pts in the DEX arm and 82.4% (SE 1.5%) in the PRED arm (hazard ratio (HR) = 0.99, 98.8% CI 0.72–1.36, p=0.94); the futility boundary was crossed. In precursor-B ALL pts, the 5 y. EFS rate was 84.2% (DEX) vs 84.1% (PRED) (HR=0.95, p=0.75) and in precursor-T ALL the 5y. EFS rate was 70.7% vs 72.0% (HR=1.06, p=0.83). Isolated and combined CNS relapse crude rates were 1.1% each (DEX) vs 1.6% and 2.2% (PRED) respectively (resp.). The 5-y CNS incidence rate was 2.9% (DEX) vs 4.9% (PRED), the non-CNS incidence rate was 10.9% (DEX) vs 9.4% (PRED), and the 5-yr death in CR incidence rate was 2.7% (DEX) vs 2.1% (PRED). During induction the incidence of grade 3–4 infection was very similar in the two arms. During post-induction consolidation (“protocol IB”), it was higher in the DEX arm (23.5% vs 21.1%), in particular in pts randomized to prolonged L-asparaginase arm: 29.1% (DEX) vs 21.8% (PRED). Conclusion: DEX and PRED, used at the doses of resp. 6 and 60 mg/sm/d during induction, had equal efficacy. DEX decreased by 2.0% the 5-yr CNS incidence rate but increased by 1.5% the non-CNS incidence rate and by 0.6% the death in CR incidence rate. DEX in induction entails a higher infection rate during the consolidation, particularly when L-asparaginase is pursued throughout this phase. The optimal dosage of either glucocorticoid, compatible with acceptable toxicity, remains to be determined.

Background: Cranial irradiation (XRT) in combination with intrathecal chemotherapy has markedly reduced the incidence of meningeal relapse in childhood acute lymphoblastic leukemia (ALL), and is still recommended for patients (pts) at high risk of relapse within the CNS. Because of late adverse effects of XRT, the previous CLG trial (EORTC 58881, 1989–1996) deleted XRT from the treatment regimen of all ALL patients. Nevertheless, the results (5-year event-free survival (EFS) rates) of 58881 trial were good in CNS-1 (72.1%), dubious CNS-2 (62.2%), surreptitious CNS-2 (64.6%) and particularly good in pts with CNS leukemia involvement (70.3%, SE 6.2%), emphasizing the importance of systemic chemotherapy in such pts, of whom, 50% were treated according to a very high risk group protocol (ASH, 2006). In order to validate this therapeutic strategy, we evaluate the prognostic significance of CNS status at diagnosis in ALL children enrolled from 12/1998 to 2/2008 in the EORTC CLG 58951 randomized phase III trial. Methods: Treatment design was according to BFM. Three randomizations were programmed: R1) the value of Dexamethasone (DEX) vs Prednisolone (PRED) during induction (all pts); R2) the value of prolonged (24 injections) vs conventional (12 injections) duration of L-asparaginase courses during consolidation and late intensification (all except very high risk pts); R3) the value of 6 (DEX or PRED + vincristine) pulses every 10 weeks in maintenance therapy (average risk pts). CNS-directed therapy consisted in i.v. methotrexate (MTX) (5 g/sqm over 24 hours) in 4 to 10 courses, according to the degree of initial CNS involvement, and intrathecal MTX. No radiotherapy was used. According to CNS status, pts were classified in 4 groups: CNS-1: no blasts and WBC5/μl, RBC Only CNS-3 pts were to receive 10 courses of i.v. MTX, but some of dubious (n=21) and surreptitious CNS-2 pts (n=38) did eventually receive 10 courses as well. Results: Between 12/1998 and 2/2008, a total of 1853 ALL pts were registered in 58951 trial. On 2/2008 a total of 1686 were evaluable for EFS; the distribution according to initial CNS status was: CNS-1 (n=1494, 88.6%), dubious CNS- 2 (n=100, 5.9%), surreptitious CNS-2 (n=59, 3.5%) and CNS-3 (n=33, 2%). The higher the degree of CNS involvement, the higher the incidence of unfavourable features: initial WBC□100000/μl, T-lineage, NCI high risk; very high risk (VHR) initial features (peripheral blasts ≥1000/μl post prephase, high-risk cytogenetics). In CNS-3 group, 10/33 (30%) pts were treated according to VHR protocol. Median follow-up was 4 years. CNS-1 Dubious CNS-2 Surrept. CNS-2 CNS-3 No CR 17 (1.1%) 0 (0%) 0 (0%) 1 (3.0%) CCR 1286 (86.1%) 84 (84.0%) 50 (84.7%) 22 (66.7%) Isolated CNS rel. 17 (1.1%) 3 (3.0%) 1 (1.7%) 2 (6.1%) Combined CNS r. 23 (1.5%) 1 (1.0%) 2 (3.4%) 2 (6.1%) Non-CNS relapse 20 (13.4%) 2 (2.0%) 1 (1.7%) 5 (15.2%) Death in CR 31 (2.1%) 2 (2.0%) 1 (1.7%) 1 (3.0%) 4-yr EFS (%, SE) 84.0% (1.1%) 88.2% (3.5%) 82.4% (5.4%) 55.1% (10.8%) 4-yr OS (%, SE) 90.7% (0.9%) 92.0% (2.9%) 88.0% (4.6%) 63.4% (12.8%) Conclusion: In comparison with previous EORTC 58881 trial, and according to CNS status, EFS, OS, and isolated and combined CNS relapses rates improved in 58951 trial, except for CNS-3 pts. These “disappointing” results in CNS-3 pts (representing 2% of the entire population), less heavily treated in 58951 than in 58881, confirm the importance of systemic chemotherapy in such pts.

Introduction: In 2002 the EORTC and the German MDS Study Group initiated a randomized phase III study comparing low dose Decitabine to supportive care in patients (pts) of 60 years or older with primary or secondary MDS or CMML. MDS patients with either 11–20% BM blasts or ≤ 10% blasts and poor cytogenetics could be included. Pts with a BM blast count between 21–30% without signs of disease progression for at least one month were also candidates for the study. Methods: Patients were centrally randomized; stratification factors were cytogenetics risk group, IPSS, MDS (primary vs secondary) and study centre, The treatment schedule was 15 mg/m2 Decitabine i.v. over 4 hours every 8 hours for the first 3 three consecutive days, of every 6 week-cycle, for a maximum of 8 cycles. Results were evaluated every 2nd cycle. When a complete remission was reached at least another 2 courses were given. The primary endpoint of the study was Overall Survival. AML free survival, Progression Free Survival (PFS), response rate, toxicity and QoL were secondary endpoints. A total of 185 deaths were required to detect a hazard ratio (HR) of 0.66 (alpha=5%, beta=20%). Intent-to-treat analysis was used. Results: Between 10.2002 and 5.2007 a total of 233 pts (149 male and 84 female) were recruited from 40 centres. The median age was 70 (60–90 years); RAEB-t was diagnosed in 32% of the pts. Most pts had an IPSS Intermediate-2 (55%) or high risk (38%). Poor risk cytogenetics was found in 46% of the patients. Prior therapy for MDS (not being intensive chemotherapy) was given in 20% of pts. The randomized groups were well balanced regarding stratification factors, age and FAB classification. The median follow up was 2.5 years. Time to Off Study was 180 (Decitabine) vs 112 days (SC arm). The median number of cycles given to the patients was 4 with 40%getting no more than 2 cycles. In a significant number of pts, subsequent treatment, consisting of transplant (10%) or induction chemotherapy (11%), was given. The distribution of best response in Decitabine vs SC arm was CR (13% vs 0%), PR (6% vs 0%), HI (15% vs 2%), SD (14% vs 22%), PD (29% vs 68%), hypoplasia (14% vs 0%), inevaluable (8% vs 8%). The 18 pts on Decitabine with a HI showed the following responses: 3-lineage (n=7), 2-lineage (n=5) and 1-lineage (n=6). The median time to response (CR/PR/HI) was 0.32 yrs and the response duration was 0.72 years. Median OS was 0.84 (Decitabine) vs 0.71 years (SC arm), estimated HR was 0.88, 95% CI 0.66–1.17, p=0.38 (logrank 2-sided). The PFS was significantly (p=0.004) longer in Decitabine vs SC arm: median was 0.55 vs 0.25 years, HR=0.68 (95% CI 0.52–0.88). Time to AML or Death was not significantly improved (p=0.24): median was 0.73 vs 0.51 years (HR=0.85, 95% CI 0.64–1.12). Toxicity. The toxicity was mainly cytopenia related toxicity that was either disease related or hematotoxicity; CTC grade 3–4 febrile neutropenia was 26% (Decitabine) vs 7% (SC arm) and Grade 3–4 infection was 59% vs 47%. Differences in non hematologic toxicities were mainly gastrointestinal: grade 1–2 nausea (28% vs 16%) and grade 1–2 vomiting (16% vs 9%). During the study period, 29 (Decitabine) vs 25 (SC arm) patients died: due to either progression to MDS/AML (7 vs 20), toxicity (9 vs 0), progression and/or toxicity (10 vs 1), other reasons (3 vs 4). Conclusions. Decitabine was found to be an effective drug in these high risk MDS patients with a overall RR of 34%, (similar to earlier studies), leading to a significant PFS improvement as compared to SC arm. The difference Decitabine vs SC arm regarding time to AML or Death was not significant. Due to shorter treatment duration (not being continued beyond 8 cycles) and maybe also due to subsequent treatments administered after disease progression, the difference regarding OS was lower (HR=0.88) and not statistically significant.

Introduction: There is strong evidence that the cytopenia(s) in MDS might be caused by excessive, cytokine induced, intramedullary apoptotic death of progenitor hematopoietic cells. TNFα is a key cytokine that may trigger and sustain the excessive apoptosis processes in early disease. Infliximab is a chimeric human-murine monoclonal antibody with high affinity for human TNFα. Infliximab effectively prevents TNFα specific signaling in immune mediated inflammatory diseases. The therapeutic potential of suppressing TNFα mediated apoptosis in MDS was investigated. Patients and methods: The EORTC LG conducted an open label 2-arm randomized, Simon 2-stage design, phase II study, with the primary objective of assessing the activity of two different dose levels of Infliximab, as single agent, in patients (pts) with low-/intermediate-risk MDS according to IPSS. Activity was assessed by response rate, using the International Working Group criteria: Complete Response (CR) + Partial Response (PR) + Hematological Improvement (HI). Toxicity was assessed as a secondary objective. Results: Between February 2004 and March 2006, 37 eligible/evaluable pts (targeted sample size for the analysis of first stage) were randomly assigned to receive Infliximab, 3 mg/kg (18 pts) vs 5 mg/kg (19 pts), intravenously on days 1 and 15, thereafter every 4 weeks, for a total of 8 courses. Baseline characteristics by treatment arm (3 mg/kg vs 5 mg/kg) were: median age (65 vs 69 years); IPSS risk score: low (2 vs 6 pts), Intermediate-1 (14 vs 10 pts), Intermediate-2 (2 vs 3 pts); cytogenetic risk group: good (9 vs 12 pts), intermediate (5 vs 4 pts), unknown (4 vs 3 pts). Treatment applicability (3 mg/kg vs 5 mg/kg): 20 pts (10 vs 10) completed the 8 cycles of therapy, and 17 pts (8 vs 9) stopped earlier due to: progressive disease (2 vs 4), excessive toxicity (3 vs 0), patient’s refusal (2 vs 2), death due to an unrelated cause (1 vs 1), other reasons (0 vs 2). Activity (3 mg/kg vs 5 mg/kg): 3 pts responded to treatment in the 3 mg/kg arm: 1 CR, 1 PR and 1 HI (neutrophils), while no patient responded in the 5 mg/kg arm. A total of 21 pts (7 vs 14) had stable disease, 11 pts (7 vs 4) had documented disease progression and 2 pts were inevaluable for response (1 vs 1). After a median follow-up of 1.5 years, 8 pts (6 vs 2) died. Adverse events: 3 out of 18 patients died due to infections in the 3 mg/kg arm vs 0/19 in the 5 mg/kg arm. Two of the lethal infections were considered likely related to protocol treatment: one patient developed a fatal mucormycosis during treatment and one patient developed a fatal sepsis shortly after the eighth Infliximab infusion and thereafter also had documented progression to AML. There were few other AE/toxicities. Conclusion: Infliximab in the 3 mg/kg dose/schedule showed some activity in this study. Infliximab has limited activity as single agent but may warrant further investigation in combination with other active agents. Patients must be monitored closely for occurrence of severe infections.

To evaluate the prognostic significance of blasts in the CSF at diagnosis in children with ALL, 2049 patients (pts) enrolled from 1989 to 1996 in EORTC 58881 trial were retrospectively studied. Treatment design was according to BFM. Central nervous system (CNS)-directed therapy consisted in i.v. methotrexate (MTX) (5 g/sqm over 4 hours) in 4 to 10 courses, according to grade of initial CNS involvement, and intrathecal MTX. No radiotherapy was used. Three randomizations were programmed: Erwinia vs Medac E.coli asparaginase (all pts); addition or not of i.v. Ara-C to i.v. MTX (for increased-risk pts); addition of monthly courses of i.v. 6-MP in maintenance therapy (all pts). According to CNS status, pts were classified in 4 groups: 1) CNS-1: 100/μl; 3) surreptitious CNS-2: presence of blasts, 5 WBC/μl, RBC 100000/μl; T-lineage; NCI high risk; very high risk (VHR) features (≥1000 peripheral blasts/μl post prephase, high-risk cytogenetics). Median follow-up was 7.5 years. The 5-yr overall event-free survival (EFS) and overall survival (OS) rates (SE%) were 71.6 % (1.0 %) and 82.6 % (0.8%) respectively. The 5-yr EFS rate (SE%) was 72.1 % (1.0%) for CNS-1, 62.2 % (6.6%) for dubious CNS-2, 64.7 % (6.7%) for surreptitious CNS-2, and 70.3 % (6.2%) for CNS-3 group. Overall, pts with blasts in the CSF (dubious CNS-2, surreptitious CNS-2 or CNS-3) had a significantly (p=0.02) shorter EFS than those in the CNS-1 group: 5-yr EFS rate 65.6% (3.8%) vs 72.1%. Multivariate analysis indicated that low WBC, Medac E-Coli asparaginase, absence of VHR features, middle age group were, together, predictive for longer EFS, whereas CNS involvement (CNS-2/-3 vs CNS-1) lost its prognostic value (p=0.87). Out of 2018 pts who reached CR, a total of 71 isolated and 78 combined CNS relapses were reported. The 5-yr isolated CNS relapse rate was 3.8%: 3.5% in CNS-1, 6.7% in dubious CNS-2, 10.5% in surreptitious CNS-2 and 7.1% in CNS-3 group. The 5-yr isolated or combined CNS relapse rate was 7.9%; in the 4 CNS-groups it was 7.6%, 11.1%, 14.7% and 9.2% respectively. The 5-yr OS rate (SE%) was 83.5% (0.9%) in CNS-1 vs 72.4% (3.9%) in CNS-2/-3: p=0.0003. Prognostic importance was lost (p=0.23) in multivariate analysis. Conclusion: the presence of blasts in the CSF, with or without pleiocytosis, is associated with unfavorable prognostic features and with worse outcome. Intensification of CNS-directed chemotherapy, without CNS radiation, is an effective treatment of initial meningeal leukemic involvement.

The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) with the same drugs. Patients (pts) in complete remission (CR) received consolidation (Co) consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after Co in pts without a donor: auto-SCT followed or not by low dose IL-2. From 9 1999 till 7 2006, 1675 AML pts (APL excluded), age 50x109/l) was longer (median 4.0 vs 3.3 weeks; P=0.01). Among 886 pts randomized until 7 2005 by EORTC centers and 6 large GIMEMA centers, median follow-up of 2.5 years, 815 were evaluable for response. Out of 643 pts who reached CR, 57 went off study (toxicity, early progression). Among the remaining 586 who received Co, 37 could not be evaluated (early death/relapse, too early) and 549 were still CR after Co: 297 pts had no donor/no sibling, 197 had a donor and 55 were not typed. In these 3 groups the present estimates of the SCT rates are: 63% (auto-SCT), 71% (allo-SCT) and 69% (auto-SCT), resp. The 2.5-yr DFS rates (SE%) were 45% (3%), 61% (4%), and 67% (7%), resp. In pts < 50 yrs, 216 pts had no donor/no sibling, 135 had a donor and 14 have not been typed. For the first 2 groups, the 2.5 yr DFS rates (SE%) were 50% (4%) vs 68% (4.5%), hazard ratio=0.64, 95% CI (0.44, 0.93), P=0.02. In pts without a donor/a sibling successful mobilization of blood stem cells (b-SC) after Co was in HD-Ara-C vs SD-Ara-C arm 53 vs 69%, of failure/postponement 37 vs 24%, and other 9.5 vs 7%. The rate of auto-SCT was similar (65 vs 64%), but harvest of BM cells was more often required in the HD-AraC group (15 vs 4.5%). Pts with an insufficient/delayed b-SC harvest had a longer (P 50x109/l) after Co than those with a successful harvest: median = 6.7 vs 3.3 wks. Among 393 pts with information on cytogenetics, 14% had good risk, 50% normal, 23% other and 13% poor risk (-5/5q-, -7/7q-, complex). The 2.5-year EFS (no CR, time to relapse or death in CR) rates (SE%) were 68% (7%), 42% (4%), 32% (5%) and 14% (5%), resp. So far: toxicity of HD-Ara-C was acceptable; in those who received HD-AraC in induction platelet recovery after Co was longer and the rate of successful b-SC collection was lower; SCT rates are high and similar in the 2 randomized arms; pts

In some recent trials high dose of Dexamethasone (Dexa) combined with chemotherapy has been used for induction therapy in adults with ALL because it may exert higher antileukemic activity. Increased level of drug in the cerebrospinal fluid might also prevent meningeal leukemic infiltration. However, high dose of Dexa may be associated with an increased risk of sepsis and fungal infections. By using a lower dose of dexamethasone these serious infections may be circumvented without jeopardize the antileukemic activity. The main aim of the EORTC ALL-4 study was to determine the efficacy and toxicity of a lower dose of Dexa administered during the induction therapy, as vs the ones of conventional dose of prednisone (Pred). In the ALL-4 study, patients (pts) ≤ 60 years had to receive either dexamethasone (10 mg/m2/day) or 6-methyl-prednisolone (60 mg/m2/day) on days 1–8 and 15–22 with standard induction chemotherapy (cyclophosphamide i.v. 750 mg/m2 on day 1 and 8; daunorubicine 30 mg/m2 on day 1–3 and 15–16; vincristine 1.4 mg/m2 (maximum 2 mg) and methotrexate /MTX/ i.t. 15 mg on days 1, 8, 15 and 22). All pts than receive the HAM consolidation course (HD-AraC 3 g/m2 every 12 hours on days 1–4; mitoxantrone 10 mg/m2 on days 5–7 and MTX 15 mg i.t. on day 1). Pts in CR received two courses of MA consolidation (MTX 1.5 g/m2 i.v on day 1 and L-asparaginase 104 IU/m2 on day 2). All pts with a family donor were assigned to undergo allo-SCT. Pts without the donor were randomized either to receive autologous stem cells from peripheral blood or continuous standard high maintenance chemotherapy. After a median follow-up of 4.9 years, 198 pts died. Between 1996 and 2003 a total of 325 pts were randomized in the ALL-4 study: 163 in the Dexa arm and 162 in the Pred arm. CR after induction/HAM was achieved in 128 (78.5%) pts receiving Dexa and in 120 (74.1%) pts treated with Pred. Among them, in Dexa group 61 pts relapsed, 19 died in CR and 48 are still in CCR, whereas in the Pred group, 58 pts relapsed, 8 died in CR and 54 are in CCR. The 5-year DFS rates was 32.7% in the Dexa group vs. 34% in the Pred group, the HR=1.15, 95% CI 0.83–1.59, p=0.40. The relapse rates were extremely similar (HR=0.99, p=0.96), whereas the death in CR rate was higher in the Dexa group compared to Pred group: HR=2.33, 95% CI 1.02–5.33, p=0.04. The overall 5-year survival rate in Dexa vs Pred group was 30.7% and 32.5% respectively (HR=1.11, 95% CI 0.84–1.43, p=0.46). The incidence of infection was similar during induction (Dexa: 55% vs Pred: 59%) and during HAM consolidation (Dexa: 85% vs Pred: 78%). More pts were allografted in CR1 in the Dexa than in the Pred arm (45 vs 33), and the mortality post allo-SCT was higher in the Dexa group (12/45=26.7%) than in the Pred group (5/33=15.2%). The results of ALL-4 trial indicate that there is no benefit of dexamethasone compared to 6-methyl prednisone during induction therapy in adult ALL-NHL pts.

Allo-SCT is currently considered the only curative treatment option of patients (pts) with advanced stages of MDS. The CRIANT study tested in pts without an HLA-id. sibling the value of auto-SCT versus one additional course of high dose cytarabine (HDAC). Pts with identified HLA-id. sibling(s) were candidates for allo-SCT. All pts received remission-induction therapy consisting of idarubicin, cytarabine and etoposide (ICE). Pts who reached CR received one consolidation course (cons) with intermediate dose of cytarabine and idarubicin. All pts without a HLA-id. sibling received filgrastim during the recovery phase of 1st cons to mobilize stem cells and were randomized between ASCT and 2nd cons. Between November 1996 and September 2003, 345 pts were registered (69% of them ≤ 55 years of age and 77% with MDS). Reviewed cytogenetic data were available of 295 (86%) and FISH data of 167 pts (48%). Out of 341 evaluable pts 256 have died and the median follow-up was 5.3 years. The median survival was 1.3 years and the 4-year survival rate was 29% (SE=3%). Age (> vs ≤ 55 yrs: HR=1.5, p=0.003) and the IPSS cytogenetic/FISH score (intermediate vs low: HR=1.5, p=0.02; high vs low: HR=3.1, p

Gemtuzumab ozogamicin, a conjugate of a humanized anti-CD33 monoclonal antibody linked to the cytotoxic antibiotic calicheamicin, has shown significant antileukemic activity in relapsed AML with a favorable toxicity profile. The EORTC-LG performed a phase II study to investigate the activity and toxicity of GO used alone and in combination with conventional chemotherapy for remission induction in medically fit elderly pts (age between 61 and 75 years; WHO PS 0-1) with untreated AML. GO was administered iv over 2 hrs at the FDA-approved dose of 9 mg/m2. A second dose was given on day 15 in the absence of progressive disease or excessive toxicity and response was assessed four weeks later. This was to be followed by a course of conventional chemotherapy with mitoxantrone, cytarabine and etoposide (MICE regimen) and no further treatment in complete responders. Between 09/00 and 10/01 64 pts were enrolled , 57 of whom were evaluable for response and toxicity. The median age was 68 yrs (range 61–73); 43 pts had primary AML; CD33 positivity (≥20% marrow blasts) was documented in 44 pts (85%). GO therapy was completed by 47 of the 57 pts (82%): primary reasons 10 pts did not receive the scheduled second dose were disease progression (4), early death (2), toxicity (2) and protocol violation (2). The rate of initial response to GO was 35.1% (95% CI, 22.9%–48.9%) with 13 pts achieving complete remission (CR) and 7 CRp (complete remission with incomplete platelet recovery); 6 additional pts entered partial remission (PR). There were 3 (5.3%) toxic deaths (1 ARDS, 1 VOD, 1 infection) and 28 pts had resistant disease. Severe myelosuppression was the primary toxicity to GO. Grade 3 or 4 non-hematologic toxicities in more than 5% of pts during GO therapy included febrile neutropenia (39%), infection (28%), elevations of bilirubin, SGPT and creatinine of 8%, 6% and 6%, respectively. A clinical picture compatible with hepatic VOD developed in 3 pts (5%) resulting in 2 deaths (1 early, 1 in CRp). No baseline characteristics predicted for response to GO, but pts expressing CD33 in >80% marrow blasts tended to respond more favourably to the immunoconjugate (CR+CRp 7/14, 50%). Altogether, 51 pts survived GO therapy and 38 of them (75%) went on to receive a course of MICE after a median interval of 49 days (range 12–77) from the first dose of GO. Excessive toxicity (11 pts), protocol violation (1 pt) and treatment refusal (1 pt) were the main reasons for not starting chemotherapy. The ultimate best response rate was 54.4% (31/57; CR 35.1% and CRp 19.3%) increasing up to 65.8% among the 38 pts who were able to complete the whole induction sequence. Five pts died of toxicity during the MICE segment (2 VOD, 1 infection, 1 heart failure, 1 multi-organ failure) for an overall treatment related mortality of 14.1% (8/57). With a median follow-up of 3 yrs, 2-year overall survival (OS) and disease-free survival (DFS) estimates were 11.0% (SE=4.1%) and 12.1% (SE=3.5%), respectively. We conclude that: 1) single agent, standard dose GO has significant activity in untreated AML of the elderly with an acceptable safety profile; 2) sequential combination with standard chemotherapy is feasible and may improve treatment outcome in this poor risk disease, but myelotoxicity and liver dysfunction are of concern. An ongoing randomized trial will determine the contribution of GO given at reduced dose (6 mg/m2) to the observed antileukemic effect and toxicity.

Background: Deletions of the 9p21 chromosomal region which encompasses CDKN2A, a gene encoding both p16INK4a and p14ARF, are frequent in childhood acute lymphoblastic leukemia (ALL). Their prognostic relevance is controversial. Indeed, small retrospective series of patients were analysed so far, which usually mixed B- and T-lineage ALL. Moreover, the prognosis could vary according to the extent of the deletion since the inactivation of contiguous genes such as CDKN2B encoding p15INK4b or MTAP encoding methylthioadenosine phosphorylase, may influence chemosensitivity. Methods: 9p21 deletions were retrospectivelly studied in 227 children (aged 2 mo to 16 yrs) with B-lineage ALL, using a real-time PCR assay for CDKN2B, CDKN2A (e1b and e3), and MTAP gene dosage, and loss of heterozygosity analysis (Bertin et al., 2003). CDKN2A and CDKN2B inactivation by promoter methylation was also investigated. TEL-AML1 fusion was screened in 182 (80%) of these patients. All patients were enrolled in EORTC trials 58 881 or 58 951. Median follow-up was 6 years; total number of events was 55 and the overall 6-year EFS rate was 74%. Results: CDKN2A bi- and mono-allelic inactivation was found in 38 (17%), and 31 (14%) B-lineage ALL respectively. Patients with a bi-allelic inactivation did not differ from undeleted ones regarding age, sex, immunophenotype and response to prephase treatment, but tended to have a higher WBC count at diagnosis and were more often allocated to the NCI high risk group (42% vs 27%). Genetic defects, including TEL-AML1, were independent of 9p21 alteration with exception of hyperdiploidy (>50 chromosomes) which was less frequent in patients with CDKN2A inactivation (5% vs 34%). The 6-year EFS rates of patients with bi-allelic, mono allelic and no inactivation did not differ significantly (68%, 80%, and 75% respectively). Bi-allelic CDKN2B inactivation by either deletion or promoter methylation was found in 36 (16%) patients and the 6-year EFS rate of these patients was similar to that of undeleted patients (71% vs 74%). MTAP bi-allelic inactivation was found in 24 (11%) of patients. Although MTAP deficient cells are in vitro very sensitive to methotrexate, the 6-year EFS rate (70% vs 75%) did not differ from that of MTAP positive patients even when the analysis was restricted to CDKN2A inactivated ALL. Conclusion: Although bi-alleic CDKN2A inactivation was more often associated with bad prognostic parameters in B-lineage ALL, it failed to significantly influence the outcome of the patients. We did not observe either any influence of the co-inactivation of CDKN2B and MTAP on the outcome. Considering that our study is the largest so far using molecular analysis of the 9p21 region, we assume that any bad prognosis associated with 9p21 alteration, if present, should be weak in B-lineage ALL, and would probably require larger cohorts of patients to be ascertained.

The use of intensive antileukemic treatment is less widely accepted in high-risk MDS pts compared to de novo AML, due to the reported inferior results. It is questionable whether the poorer outcome reflects an intrinsic property of the involved stem cell or a higher frequency of poor prognostic factors. The purpose of this analysis is to identify disease-specific prognostic factors for outcome of young (aged 100 (HR=1.67, p=0.02) and donor availability (HR=0.77, p=0.04). Some variables were of prognostic value for OS in only one of the studies: in the CRIANT study number of cytopenias (3 vs 0–2) and AHD >6 months appeared of prognostic importance for OS, wherease FAB subtype M2/M4 and cytogenetics inv(16)/t(8;21) were prognostic in AML-10. Therefore a specific prognostic score for OS was established for each study, AML-10 (based on cytogenetics, PS, FAB, WBC and age) and CRIANT (based on cytogenetics, nr of cytopenias, age, AHD and WBC). The AML-10 study distinguished 5 groups with an estimated 4-year survival rate of 69%, 40%, 45%, 26% and 17%, resp. The prognostic value of this score has been validated on patients treated in the AML-10 study with mitoxantrone instead of idarubicin: the 4-year survival were 76%, 46%, 41%, 33% and 18%, resp. The CRIANT study distinguished 5 groups with a 4-year survival rates of 72%, 44%, 39%, 12% and 0%, resp. In conclusion: the prognostic scores identify a group of 26% AML and 42% MDS pts, with a 4-year survival less than 20%. Apparently current treatment modalities are unsatisfactory for these poor-risk pts and novel treatment strategies should be offered to these pts in the context of clinical trials. Our finding that different variables are of prognostic importance in MDS/sAML and de novo AML pts supports the hypothesis that these are intrinsically different disorders. The CRIANT-derived score is a valuable alternative for the IPSS in intensively treated high-risk MDS pts.

Monosomy 7 (−7) and deletion 7q [del(7q)] are rare in childhood AML and are considered to be associated with a poor outcome. We retrospectively analyzed data on 267 children with de novo AML or RAEB-T (PB or BM blasts > 20%) with −7 or del(7q) with or without additional cytogenetic aberrations (other). Patients were diagnosed between 1985 and 2003. Karyotypes showed −7 (n=90), −7 other (n=82), del(7q) (n=22), and del(7q) other (n=73). All 24 patients with RAEB-T had −7 +/− other. The median age at diagnosis was 7.6 years (range; 0–18.1) with no difference in age distribution between cytogenetic subgroups. The most common additional cytogenetic aberrations were inv(3)/t(3;3) in 19 patients (−7, n=17; del(7q), n=2) and favorable aberrations [t(8;21), inv(16), and t(15;17)] observed in 25 patients (−7, n=3; del(7q), n=22). The 5-year overall probability of survival for the whole group was 39%, SE=3%, and survival was higher in patients with del(7q) +/− other compared with −7 +/− other (52% vs. 30%). The survival of patients with del(7q) and favorable cytogenetic aberrations (n=22) was higher than that of other patients with del(7q) (75% vs. 46%, p=0.026). There was no significant difference in survival for patients with −7 and −7 other. Complete remission (CR) was obtained in 188 patients (−7 +/− other 62%; del(7q) +/− other 88%), of these, 67 received hematopoietic stem cell transplantation (HSCT) in CR1. There was no significant difference (Mantel-Byar test) in survival for patients who received HSCT in CR1 (49%, SE= 7%) and those who received chemotherapy only (51%, SE=5%, 54% for patients surviving at least the median time to HSCT). In conclusion childhood AML subgroups −7 and del(7q) differ in their associated cytogenetic aberrations and response to therapy.

We read with interest the paper of Dordelmann et al[1][1] on prednisone (PDN) response as the strongest predictor value of outcome in infant acute lymphoblastic leukemia (ALL). Between June 1989 and November 1998, 60 (3.1%) infants, among 1963 children less than 18 years of age, were registered

Two hundred and seventeen patients, 1–50 yr old, with acute lymphoblastic leukemia in complete remission were randomized to receive a 1-yr consolidation chemotherapy of either type P, comprising 7 different drugs, or type M, consisting of methotrexate interspersed with prednisone and vincristine. Thereafter, they were randomized a second time to receive a 4-yr maintenance of either chemotherapy or immunotherapy, comprised of allogeneic blasts and bacillus Calmette- Guerin (BCG). Consolidation P caused more toxicity than consolidation M. However, comparison between the consolidation therapies P and M showed no significant difference, neither for disease-free interval nor for duration of survival. Chemotherapy showed more lethal toxicity in adults than in children. Comparison between chemotherapy (C) and immunotherapy (I) as maintenance treatment showed a significant (p = 0.016) superiority of C for disease-free interval (DFI). The difference was even more pronounced (p = 0.009) in the group with less than 8 g/dl of hemoglobin (Hb) at diagnosis before therapy. On the other hand, for patients with more than 8 g/dl Hb at diagnosis, presumably those with T- ALL, no difference in DFI was seen. No difference has been seen so far between maintenance therapies I and C concerning the duration of survival. The patients who were receiving maintenance I when they relapsed and who were consequently retreated by chemotherapy, survived longer from relapse than those patients retreated for relapse while receiving maintenance C.