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8504 Background: EORTC 18991 is the largest adjuvant trial ever conducted in stage III melanoma. It assessed the efficacy and toxicity of long term PEG-IFN vs Observation (Obs.). Methods: PEG-IFN (Induction at 6μg/Kg/wk, sc, 8 weeks; followed by Maintenance at 3μg/Kg/wk, sc) for a total treatment duration of 5 years was compared to Obs. in 1256 patients (pts) with stage III melanoma (anyTN1–2M0 without in-transit metastases). Randomization was stratified for nodal involvement N1 (microscopic) vs N2 (palpable nodes), # of nodes, Breslow and ulceration of primary, sex and center. Distant Metastasis-Free Survival (DMFS) was the primary endpoint. Relapse-Free Survival (RFS) was the pre-specified regulatory primary endpoint. Overall survival (OS) was the secondary endpoint. Intent-to-treat analysis was performed. Results: Median follow-up was 3.8 yrs: HR = Hazard Ratio; NR = Not Reached In N1-pts (n=543) the benefit of PEG-IFN seemed more pronounced than in N2-pts (n=713): RFS (HR 0.73 p=0.02 and HR 0.86 p=0.12 for N1 and N2, respectively), DMFS (HR 0.75 p=0.03 and HR 0.94 p=0.53) and OS (HR 0.88 p=0.43 and HR 1.01 p=0.91). PEG-IFN therapy relative dose intensity (actual/planned dose while treated) reached median 88% (induction) and 83% (maintenance). 251 pts (40 %) stopped PEG-IFN because of toxicity. Grade 3–4 - mostly grade 3 - toxicities were reported in 45% (PEG-IFN), vs 12% (Obs.), including most frequently fatigue (15%), hepatotoxicity (10%) and depression (6%) with ECOG 0–1 Performance Status maintained in 83% of pts during maintenance. Conclusions: Long term PEG-IFN therapy in stage III melanoma had a significant and sustained impact on RFS, but not on DMFS and OS. Pts with only microscopic nodal involvement (Sentinel Node positive) seemed to have greater benefit in terms of both RFS and DMFS. Similar better effects of adjuvant IFN therapy in pts with lower disease burden are observed in 2 consecutive EORTC trials (18952 and 18991) involving 2644 pts. [Table: see text] [Table: see text]

8552 Background: Two large studies with identical eligibility criteria and using serum LDH as stratification for randomization were re-analyzed in order to 1) confirm the prognostic importance of LDH in advanced melanoma; 2) to assess whether an interaction between LDH and treatment efficacy exists. Methodology: Oblimersen (OBL) trial GM301 randomized 771 pts between DTIC vs. DTIC+OBL, whereas EORTC trial 18951 randomized 365 pts between biochemotherapy vs biochemotherapy+IL2 (JCO, 2004). LDH was divided into 5 groups: 5 UNL. Cox model was used to asses the prognostic importance of LDH, treatment difference and LDH-treatment interaction regarding the main endpoint, overall survival (OS). Results: In each study LDH appeared to be of strong and incremental prognostic importance (p No significant financial relationships to disclose. [Table: see text]

8507 Background: Appearance of auto-AB during IFN-adjuvant therapy is a prognostic factor in melanoma pts. We evaluated this in the EORTC 18952 trial including pts without IFN. Methods: Anti-cardiolipin (C) anti-thyreoglobulin (T) and anti- nuclear (N) AB levels of serial samples between 0 and 48 months (mt) were assessed centrally. Prognostic impact of CTN on relapse-free survival (RFS) was assessed by 3 methods: 1) usual Cox model (lead-time bias); 2) Cox Time dependent model using the latest positive CTN value; 3) Cox Time dependent model using the latest any CTN value. Results: In 278 pts the presence of auto-AB at any time was determined. Among them, 187 pts (43 stage IIb, 144 stage III), Obs (32) or 13-mt-IFN (80) or 25-mt-IFN (75), had their initial auto- AB status assessed: 60 (32%) were CTN-positive (pos) (similar % in 3 arms) and 127 (68%) were CTN-negative (neg). Of these 127 pts, during the study, at least once, the following became CTN-pos: Obs (7/24=29%), 13-mt-IFN (19/55=36%), 25-mt-IFN (20/48=42%); 1-yr conversion rate was 23%, 34% and 38% in the 3 arms respectively; 2-yr rate was 23%, 46% and 61%. Median follow-up = 4.2 yrs. Relapse occurred in 122/187 pts. Median RFS = 2.1 years. In the 187 pts with a known initial CTN-status, using the classical Cox model the hazard ratio (HR) of those who were/became CTN-pos vs the others, was 0.50. In order to overcome the Lead Time Bias, the Cox time dependent model was used: the HR for pts with at least one pos CTN-status vs always CTN-neg was 0.63 and for those with the latest CTN-status pos vs those with latest CTN-status neg was 0.87. All analyses were adjusted for # of pos nodes. Results were similar when only IFN pts or Obs only pts were considered (test for interaction: P>0.50), or when all pts (278) or only pts CTN-neg at randomization (127) were assessed. Initial CTN status known. Conclusions: We could not confirm presence or appearance of auto-AB as a strong prognostic factor in melanoma pts and did not find a strong interaction with IFN therapy. [Table: see text] [Table: see text]

8518 Background: S100B serum levels have been reported to correlate with tumor stage and outcome, especially in metastatic melanoma. In the EORTC 18952 randomized trial assessing the value of intermediate doses (10 MU or 5 MU) of IFNa vs Observation, a side study on S100B has been set-up in order to assess 1) the prognostic importance of initial measurement of S100B; 2) the risk of developing distant metastases in patients with a S100B≥0.2 μg/l; 3) the prognostic importance of the latest measurement of S100B level on the subsequent outcome. Methods: The serial measurements of S100B, made by immunoluminometric assay LIA-mat (Sangtec Medical, Sweden) have been performed at randomization in 18952 study, at end of 4-week IFNa induction/observation, and thereafter, at month 1, 3, 6, 9, 12, 16, 20, 24, 30 and 36. The prognostic impact regarding DMFS of the latest value of S100B was assessed via the Cox time-dependent model. Results: A total of 211 patients, stage IIb (N=51) or stage III (N=160), were randomized in the 18952 study between 1996 and 2000, had their initial serum S100B protein level assessed: in 178 patients (84%) S100B was [Table: see text]

8526 Background: Many randomised trials have evaluated the role of adjuvant interferon-a (IFN) in high-risk melanoma, some suggesting benefit and others not. To assess the totality of current evidence, an individual patient data (IPD) meta-analysis of all available trials was performed. Methods: Standard IPD meta-analysis methods were used to assess event-free (EFS) and overall survival (OS), with odds ratios (OR) and 95% confidence intervals (CI) calculated. Trials were divided by dose of IFN - high (20 MU/m2), intermediate (5–10 MU), low (3 MU) and very low (1 MU). Subgroup analyses by patient age, gender and disease characteristics were also performed. Results: IPD was provided for 10 of 13 reported trials of IFN vs. no IFN (for the other 3 trials published data were used). 6067 patients (IPD available for 85%) were included in the analysis, with over 3,700 and 3,000 events for EFS and OS. There was statistically significant benefit for IFN for both EFS (OR=0.87, CI=0.81–0.93, p=0.00006) and OS (0.9, 0.84–0.97, p=0.008). There was no evidence of differences according to dose (Table 1; trend p>0.1) or duration of IFN. This proportional survival advantage translates into an absolute benefit of about 3% (CI 1%-5%) at 5 years. The effect of IFN did not differ with age, gender, tumor site, Breslow thickness, clinical nodes or disease stage. Only for ulceration was there some evidence of an interaction (p=0.03); patients with ulcerated tumors had greater benefit from IFN (EFS: OR=0.76, OS: OR=0.77) than those with no ulceration (EFS: OR=0.94, OS: OR=0.98). Conclusions: This meta-analysis provides evidence that adjuvant IFN significantly reduces the risk of relapse and improves overall survival, although the absolute survival benefit is relatively small. This analysis does not however, clarify the optimal (high, intermediate or low) dose of IFN. Given the large number of subgroup analyses performed, the apparent increased benefit in patients with ulceration requires confirmation. No significant financial relationships to disclose.

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

In elderly patients with AML, the induction treatment requires 4–5 weeks of hospitalization. The aim of the phase III AML-13 trial of the EORTC Leukemia Group is to assess two types of consolidation chemotherapy in patients who reach complete remission after the induction cycle : 3 drugs during 7 days, using a classical continuous infusion, on an inpatient basis, or the same kind of drugs but delivered subcutaneously or orally, on an outpatient basis. In the second group, patients are hospitalized only in case of complications. The evaluation parameters are not only disease-free survival and overall survival, but also cost-effectiveness and quality of life. The latter endpoints pose specific methodological challenges. We decided to use a diary to collect information concerning treatment compliance, side-effects of treatment and their impact on quality of life, and use of health care facilities. In addition information concerning resource utilisation during hospital treatment is being collected through the clinical Case Report Forms. This communication aims to discuss the methodological approach to integrate economic and quality of life aspects in this large scale clinical trial.

To assess the effects of GM-CSF in patients with myelodysplasia, a total of 101 patients with refractory anemia (RA), RA with ringed sideroblasts (RARS), and RA with an excess of blasts provided that the percentage of blasts in the bone marrow did not exceed 10% (RAEB) were enrolled in the EORTC Leukemia Cooperative Group study 06885. They were randomized to receive two daily subcutaneous injections of rhGM-CSF (mammalian, glycosylated, Sandoz/Schering-Plough) at a daily dose of either 108μg glycoprotein (group I) or 216μg glycoprotein (group II) for 8 weeks. Response was defined as an increase in Hb (> 2.5 g%), neutrophil count (more than 100%), or platelet count (more than 100%) without progression of the disease. After exclusion of 19 patients who did not meet the entry criteria, 82 were evaluated. Fifty-four patients (66%) responded (27 of 42 patients in group I and 27 of 40 in group II). Progressive disease was seen in two patients of group I and in four of group II. Two of the latter developed leukemia. All responses were reflected in the granulocytic series. In two patients platelet numbers also increased. Cytogenetic analysis, successfully performed in 43 cases, showed that 14 of 16 patients with normal karyotypes responded, compared with 14 of 27 patients with abnormal karyotypes (p=0.008). In some cases GM-CSF was reduced in dose or discontinued prematurely due to side effects so that only 35% of all evaluable patients finished 8 weeks of treatment without a change of dose.

Sixty-one evaluable patients with measurable advanced malignant melanoma received 4-week courses of a combination of cisplatin 100 mg/m 2 as a 24-hr i.v. infusion on day 1 and vindesine 3 mg/m 2 as an i.v. bolus on days 1, 8, 15 for two courses and every other week thereafter. Two patients achieved complete response for 46 and 81+ weeks respectively, eleven patients achieved partial response for a median of 17 weeks (range 8–26) and three patients had no change for 24 weeks or more. The overall response rate of 21% did not seem to be affected by prior chemotherapy or site of indicator lesions, soft tissue vs visceral. Myelosuppression, consisting essentially of leucopenia, required dose schedule modifications in 41% of the first two courses and 12% of the remaining courses, but never produced major complications. Non-hematologic toxic effects were prominent, especially nausea and vomiting, which were universal. Alopecia was seen in 71% of the patients, neuromuscular manifestations in 39%, diarrhea in 30%, renal impairment in 25%, mucositis in 12%, ototoxicity in 7% and phlebitis in 3%. These results do not suggest striking additive or synergistic antitumor activity of cisplatin and vindesine in advanced malignant melanoma, at least with the method of drug administration selected for this trial.

A Phase II study combining cisplatin, vindesine, and dacarbazine was performed on patients with disseminated malignant melanoma by the European Organization for Research and Treatment of Cancer (EORTC) Malignant Melanoma Cooperative Group (MMCG). The treatment consisted of intravenous administrations of dacarbazine 450 mg/m2, vindesine 3 mg/m2, and cisplatin 50 mg/m2 on day 1 and 8 of each course. Courses were repeated every 4 weeks. Treatment was discontinued in case of progression after two courses, otherwise continued until progression or for a minimum of six courses. One hundred five patients entered the trial with 92 patients being evaluable. The response rate calculated after clearance by the Extramural Review Committee shows four complete and 18 partial responses, i.e., 24%, with a median remission duration of 23 weeks. Toxicity and subjective tolerance to this regimen were moderate, requiring 140 modifications of 642 administrations (22%). Main toxicities were nausea and vomiting (95%), leucopenia (70%), alopecia (56%), peripheral neuropathy (32%), and nephrotoxicity (17%). The discussion emphasizes some particular points of interest in the management of advanced malignant melanoma.

After modified radical mastectomy, 490 primary breast cancer patients were followed for a median of 75 months. Bloom grade was measured in 340 patients and ER status in 341. Follow-up of these patients has yielded the following results: (a) The value of traditional indices has been reaffirmed. (Cox's multivariate analysis identified, in order of decreasing importance, the number of invaded lymph nodes, the initial tumor size and the histological grade. Other variables were found to be of lesser importance and were correlated with the three main indices.) (b) The value of ER status disappeared after more than 3 years of follow-up. (c) ER positive patients fared better after recurrence. This was interpreted as being a consequence of their responsiveness to hormonal treatment.

A case of T-cell acute lymphoblastic leukemia with a translocation between chromosomes #1 and #18 is described. The breakpoints were at bands 1q23 and 18q21. A single cell contained the translocation t(1;19)(q23;p13). The breakpoint on chromosome #1 was the same in both translocations, and the breakpoint on chromosome #18 was the same as that in t(14;18)(q32;q21) associated with follicular lymphoma. The possible relationship between chromosome bands 1q23 and 18q21 and the morphologic features of the leukemic cells is discussed.

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.

The factor-dependent myeloid precursor cell line D35 mutates spontaneously at a frequency greater than 2.4 x 10(-7) to growth factor autonomy. This frequency could be increased at least 20-fold by retrovirus insertional mutagenesis. The isolation and characterization of factor-independent mutants allowed the identification of genes involved in growth autonomy. Mutants could be subdivided into two sets: those that secreted a stimulating factor (10/11) and those that did not (1/11). In one case, the factor released was distinct from previously characterized growth factors. In most mutants (6/9), the activation of a growth factor gene was associated with rearrangement that could be attributed to the insertion of a transposable-like element either 5' or 3' of the factor coding region in all cases examined, excluding oncogene involvement. All factor-independent mutants were tumorigenic, consistent with the hypothesis that growth-factor independence initiated by aberrant growth factor gene activation is an important and early step in tumorigenesis.

Twenty-three European centers participated in a randomized clinical trial (AML-5) to study the effect of androgens and immunotherapy during maintenance in adult acute myelogenous leukemia. Induction treatment consisted of Adriamycin (doxorubicin) 50 mg/m2 day 1, vincristine VCR 1 mg/m2 day 2, and cytosine arabinoside 80 mg/m2 every 12 hours by push injection days 3-9. Patients in complete remission were randomized into four groups: (1) 6-mercaptopurine 70 mg/m2 days 1-14, methotrexate 15 mg/m2 twice weekly days 15-28, and reinduction with daunorubicin 35 mg/m2 and vincristine 1 mg/m2 day 29; (2) chemotherapy as in group 1 plus stanozolol 0.15 mg/kg/day; (3) 6-thioguanine 70 mg/m2 orally on 4 consecutive days and cytosine arabinoside 80 mg/m2 subcutaneously day 5 every week; and (4) chemotherapy as in Group 3 plus irradiated blast cells treated with neuraminidase. Three hundred forty-eight patients were eligible and 295 were evaluable. The median age was 45 yrs. A complete remission was achieved in 64% of the patients, with 158 complete remissions randomized. Patients not randomized and patients receiving bone marrow transplantation (BMT) were analyzed separately. There was no difference in disease-free survival (DFS) or survival in the four maintenance arms. For patients reaching complete remission, the median DFS was 40 weeks, and median survival was 22 months with 30% surviving at 4 years. The overall survival was 18% at 4 years. There was no beneficial effect for DFS or survival by adding either immunotherapy or androgens to chemotherapy during maintenance. However, patients receiving immunotherapy seemed to have a higher rate of responses to reinduction after relapse than those in the other treatment arms.

The prognostic value of some current cytologic characteristics was assessed in 174 adult patients with acute myelogenous leukemia (AML) treated according to the AML‐5 protocol of the EORTC Leukemia and Hematosarcomas Group. A significantly higher rate of complete remission (CR) was observed in patients with low bone‐marrow (BM) cellularity, with BM blasts less than 80%, and with Auer rod positive cells more than 2.5% of the total blast cell population. A leukocyte count of less than 50 × 109/1 in the peripheral blood was also associated with a higher CR rate. No significant difference was found between the various French‐American‐British (FAB) subtypes, in spite of a trend towards a lower CR rate in patients with an M1, myeloblastic, poorly differentiated, subtype. The leukocyte count and the percentage of Auer rod positive cells were the only significant parameters for duration of survival from the beginning of maintenance treatment. However these features had no prognostic value for the duration of remission. It seems therefore that patients with a higher percentage of Auer‐rod‐positive cells and lower peripheral leukocyte counts can enter remission more easily, and can also more readily achieve subsequent remissions following relapse. The prognostic value of these routine cytologic features is probably related to their relationship with proliferative activity and tumor burden: the percentage of Auer‐rod‐positive cells correlates inversely with the leukocyte count, whereas leukocyte count, BM cellularity, and percentage of BM blasts are linked together. Copyright © 1984 American Cancer Society

Two randomized trials were started in 1976 by the European Organization for Research on Treatment of Cancer urological group. Trial 30761 compared 1 mg. diethylstilbestrol orally 3 times daily to 250 mg. oral cyproterone acetate daily and to 500 mg. medroxyprogesterone acetate intramuscularly 3 times weekly for 8 weeks, then 200 mg. orally daily. Trial 30762 compared 3 mg. diethylstilbestrol to 560 mg. estramustine phosphate orally for 8 weeks and then 280 mg. daily. The 239 patients in study 30761 and 226 in study 30762 were evaluated for cardiovascular toxicity during treatment. Various types of side effects (fluid retention, hypertension, electrocardiographic changes, myocardial infarction and thromboembolic disease) and their degrees of severity were analyzed. In both studies the most frequent type of cardiovascular toxicity was represented by fluid retention. Cardiovascular toxicity as a whole was higher with diethylstilbestrol than with estramustine phosphate or medroxyprogesterone acetate therapy, and was the lowest with cyproterone acetate therapy. The risk of severe cardiovascular complications developing was the highest during the first 6 months of treatment. Increasing age, body weight greater than 75 kg. and, especially, the presence of previous cardiovascular disease represented adverse factors in the development of cardiovascular toxicity.

In a retrospective analysis, patients with acute myelogenous leukemia (AML), treated in first complete remission (CR) with chemotherapy or with allogeneic or autologous bone marrow transplantation were compared with respect to their leukemia-free survival from CR. Two hundred and thirty-six patients treated with chemotherapy according to the EORTC AML- 5 and AML- 6 trials were included. The data of the transplanted patients were taken from two EBMT registries; 453 with an allogeneic and 182 with an autologous BMT. The very different sources of the data (trials and registries) forced us to be cautious in our conclusions. However, for the patient cohorts analyzed in the present study, BMT patients tended to have a better leukemia-free survival than chemotherapy patients. This was especially the case for the allogeneic BMT after 6 months of transplant.

Since its inception in 1969, the EORTC Melanoma Group has employed a multidisciplinary approach in the fight against melanoma and has registered significant achievements in many areas of melanoma treatment and research. The group showed that sentinel node (SN) tumor burden according to the Rotterdam Criteria and the microanatomic location were the most important prognostic factors for melanoma-specific survival and non-SN positivity in the completion lymph node dissection specimen. They demonstrated that extended schedule escalated dose temozolomide is feasible and has an acceptable safety profile. They also showed that the interferon-a targeted therapy should occur in a targeted patient population, and should probably not be offered to 70% of the patients that are currently being given this treatment. Through EORTC trial 18991, Sylatron™, pegylated interferon a-2b, for the treatment of melanoma patients with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy, was approved by the US FDA. The present article describes the achievements and future strategies of the Melanoma Group. © 2012 European Organisation for Research and Treatment of Cancer., SCOPUS: ar.j, info:eu-repo/semantics/published

In a randomized phase III trial performed by the Urological Group of the European Organization for Research on Treatment of Cancer low dose estramustine phosphate (280 mg. twice daily for 8 weeks and 140 mg. twice daily thereafter) was compared to diethylstilbestrol (1 mg. 3 times daily) in patients with stages T3 to T4, M0 or M1 prostatic cancer. Of 248 patients entered 227 were evaluable for analysis: 115 received estramustine phosphate and 112 received diethylstilbestrol. The best response of the local tumor as assessed by palpation was seen in patients receiving diethylstilbestrol. There was no significant difference between treatments for response rate of metastases, interval to local progression, distant progression, over-all survival and death of carcinoma of the prostate. Duration of survival was correlated with the assessment of local response as determined by palpation. The response of distant lesions also was correlated closely with survival. Diethylstilbestrol (1 mg. 3 times daily) was associated with a significantly worse degree of cardiovascular toxicity than estramustine phosphate. This finding was especially obvious in patients who had no history of cardiovascular disease. Gastrointestinal toxicity occurred in 25 patients treated with estramustine phosphate, including 6 in whom cessation of treatment was necessary. Further studies are required to determine the optimum dose of diethylstilbestrol and estramustine phosphate, and to establish the best form of hormonal treatment for prostatic carcinoma.

In 1981, 13 French and Belgian institutions started a clinical study using the German BFM protocol for the treatment of children with acute lymphoblastic leukemia (ALL). The objectives of the study were (a) to evaluate the feasibility and toxicity of this aggressive regimen, (b) to reevaluate the weight of the prognostic factors (number of circulating blasts, hepatomegaly, and splenomegaly) used for the classification of patients into different risk categories, and (c) to identify other possible prognostic features.

In childhood acute lymhocytic leukemia (ALL), the initial reduction of the leukemic cell mass by intensive combination chemotherapy is important both for inducing a complete remission and for long-term control and cure of the disease [1]. Intensification of induction treatment, consisting of vincristine (VCR) and prednisone (Pred), by addition of a third drug, l-asparaginase (l-Asp), has increased the remission rate and the duration of the remission [2]. The current study, ALL V, was undertaken to evaluate the effectiveness of further intensification of the induction treatment with a fourth drug, rubidomycin (Rub), in children with standard-risk ALL. Criteria for standard risk, based on a previous study ALL II [3] by the Dutch Childhood Leukemia Study Group (DCLSG) included, age of 0–15 years, initial leukocyte count of < 50 × 109/liter, absence of mediastinal mass, and absence of cerebromeningeal involvement by the end of induction treatment.

The results of treatment of acute lymphoblastic leukemia (ALL) in adolescents and adults were poor 10 years ago [1] and have improved considerably since then. A recent review [2] of the subject has indicated that, indeed, around three-quarters of the patients can achieve complete remission (CR) and that median durations of CR lasting over 2 years have now been reached.

The interest of estrogen receptor assays has been pointed out by numerous authors [1], especially with reference to the determination of potential responders to endocrine therapy among generalized breast cancer patients. The relationship between the estrogen receptor level in breast primaries and other prognostic factors remains a matter of controversy and is the subject of the following article, which is based on a series of 490 previously unreported cases.

We report the results of a prospective study in patients more than 65 years of age in whom two different therapeutic strategies were compared: immediate intensive-induction chemotherapy (arm A) versus "wait and see" and supportive care and mild cytoreductive chemotherapy only for relief of progressive acute myeloid leukemia (AML)-related symptoms (arm B). The major objective of the study was to compare survival outcome of both regimens. Thirty-one patients on arm A received one or two courses of daunorubicin, vincristine, and cytarabine for remission induction followed by one additional cycle for consolidation in case of complete remission (CR). Among 29 patients on arm B, cytoreductive chemotherapy (hydroxyurea, cytarabine) had to be initiated for palliation of leukemia-associated complications in 21 patients at a median of 9 days after diagnosis. Overall survival duration for patients treated on arm A was significantly (P = .015) longer than the survival in arm B (median survival, 21 weeks v 11 weeks; projected survival at 2.5 years, 13% v 0%). Eighteen (58%) of arm A patients and none (0%) of arm B patients entered CR. Of the first group, projected disease-free survival at 2 years is 17%. The median percentages of days spent in the hospital by arm A and B patients were 55% and 50%, respectively. This study shows that a strategy based on modern supportive care and a wait and see approach yields extremely poor results. It is not superior in regard to the frequency of hospital admission and is inferior regarding survival outcome.

Four cases with trisomy 11 as the sole chromosomal anomaly are reported, three with de novo acute nonlymphocytic leukemia (ANLL) and one with a myelodysplastic syndrome (MDS) after treatment for multiple myeloma. In reviewing the literature, we found 19 additional cases with trisomy 11 as the sole cytogenetic defect. All patients except one were reported to have ANLL or MDS. Thus, it seems that trisomy 11 is another rare but nonrandom chromosomal anomaly in ANLL and MDS. So far, no apparently characteristic clinical or cytologic signs have been found in these cases.

One of the main problems encountered in drawing conclusions from clinical trials is the wide variability in the methods used to assess treatment efficacy. In addition, it is often difficult to put the results of a study in their proper perspective due to the large differences between trials with respect to the patient population studied and variations in the definition and evaluation of end points and toxicity. When reporting the results of treatment, it is recommended to indicate [1, 2]: The total number of patients randomized or registered, irrespective of eligibility or evaluability. The total number of patients randomized or registered who are eligible and treated, regardless of the amount of treatment they received. The total number of patients randomized or registered, eligible, and adequately treated according to the protocol (so-called “fully evaluable”).

At the end of 1976 and the beginning of 1977 respectively, the EORTC Genito-Urinary Tract Cancer Cooperative Group started two randomized phase III protocols in previously untreated patients with advanced T3–4 prostatic cancer (1–3). The first trial, 30762, compared Stilboestrol and Estracyt, while the second, 30761, was a randomized comparison of Stilboestrol, Cyproterone Acetate and Medroxyprogesterone Acetate. Both trials have now been closed to patient entry and the principal endpoints of the studies analyzed. This paper will present the interim results which have emerged from these two studies.

Seventy-nine patients (aged 17–76 years) with acute myelogenous leukemia in first (56) or second (3) relapse, primary refractory leukemia (15) or leukemia occurring as secondary malignancy that developed after a preleukemic phase (3) or after another tumor (2) were given remission induction therapy consisting of cytosine arabinoside (Ara-C, 1 g/m 2 as a 2-h infusion every 12 h for 6 days) and m-AMSA (120 mg/m 2 , i.v. on days 5, 6, 7). In total 45 patients (57%) achieved complete remission. Younger patients and those with a relatively low initial white blood cell count, a good performance status or in first relapse had a higher response rate. Thirty-five patients were given one or two courses of consolidation chemotherapy consisting of Ara-C (3 g/m 2 as a 2-h infusion every 12 h for 4 days) and m-AMSA (120 mg/m 2 i.v. on day 5). Three patients received on allogeneic bone marrow graft after the induction courses and four patients received an autologous bone marrow transplantation after consolidation therapy. The median of the disease-free survival curve was 21 weeks. The median duration of survival was 25 weeks. The response rate for this intermediate dose Ara-C regimen is satisfactory and does not differ from that reported for high dose Ara-C. The impact of consolidation chemotherapy in bad risk acute myelogenous leukemia is questionable.

Abstract 2571 Background: In our previous EORTC 58881 trial in childhood ALL, we have shown the prognostic impact of the MRD, quantitated by polymerase chain reaction assay. Patients with TP1 MRD ≥10–2 (D35), had a higher risk of relapse than those with TP1 MRD Methods: Between December 1998 and July 2008, 1955 children (1y-18y) with ALL were enrolled in the 58951 trial, 1459 being evaluable for the MRD (TP1) by PCR (rearrangements of the T-cell receptor and immunoglobulin heavy chain genes). Seventy-nine patients with Phi-negative ALL had a TP1 MRD ≥10-2, and 69 of them achieved a complete hematological remission after induction. Here we report on the outcome of these 69 patients. Results: At a median follow-up of 7.6 years, the overall 5-years EFS and OS rates for the 69 patients were 56.1% (SE 6.0%) and 62.0% (SE 5.9%) respectively. Prephase good responders (PGR) ( 51 chromosomes were PGR. TP2 MRD (after consolidation) was assessed in 59 pts. All patients but one (1/13) with TP2 MRD ≥10-2 died. In PGR patients, those with TP2 MRD < 10-3 (N=18) had a significant better OS rate at 5 years than those with TP2 MRD ≥10-3 (N=17): 88.9% (SE 7.4%) vs 52.3 % (SE 12.3%), hazard ratio=0.17, p=0.009. We observed no relapses among patients with hyperdiploidy > 51 chromosomes and TP2 Conclusions: The prognosis of children ALL with TP1 MRD ≥10-2 has improved with early intensification of the treatment as compared to the one observed in our previous 58881 study. However the outcome of these patients was still heterogeneous and the prephase response was still of prognostic importance. Patients with GPR and TP2 For other patients with PPR and/or TP2 ≥10-3 the prognosis was worse and these patients may benefit from alternative therapy and/or intensification with HSCT. Disclosures: No relevant conflicts of interest to declare.

The methodology for conducting cancer clinical trials has undergone enormous changes over the past 25-30 years since the EORTC Data Center was created. The purpose of this paper is to highlight and to provide a historical perspective for the main methodological concepts, both practical and theoretical, which form the basis for the design and analysis of phase III cancer clinical trials within the EORTC Data Center. Some statistical aspects of other associated topics such as quality of life, health economics, meta-analysis and treatment outcome will also be briefly discussed. Finally, some future perspectives and topics for further statistical methodological research will be presented in order to spur statisticians to meet the challenge of efficiently designing and analysing the clinical trials of tomorrow.

Abstract 909 T-ALL accounts for approximately 15% of childhood ALL. Despite major improvement of treatments, relapses still occur with dramatic prognosis. Efforts made in the past decade to understand T-ALL oncogenesis led to the identification of a number of oncogenes deregulated by genomic abnormalities, including TAL1, HOX11/TLX1, HOX11L2/TLX3, CALM-AF10, NUP214-ABL1, and MYB, some of them determining subtypes with distinct biological profiles. However, in EORTC trials, using BFM-derived protocols, these various genetic lesions have no prognostic impact, with the exception of a trend toward a favourable outcome for SIL-TAL1 fusion or HOX11 over expression (Cavé et al. 2004). Thus, risk-stratification remained based on early response to chemotherapy, as assessed by poor response to the (corticosteroid) prephase (PPR) and, in addition (58951 trial), on a high level (>10-2) of minimal residual disease (MRD) at completion of induction therapy. Hyperactivation of the NOTCH pathway by mutations of NOTCH1 or FBXW7 has been recently demonstrated in T-ALL. We investigated whether NOTCH1 and/or FBXW7 status could help to improve risk-stratification in T-ALL. We screened NOTCH1 and FBXW7 mutations by direct sequencing in 133 children with T-ALL enrolled in EORTC-CLG trials 58881 and 58951. Activating NOTCH1 mutations were found in 75 (56%) patients. Inactivating FBXW7 mutations were found in 20 (14%) patients, mostly in association with NOTCH1 mutations. Overall, 78 (59%) patients were considered NOTCH+ (NOTCH1 and/or FBXW7 mutated) whereas 55 (41%) were NOTCH- (NOTCH1 and FBXW7 wild type). NOTCH+ patients were distributed through all genetic subgroups. No significant relationships between NOTCH status and sex, age, WBC count, CNS or mediastinal involvement were observed. However, NOTCH+ had more often a cortical immunophenotype (53% vs 28%; p=0.02). NOTCH+ patients had a better early response to chemotherapy vs NOTCH- patients: lower PPR rate (20% vs 42%; p=0.02), and a lower incidence of high MRD level (13% (6/45) versus 30% (9/30); p=0.14). This led to less frequent switch to a very high risk (VHR) protocol for NOTCH+ versus NOTCH- patients (29% vs 49%, p=0.05). After a median follow-up of 4.6 years, 3 patients did not reach CR, 25 relapsed, 1 died in CR and 84 remained alive in CR; a total of 18 patients died. The outcome of NOTCH+ patients was similar to that of NOTCH- patients. The 5-yr EFS were 74% and 69% (p=0.8), respectively, and the 5-yr overall survival were 82% and 80% (p=0.7), respectively. However, prognostic importance of NOTCH status differed according to early response to treatment. In patients with a PPR, the NOTCH+ patients had a worse outcome than NOTCH- patients (5-yr EFS was 44% vs 58%; HR=1.54, p=0.43), whereas in non-PPR subgroup a reverse trend was observed (5-yr EFS was 83% vs 76%; HR=0.94, p=0.91). Similarly, in patients with high MRD levels the outcome was worse in NOTCH+ vs NOTCH- patients (5-yr EFS was 0% vs 47%, HR=11.7, p=0.03) whereas in MRD- patients the trend was reversed (5-yr EFS was 79% vs 71%, HR=0.88, p=0.83). Thus, although NOTCH1+ patients responded earlier and better to chemotherapy as compared to NOTCH1- patients, they did not show, overall, a better EFS. This was due to the poor outcome of NOTCH+ patients who had VHR features. In the German BFM trials, NOTCH1 mutations were also associated with lower rate of “poor response” to chemotherapy but this translated into a favourable outcome (see the ASH 2009 abstract of Kox et al.) NOTCH1- patients had a similar outcome in EORTC and BFM studies (5-yr EFS: 69% vs 74%) whereas NOTCH1+ patients had a lower 5-yr EFS in EORTC than in BFM studies (74% vs 87%). Noteworthy, in the EORTC trials the rate of isolated CNS relapses was quite high in NOTCH1+ patients (7.8%=6/77) as compared to NOTCH- patients (1.9%=1/53). Recently it was shown that NOTCH1 positively controls the expression of the chemokine receptor CCR7, an adhesion signal required for targeting T-ALL cells into the CNS (Buonamici et al. 2009). This may explain the higher propensity of NOTCH+ ALL to relapse in CNS. Although this is not the only difference in treatment between EORTC and BFM, the use of high dose methotrexate and intrathecal chemotherapy only, with omission of cranial irradiation prophylaxis in EORTC protocols, might have led to a suboptimal prevention of CNS relapses in NOTCH+ T-ALL, resulting in a lower EFS in EORTC trials as compared with German BFM in this group of patients. Disclosures: No relevant conflicts of interest to declare.

Introduction: Despite the use of current risk classification in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), a substantial proportion of so-called standard risk patients will experience a hematological relapse. Detection of DNA copy number abnormalities in BCP-ALLs has revealed additional genetic alterations, some of which are associated with outcome and may be included in future stratification strategies. Materials and methods: Using array-comparative genomic hybridization in a selected cohort of 70 intermediate risk pediatric BCP-ALLs, we characterized a recurrent RAG-mediated deletion of the CD200 and BTLA genes in 10% of patients. A breakpoint-specific PCR assay was designed and used to screen an independent non-selected cohort of 1154 genetically well-characterized BCP-ALLs uniformly treated according to the BFM-based EORTC-58951 protocol. Results: CD200/BTLA deletions were identified in 56 patients of the non-selected cohort (4.8%). Survival analysis revealed that CD200/BTLA deletions are associated with an inferior 8-year event free survival (EFS) of 70.2% ± 1.2% for patients with the deletions versus 83.5% ± 6.4% for non-deleted cases (HR 2.02; 95% CI 1.23-3.32; p=0.005) in the complete cohort of 1154 BCP-ALL patients. We observed a strong association between CD200/BTLA deletions and ETV6-RUNX1 positive leukemias (Table 1). The presence of ETV6-RUNX1 is a good prognostic marker in BCP-ALL and CD200/BTLA deletions did not affect prognosis within this genetic subtype. However and most notably, CD200/BTLA deletions were also identified in patients without any known genetic lesion, who are classified as having an intermediate outcome and belong to the intermediate-risk genetic group (defined in Table 1). Within this genetic group an inferior 8-year EFS rate of 33.3% (95% CI 7.8%-62.3%) was observed for patients with the deletions versus 76.2% (95% CI 71.0%-80.6%) for non-deleted cases (HR 4.00; 99% CI 1.34-11.93; p Discussion and conclusion: Altogether, these findings suggest that the prognostic value of CD200/BTLA deletions is restricted to intermediate risk BCP-ALL cases that lack any of the currently known prognostic indicators and underscore the rationale for implementing additional genetic markers in future risk stratification strategies. Table 1: Frequency of CD200/BTLA deletions according to BCP-ALL genetic subtypes and genetic risk groups Not deleted Deleted p-value No (%) No (%) All patients 1098 56 Genetic subtypes Table 2: Event types in CD200/BTLA deleted versus non-deleted patients Not deleted Deleted No (%) No (%) Intermediate-risk genetic group 361 9 EFS status NoCR 7 (1.9) 2 (22.2) CCR 283 (78.4) 3 (33.3) Relapse 67 (18.6) 4 (44.4) TRM 4 (1.1) 0 (0.0) Abbreviations: CR, complete remission; CCR, continuous complete remission; TRM, treatment related mortality. Disclosures No relevant conflicts of interest to declare.