ALBERT

Description: Background: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy and risk stratification based on genetic and clinical variables is standard practice. However, current models incorporating these factors accurately predict clinical outcomes for only 64-80% of patients and fail to provide clear treatment guidelines for patients with intermediate genetic risk. A plethora of prognostic gene expression signatures (PGES) have been proposed to improve outcome predictions but none of these have entered routine clinical practice and their role remains uncertain. Methods: To clarify clinical utility, we performed a systematic evaluation of eight highly-cited PGES i.e. Marcucci-7, Ng-17, Li-24, Herold-29, Eppert-LSCR-48, Metzeler-86, Eppert-HSCR-105, and Bullinger-133. We investigated their constituent genes, methodological frameworks and prognostic performance in four cohorts of non-FAB M3 AML patients (n= 1175). All patients received intensive anthracycline and cytarabine based chemotherapy and were part of studies conducted in the United States of America (TCGA), the Netherlands (HOVON) and Germany (AMLCG). Results: There was a minimal overlap of individual genes and component pathways between different PGES and their performance was inconsistent when applied across different patient cohorts. Concerningly, different PGES often assigned the same patient into opposing adverse- or favorable- risk groups (Figure 1A: Rand index analysis; RI=1 if all patients were assigned to equal risk groups and RI =0 if all patients were assigned to different risk groups). Differences in the underlying methodological framework of different PGES and the molecular heterogeneity between AMLs contributed to these low-fidelity risk assignments. However, all PGES consistently assigned a significant subset of patients into the same adverse- or favorable-risk groups (40%-70%; Figure 1B: Principal component analysis of the gene components from the eight tested PGES). These patients shared intrinsic and measurable transcriptome characteristics (Figure 1C: Hierarchical cluster analysis of the differentially expressed genes) and could be prospectively identified using a high-fidelity prediction algorithm (FPA). In the training set (i.e. from the HOVON), the FPA achieved an accuracy of ~80% (10-fold cross-validation) and an AUC of 0.79 (receiver-operating characteristics). High-fidelity patients were dichotomized into adverse- or favorable- risk groups with significant differences in overall survival (OS) by all eight PGES (Figure 1D) and low-fidelity patients by two of the eight PGES (Figure 1E). In the three independent test sets (i.e. form the TCGA and AMLCG), patients with predicted high-fidelity were consistently dichotomized into the same adverse- or favorable- risk groups with significant differences in OS by all eight PGES. However, in-line with our previous analysis, patients with predicted low-fidelity were dichotomized into opposing adverse- or favorable- risk groups by the eight tested PGES. Conclusion: With appropriate patient selection, existing PGES improve outcome predictions and could guide treatment recommendations for patients without accurate genetic risk predictions (~18-25%) and for those with intermediate genetic risk (~32-35%). Figure 1 Disclosures Hiddemann: Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Metzeler:Celgene: Honoraria, Research Funding; Otsuka: Honoraria; Daiichi Sankyo: Honoraria. Pimanda:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Beck:Gilead: Research Funding.

Description: Key Points AML patients with isolated trisomy 13 have a very poor clinical outcome Isolated trisomy 13 in AML is associated with a high frequency of mutations in SRSF2 (81%) and RUNX1 (75%)

Description: Abstract 327 Introduction: Older patients (≥ 60 years) with acute myeloid leukemia (AML) display a dismal prognosis with only half of the patients reaching a complete remission after intensive induction therapy. The decision whether or not to use intensive chemotherapy is often difficult given the limited number of known markers that might predict the chance to achieve a complete remission. The aim of this study was to establish a risk score for therapy-failure based on clinical variables for older but medically fit AML patients. Patients and Methods: 1379 patients ≥ 60 years of age with AML evaluable for an induction result after treatment with an intensive induction regimen (randomized standard-dose cytarabine containing TAD or high-dose cytarabine (1g/sqm × 6) containing HAM, with a second induction course HAM in case of blast persistence after the first course) within the AMLCG1999 study of the German AML Co-operative Group were evaluated. The following parameters were evaluated for risk prediction in an exploratory analysis: Age, sex, de novo versus secondary leukemia, performance status, body mass index, body temperature, presence of extramedullary manifestations, spleen size, presence of lymph node enlargement, hemoglobin, peripheral blood leukocytes, platelets, blast percentage in peripheral blood and bone marrow, total protein in serum, alanine aminotransferase (ALT), alkaline phosphatase (AP), bilirubin, lactate dehydrogenase (LDH), FAB classification, prothrombin time (PT) and fibrinogen. Since cytogenetics and molecular markers are often not available at the time of decision making, these data were not included. Results: Within this cohort of patients, 744 (54 %) achieved a complete remission. Among the analyzed parameters, age, de novo versus secondary leukaemia, body mass index, body temperature, hemoglobin, peripheral blood leukocytes, platelets, bone marrow and peripheral blood blasts, ALT, AP, LDH, PT and fibrinogen were significantly associated with a CR (p 36°C – 38°C, 〉 38°C), hemoglobin (≤ 10.3 g/dl versus 〉 10.3 g/dl), platelets (≤ 28,000, 〉 28,000 - 53000, 〉 53,000 – 103,000, 〉 103,000 per μl), AP (≤ 89 U/l versus 〉 89 U/l), PT (≤ 75 %, 〉 75 – 87 %, 〉 87 – 98 %, 〉 98 %) and fibrinogen (≤ 150 mg/dl versus 〉 150 mg/dl). Based on these parameters, the predicted remission rates were: minimum, 18.3 %; 1st quartile, 43.9 %; median, 54.4 %;3rd quartile, 64.3 %; maximum: 88.1 %. The observed remission rates were: 1st quarter, 35.7 %; 2nd quarter, 50.3 %; 3rd quarter, 60.2 %; 4th quarter, 69.8 %. Conclusions: Taken together, this risk prediction score based on pre-treatment values predicted the remission probability in patients ≥ 60 years of age with AML receiving an intensive induction therapy. This score may be useful for the determination of the therapy strategy in elderly patients with AML. Disclosures: No relevant conflicts of interest to declare.

Description: Background Arsenic trioxide (ATO) is regarded as the treatment of choice for relapsed PML-RARA+ acute promyelocytic leukemia (rAPL). In 2008, a European online registry of rAPL based on uniform CRFs was established under the auspices of the European LeukemiaNet (ELN) to gain insights in the clinical and biological characteristics of rAPL treated with ATO and to allow an assessment of the different options for postconsolidation therapy. Methods Eligibility criteria for prospective or retrospective registration were PML-RARA+ 1st or successive molecular or clinical relapse of APL from the year 2003 onwards. The treatment should be based on the European recommendations for treatment of rAPL (www.leukemia-net.org/content/), which offer induction and consolidation therapy with ATO and several options for post-consolidation therapy including autologous or allogeneic stem cell transplantation or chemotherapy consolidation followed by various modifications of maintenance therapy ± ATO - to be selected depending on several variables including patient age, performance status, PCR status after consolidation, type of frontline therapy, first CR duration and donor availability. Results By 30 June 2013, of 220 registered cases, 198 were evaluable (172 in 1st, 26 in ≥2nd relapse). Of these, 149 patients (pts) in 1st relapse received ATO-based salvage therapy after standard frontline therapy based on all-trans retinoic acid (ATRA) and anthracyclines (98 hematological (hematol) relapses of bone marrow combined with CNS relapse in 5 pts, 40 molecular (mol), 11 isolated extramedullary, mainly CNS). Clinical characteristics: median age at relapse 44 years (y) (4 to 81), 67% males, Sanz Risk Score at 1st diagnosis: low 23%, intermediate 48% and high 29% of pts. Median duration of first remission was 565 d (105 d to 7.0 y). The median treatment duration of ATO (0,15 mg/kg/day) plus ATRA (44% of pts) for remission induction (ind) was 30 days (d) and for consolidation (cons) 25 d. CNS relapses received ATO and additional intrathecal chemotherapy ± irradiation. WBC white blood cell count; Leuko.: leukocytosis requiring hydroxyurea; ADS: APL differentiation syndrome; 1 median; 2 hematological; 3 RT-PCR of PML-RARA negative. In non-hematological relapses, no early deaths occurred and no major side effects of ATO were seen. Median follow up of the 149 pts was 2.8 y (6 d to 10 y). Three-year overall survival (OS) was 70%, 95%CI [61;79] and 6-year OS 56% [42;70]. Three-year OS of hematological, molecular and extramedullary relapse was 69% [58;80], 66% [48;84] and 90% [81;99], respectively (p=0.2). Concerning outcome after transplantation, 3-year OS after autologous was 82% [70;94] (n=55), after allogeneic 75% [58;92] (n=32) and without transplantation 66% [48;84] (n=55) (p=0.4). Conclusions With ATO-based salvage therapy over 50% of patients in 1st relapse of APL can probably be cured. Pts in molecular relapse have a lower rate of early complications and death. Long-term survival is possible with transplantation-free approaches, but transplantation seems to improve the outcome. Disclosures: Lengfelder: TEVA/ Cephalon: Research Funding. Lo-Coco:TEVA: Speakers Bureau.

Description: Abstract 2773 Introduction: For patients with high-risk myelodysplastic syndromes an epigenetic therapy with hypomethylating agents is considered standard of care. Intensive chemotherapy can be offered to a subset of patients; however, data about the long-term outcome of MDS patients receiving intensive chemotherapy are scarce. Methods: For this evaluation, 104 adult patients with IPSS intermediate-2 or high-risk MDS with at least 10% bone marrow blasts of all age groups treated within the AMLCG1999 trial were included. Patients were randomized upfront to receive 1. double induction therapy with either standard-dose containing TAD - versus high-dose containing HAM–HAM, 2. TAD consolidation therapy followed by either a monthly maintenance therapy for 3 years after achievement of CR or an autologous stem cell transplantation (patients aged ≥ 60 years were all assigned to maintenance therapy), and 3. blast priming with filgastrim starting on day -1 of chemotherapy in selected centers. Results: Fifty-four patients had IPSS Score intermediate-2 and 50 patients were IPSS high risk. Median bone marrow blast count at diagnosis was 15%. The median age was 63.5 years (range: 27–76 years), 39 patients (37.5 %) were female. Median lactate dehydrogenase (LDH) serum level was 296 U/l, median leukocyte count at diagnosis was 5,950 per μl. The cytogenetic risk groups were as follows: favorable 3, intermediate 57, unfavourable 37, missing 7. Among 38 patients with normal karyotype, NPM1/FLT3 mutational status was available for 22 with 5 patients having the combination NPM1 mutated/FLT3 wildtype. Comparison with 2051 patients with de novo AML within the same trial revealed the following significant differences: patients with MDS were older, had a higher male to female ratio, a lower LDH serum level at diagnosis, a lower leukocyte count at diagnosis and were more likely to have adverse cytogenetic risk. Compared to 636 patients with secondary AML after MDS, cytotoxic therapy or irradiation, the cohort of patients with MDS did not display any significant differences except the sex distribution. Patients with MDS displayed a CR rate of 48% (50/104 patients), which was significantly lower than de novo AML patients (67%) and not different to secondary AML patients (47%). Median overall survival in MDS patients was 320 (95% CI: 236 to 505) days with a 2-year and 5-year survival of 33.4% (95% CI: 23.6% to 43.2%) and 22.7% (95% CI: 13.5% to 31.9%), respective, which was significantly (p=0.03) lower than in patients with de novo AML (median 484, 95% CI 435 to 541 days) and comparable to patients with secondary AML (median 282, 95% CI 224 to 311 days, p=0.13). Median relapse-free survival in responding MDS patients was 536 (95% CI: 264 to 1299) days with no significant differences of RFS compared to de novo or secondary AML patients. In multivariate analyses, the diagnosis of MDS remained an independent prognostic factor for CR probability but had no independent influence on survival compared with de novo AML patients. Nine patients proceeded to allogeneic stem cell transplantation in first complete remission of whom six remain in first complete remission between 1354 and 1911 days after achievement of CR. In addition, 16 patients remained in CR for more than one year without allogeneic transplantation. Discussion: Taken together, outcome of patients with intermediate-2 or high-risk MDS after intensive chemotherapy is comparable to the outcome of patients with secondary AML. Adjustment for known risk factors such as age, cytogenetic risk and LDH revealed that inferior outcome of MDS patients compared to patients with de novo AML is attributable to the higher incidence of adverse risk factors. CR-rates appear to be higher compared to hypomethylating therapy and a fraction of MDS patients experiences long-term survival by intensive chemotherapy. Allogeneic transplantation can improve long-term survival for patients achieving remission. Disclosures: Krug: MedA Pharma: Honoraria; Novartis: Honoraria; Alexion: Honoraria; Boehringer Ingelheim: Research Funding; Sunesis: Honoraria. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Description: Allogeneic hematopoietic stem cell transplantation (allo-SCT) from an HLA-identical sibling donor (SIB) is considered the preferred postremission therapy for younger patients with HiRi AML in CR1. The role of allo-SCT from volunteer unrelated donors (VUDs) is less clear and randomized controlled trials addressing this issue do not exist. We performed an observational landmark analysis on parallel cohorts of patients aged

Description: We have previously shown that a monthly myelosuppressive chemotherapy proved superior to high-dose cytarabine consolidation therapy (J Clin Oncol2003,21:4496) after induction therapy and induction-type consolidation therapy. In the multicenter AMLCG 1999 trial, we reported that this maintenance therapy resulted in equal results with lower therapy-related morbidity and death-rate compared to autologous stem cell transplantation in patients

Description: Abstract 2175 Eight years from the start of a cooperation among five multicenter study groups in Germany, and three years after entering the last patient we here present updated therapeutic results. A total of 3171 patients 16–60 years of age with AML including primary and secondary AML and high-risk MDS, and excluding APL with t(15;17), were treated in the five study groups cooperating by a general upfront randomization allocating 10% of their patients to a common standard treatment and 90% to the study group own regimens before any treatment had been started. The standard treatment consisted of remission induction by two courses of standard dose araC over seven days with daunorubicin 60mg/m2/d on three days. Patients in complete remission received three monthly courses of high-dose araC 3g/m2q 12 h on day 1,3 and 5. In the participating study groups a total of 2866 patients eligible by the inclusion criteria of the AML Intergroup study were treated according to the study group own regimens with 828 patients in study group A, 373 in B, 235 in C, 808 in D, 622 in E, and 305 patients were treated according to the common standard. In an attempt to conduct treatment optimization trials the study group own strategies relied on a risk-oriented stratification among treatment options (group A), a randomized stratification (group D), or combinations of randomization and risk-adaption (B, C, E). High-dose araC was used up to cumulative 54g/m2 in groups A, E, and in the standard arm, and up to 36 to 40g/m2 in groups B, C, D. Marked differences were also seen in the use of allogeneic stem cell transplantation with 27% allografts in 1st CR in study group A, 33% in B, 19% in C, 23% in D, 25% in group E, and 21% in the common standard arm. Unlike the differences in the study groups strategies in the amounts of high-dose araC, and in the numbers of allografts in 1st remission, the risk profiles regarding age, secondary AML, cytogenetic groups, mutations in NPM1/FLT3-ITD, levels of WBC and LDH were concordant between the common standard arm and the study group own populations, except for single differences in secondary leukemia (group B), cytogenetics (C), and WBC (D). The study group itself was not an independent prognostic factor for any outcome. Similar patient populations could thus be evaluated to compare the treatment strategy of each study group with that of the common standard arm. The outcome of the standard treatment was 66.7% (95% CI 61.0–72.0) complete remissions, an overall survival of 44.3% (95% CI 37.9–50.9), and a relapse free survival of 44.9% (95% CI 36.9–52.5) at 5 years. Adjusted for prognostic baseline variables no significant difference in the remission rate and overall survival between the standard arm and any of the study groups were observed. Comparable patterns were also found for relapse free survival where the long-term results of the standard treatment were not further improved in any of the five study groups. We conclude that in unselected patients with AML a prospective comparison shows very similar outcomes of any current treatment strategy when compared with that of the common standard treatment. Present reliable and unbiased analyses became possible by a strictly prospective approach and intent-to-treat evaluation. These representative results can form a solid basis for novel therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.

Description: As recently reported modifications, dose or duration of treatment had no impact on outcome of AML in older patients (Burnett et al. Blood 106: 162a, 2005). We therefore evaluated 764 patients 60 years of age or older and their various prognostic subgroups in the 1992 and 1999 mulitcenter randomized trials by the German AMLCG where patients received uniform postremission consolidation by one course of TAD (standard dose thioguanine, araC, daunorubicin) and maintenance by monthly 5 day courses of reduced TAD. For maximum homogeneity this analysis was restricted to de-novo AML and to patients with known karyotype. Before treatment started, patients were assigned to induction treatment by either TAD followed by HAM (HAM, high-dose araC 1g/m2x6 / mitoxantrone 10mg/m2x3), or to induction by two courses of HAM. The second induction course (HAM) was given to only patients with 5% or more residual bone marrow blasts. Therapy administered to the two randomized groups differed by a factor 2 in their araC dose. Despite this difference in treatment intensity patients in the two arms show similar response rate, overall survival (OS), ongoing CR, and relapse-free survival (see table). The same similarity in outcome as for de-novo AML overall is true for established prognostic subgroups as listed below. Conclusion: Intensification of induction therapy by high-dose araC has no effect on outcome in older age de-novo AML. Since potential influences other than the randomized treatment were minimized, present results do not support a risk adapted intensification strategy. TAD-HAM HAM-HAM P TAD-HAM HAM-HAM P OS 4y % OS 4y % CR 4y % CR 4y % Total 18 13 .28 22 22 .53 Favorable Karyotype 17 16 .48 41 33 .82 Intermediate Karyotype 24 18 .31 24 26 .38 Unfavorable Karyotype 4 - .81 - - .37 LDH ≤ 700U/L 21 13 .86 23 24 .47 LDH 〉 700U/L 12 10 .07 - 16 .27 WBC ≤ 20x103/ccm 21 11 .91 22 21 .81 WBC 〉 20x103/ccm 15 16 .08 22 26 .19 Day 16 Blasts 〈 10% 26 16 .87 23 22 .81 Day 16 Blasts ≥ 10% 14 8 .28 18 19 .26

Description: Background: The prognosis of patients with acute myeloid leukemia (AML) has improved in recent years, partly due to the use of intensive double induction chemotherapy. Patients with adverse cytogenetic risk factors, especially those with a complex aberrant karyotype, however, still have a grave prognosis. Previous results from the German AMLCG study group have shown that younger patients with a complex karyotype may profit from double induction therapy containing one course of high dose AraC. It is unclear whether further intensification of induction chemotherapy may prolong survival. Methods: We investigated the outcomes of patients with unfavourable cytogenetics treated with either high-dose AraC and mitoxantrone (HAM) followed by thioguanine, conventional-dose AraC and daunorubicin (TAD) or with two courses of HAM in the prospectively randomized AMLCG-2000 trial. We included patients with unbalanced chromosomal aberrations (−5, −7, del(5q) or del(7q), or abnormalities involving 3q) and patients with a complex aberrant karyotype. Results: A total of 392 patients with unfavourable cytogenetics were analysed. Of those, 261 had de novo AML, 51 had secondary AML following a myelodysplastic syndrome (sAML) and 30 had therapy-related AML (tAML). The rate of complete remissions (CR) was significantly higher in patients with de novo AML compared with secondary or therapy-related AML (39 % vs. 20% vs. 23%, P=0.01). The overall survival (OS), however, was significantly shortened only in patients with tAML but not in those with sAML (median OS, 43 d (tAML) vs. 248 d (sAML) vs. 213 d (de novo AML), P=0.027). 233 patients had a complex aberrant karyotype. Although their CR rate was similar to patients with other unfavourable cytogenetics, OS was significantly worse (median, 169 vs. 327 days, P