ALBERT

Beschreibung: 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.

Beschreibung: 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

Beschreibung: Abstract 1280 Poster Board I-302 Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF) are defined as clonal hematopoietic stem cell disorders. These disorders show an inherent tendency for transformation into leukemia (MPN-blast phase) which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, obtained a comprehensive profile of genomic alterations associated with leukemic transformation by using single-nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. A relatively high number of genomic alterations was found in MPN after leukemic transformation with 4.6 ± 0.6 abnormalities per sample compared to only 1.4 ± 0.2 changes per patient in chronic phase (p

Beschreibung: Abstract 2696 Introduction: The prognosis of older patients (≥ 60 years) with acute myeloid leukemia (AML) is generally poor. The decision whether or not to use intensive chemotherapy in this patient cohort is challenging since only half of all older AML patients will eventually achieve a complete remission (CR) with an intensive approach. We therefore sought to develop a clinically relevant risk score for estimating the chance to obtain a CR compared to the risk of early death (ED). Patients and Methods: 1406 patients ≥ 60 years of age with AML and evaluable for an induction result after treatment with an intensive induction regimen (1-2 courses of either standard-dose araC containing TAD - high-dose araC containing HAM or HAM - HAM) within the AMLCG1999 study of the German AML Cooperative Group (AMLCG) were analyzed. External validation was performed on 801 patients ≥ 61 years of age treated in the AML96 study of the Study Alliance Leukemia (SAL) treated with 1–2 courses of a ‘7+3’ induction. 16 clinical parameters as well as cytogenetic and molecular risk factors were evaluated for risk prediction in an exploratory analysis. Results: Among the analyzed parameters, age, de novo versus secondary leukemia, body temperature, hemoglobin, thrombocyte count, LDH, fibrinogen and the cytogenetic and molecular risk were significantly associated with a CR and/or with an ED within 60 days (p

Beschreibung: Abstract 1056 Poster Board I-78 Introduction: We previously showed that a prolonged myelosuppressive maintenance chemotherapy was superior to S-HAM as a postremission therapy in patients 〉 16 years of age with AML after a TAD-HAM double induction therapy and TAD consolidation chemotherapy with regard to relapse-free survival (RFS) and borderline significance of the overall survival (OS) in responding patients (Buchner et al., JCO 2003, 21:4496-4504). Here we present long-term follow-up data with a median follow-up of 7.9 years from diagnosis and 7.1 years from the date of complete remission. Patients and Methods: Eight hundred thirty-two patients (median age, 54 years; range, 16 to 82 years) with de novo AML were upfront randomized in the AMLCG1992 study of the German AML Co-operative Group to receive 6-thioguanine, cytarabine, and daunorubicin (TAD) plus cytarabine and mitoxantrone (HAM; cytarabine 3 g/m2 [age 〈 60 years] or 1 g/m2 [age ≥ 60 years] x 6 (HAM in patients ≥ 60 years only in case of blast persistence on day 16 of therapy) induction, TAD consolidation, and monthly maintenance with cycles of cytarabine combined with either daunorubicin (course 1), 6-thioguanine (course 2), cyclophosphamide (course 3), and again 6-thioguanine (course 4), and restarting with course 1 for 3 years, or to receive TAD-HAM-TAD and one course of intensive consolidation with sequential HAM (S-HAM) with cytarabine 1 g/m2 (age 〈 60 years) or 0.5 g/m2 (age ≥ 60 years) x 8 instead of maintenance. Results: A total of 576 patients (69.2%) achieved a complete remission (CR) those were 294 of 429 (68.5%) patients randomized to receive maintenance and 282 of 403 (70.0%) patients randomized to receive intensive consolidation S-HAM (p=n.s.). 190 patients received maintenance therapy as intended and 135 patients received an intensive consolidation therapy as intended. This prolonged follow-up analysis verified the superior relapse-free survival in all patients in the maintenance arm (10-year RFS 30.0 ± 5.6 versus 19.9 ± 6.1 %, p = 0.015). Stratified by age, the 10-year RFS was superior in younger patients 〈 60 years (36.9 ± 7.1 versus 25.2 ± 8.0 %, p = 0.038) and borderline significant in elderly patients (17.2 ± 4.5 versus 6.8 ± 6.2 %, p = 0.075). A subgroup analysis of known risk groups (lactate dehydrogenase (LDH) level 〈 700U/l versus ≥ 700U/l at diagnosis, cytogenetic risk profile, bone marrow blasts on day 16 after the start of the induction therapy) revealed a superior RFS in the subgroup of patients with LDH level 〉 700 U/l at diagnosis (33.5 ± 12.3 versus 18.2 ± 9.5 %, p = 0.043). This superior RFS also translated into a superior 10-year relapse-free interval (RFI) of all responding patients in the maintenance arm (35.7 ± 6.3 versus 27.6 ± 5.9 %, p = 0.015) with borderline significance in younger patients (42.9 ± 7.4 versus 35.0 ± 7.4 %, p = 0.053) and a significant difference in elderly patients (20.6 ± 10.0 versus 8.4 ± 7.5 %, p = 0.043). In this updated analysis, there was a trend, but no significant difference in the OS (maintenance arm: 10-year OS 24.3 ± 4.8, intensive consolidation arm: 19.7 ± 4.7 %, p = 0.148), and we verified a trend for a better OS in responding patients for the maintenance arm (10-year OS in responding patients 33.6 ± 7.5 versus 28.5 ± 6.2 %, p = 0.093). The event-free survival (EFS) also showed a trend towards better EFS in the maintenance arm (10-year EFS 20.7 ± 4.2 versus 14.8 ± 4.1 %, p = 0.082) which was significant in elderly patients (10-year EFS 10.5 ± 5.5 versus 3.9 ± 3.7 %, p = 0.044). Discussion: This updated analysis with a long-term follow-up of median 7.9 years from diagnosis and 7.1 years from CR verified the superior RFS and the trend for enhanced OS in responding patients. These results suggest the superiority of a prolonged monthly myelosuppressive maintenance therapy as compared to intensive consolidation S-HAM after TAD-HAM induction and TAD consolidation. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and primary myelofibrosis show an inherent tendency for transformation into leukemia (MPN-blast phase), which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, examined chromosomal abnormalities by high-resolution single nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. Frequent genomic alterations were found in MPN after leukemic transformation with up to 3-fold more genomic changes per sample compared with samples in chronic phase (P 〈 .001). We identified commonly altered regions involved in disease progression including not only established targets (ETV6, TP53, and RUNX1) but also new candidate genes on 7q, 16q, 19p, and 21q. Moreover, trisomy 8 or amplification of 8q24 (MYC) was almost exclusively detected in JAK2V617F− cases with MPN-blast phase. Remarkably, copy number–neutral loss of heterozygosity (CNN-LOH) on either 7q or 9p including homozygous JAK2V617F was related to decreased survival after leukemic transformation (P = .01 and P = .016, respectively). Our high-density SNP-array analysis of MPN genomes in the chronic compared with leukemic stage identified novel target genes and provided prognostic insights associated with the evolution to leukemia.

Beschreibung: In order to test current risk factors in a prospective multicenter setting we evaluated the AMLCG 99 trial. Patients were randomly assigned to induction by TAD-HAM (HAM with araC 3 for age

Beschreibung: Abstract 2180 Purpose: Standard chemotherapy is curative only in a minority of older patients with AML and chemotherapy efficacy in this patient group has not improved in the last decade. Epigenetic alterations such as aberrant promoter DNA methylation occur frequently in AML patients and might provide novel targets for therapy improvement. The demethylating agent azacitidine is effective as a single agent in AML and MDS but does not lead to long term remissions. In the dose-finding part of the AML-AZA study, we analyzed the feasibility of two different doses of azacitidine added to standard 7+3 induction therapy in older patients (≥61 years) with AML. Patients and Methods: Two cohorts with 6 patients each were treated with azacitidine either 37.5 or 75 mg/sqm for 5 days, followed by standard induction chemotherapy 7+3 (cytarabine 100 mg/sqm on days 6–12 and daunorubicin 45 mg/sqm on days 8–10). In patients without blast clearance on day 15, a second cycle of the same induction regime (azacitidine +7+3) was administered. Patients who achieved a complete remission received two cycles of consolidation therapy consisting of 5 days of azacitidine (same dose as for induction therapy) followed by intermediate-dose cytarabine (1g/sqm q12h days 6, 8 and 10). Results: Overall, 2 out of 6 patients at the 37.5 mg/sqm dose level and 4 out of 6 patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Character and number of adverse events were similar to reported data from elderly AML patients treated with intensive chemotherapy. Among the 12 patients, the following 4 serious adverse events occurred: a severe hemolysis (most likely induced by fluorchinolone antibiotics) which resolved, a fatal apoplectic stroke and a fatal hepatorenal syndrome four days after the end of 7+3 chemotherapy at the 37.5 mg/sqm level, and a fatal pneumonia before 7+3 therapy could be initiated at the 75 mg/sqm level. The median duration of grade 4 leukopenia (CTCAE) was 26 days and the median duration of grade 4 thrombopenia was 22 days. Two patients went on for allogenic stem cell transplantation and were censored for survival analysis at the time of transplantation. Median event free survival was not reached after a median follow up of 5.5 months, and median overall survival was 8.1 months after a median follow up of 7 months. Conclusion: Our data indicate that the combination of azacitidine with standard induction therapy is feasible in older patients with AML with a similar tolerability of 37.5 mg/sqm and 75 mg/sqm. As a result, 75 mg/sqm azacitidine was selected as the investigational arm of the currently recruiting randomized phase II study comparing standard chemotherapy in AML with versus without azacitidine (AML-AZA). The study is registered at clinicaltrials.gov (NCT00915252). Disclosures: Off Label Use: use of Azacitidine, a hypomethylating agent, in adjunct to classic chemotherapy in elderly patients with AML. Koschmieder: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees.

Beschreibung: Abstract 4693 Loss of Structural Maintenance of Chromosomes 1A Protein Expression is Associated with a Poor Prognosis in Acute Myeloid Leukemia Utz Krug, Claudia Hömme, Nicola Tidow, Horst Bürger, Gabriele Köhler, Achim Heinecke, Thomas Büchner, Wolfgang E. Berdel, Steffen Koschmieder, Carsten Müller-Tidow Introduction Acute myelogenous leukemia is a genetically heterogenous disease with many risk factors for a poor prognosis. One of the most important independent risk factor in AML is the age at diagnosis. Older patients with AML generally have a poor prognosis which suggests that the biology of AML in elderly patients differs from AML in younger patients. Methods Gene expression profiling was carried out to identify age related changes in AML blasts of 67 AML patients of different age (range: 17 to 80 years). Among the genes that correlated with age, SMC1A was selected for protein expression studies. A tissue array was created containing bone marrow histology samples of 135 patients with newly diagnosed AML of different ages and probed with an antibody against SMC1A and protein expression was quantified by the DAKO score. Results 131 genes showed a significant correlation between mRNA expression levels and patient age. Increasing age was associated with significantly decreased mRNA levels of SMC1A. 116 patient samples were evaluable for SMC1A protein expression and expression of SMC1A protein was low or absent in 74 out of 116 AML specimens. SMC1A protein expression did not show a correlation with patients' age at diagnosis. Both event free survival (2.6 months vs. 10.3 months, p=0.003, see figure) and overall survival (10.4 months vs. 22.6 months, p=0.015, see figure) were significantly worse in patients with low or absent SMC1A protein expression. In a multivariate analysis, SMC1A protein expression level remained a significant prognostic factor for event free survival (p=0.014) with a borderline significance for overall survival (p=0.066). Conclusions We identified 131 genes with putative age-dependent microarray mRNA expression and identified low levels of SMC1A protein expression as a marker for poor prognosis in patients with newly diagnosed acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: Among the entire patients with AML the majority is 60 years of age or older. In present German multicenter AML Cooperative Group (AMLCG) trial the proportion of these older patients amounts to 54% of all 2734 patients enrolled and receiving intensive chemotherapy. While older age AML is increasingly recognized as a main challenge the therapeutic outcome unlike that in younger patients has remained constantly poor. Thus, the patients of ≥ 60y show an overall survival (OS) of 13% and a relapse rate (RR) of 82% at 5y versus 40% and 52% in younger patients. Age related differences in treatment and in risk profiles are commonly used to explain the differences in outcome. In the AMLCG 99 trial including 2734 patients 16 to 85 (median 61) years of age we investigated factors determining the disease biology and outcome. For induction treatment patients received standard dose TAD and high-dose AraC 3 (age 〈 60y) and 1 (≥ 60y) g/m² × 6/mitoxantrone (HAM) or randomly HAM-HAM, for consolidation TAD, and for maintenance monthly reduced TAD randomized (in patients 〈 60y) against autologous SCT. When compared with patients younger than 60y older patients had more frequent secondary AML (29% vs 17%, p〈 0.0001), unfavorable cytogenetics (29% vs 23%, p= 0.0004), less frequent favorable cytogenetics (4% vs 12%, p〈 0.0001), and NPM1mut/FLT3-ITDneg status (26% vs 34%, p〈 0.009) in those with normal karyotype, and overall even lower median WBC (7.360 vs 12.600/μl, p〈 0.0001) and LDH (340 vs 413 U/l, p〈 0.0001). A multivariate analysis identified independent risk factors determining therapeutic endpoints such as CR rate, OS, RR, and RFS. With similar results across all endpoints, risk factors for OS were age ≥ 60y (HR 1.96, 95% CI 1.75–2.17), AML secondary to MDS or cytotoxic treatment (1.28, 1.14–1.45), unfavorable karyotype (2.17, 1.92– 2.44), WBC 〉 20×10³/μl (1.15, 1.02– 1.30), LDH 〉 700U/L (1.32, 1.15– 1.52), favorable karyotype (0.49, 0.38– 0.63) and female gender (0.90, 0.81– 0.99). In the 891 patients with normal karyotype and complete mutation status risk factors for OS were age ≥ 60y (2.00, 1.64– 2.44), and NPM1mut/FLT3-ITDneg (0.39, 0.30– 0.49). Risk factors for RR overall were age ≥ 60y (2.04, 1.75– 2.38), unfavorable karyotype (2.08, 1.47– 2.13), LDH (1.41, 1.16– 1.72) and favorable karyotype (0.40, 0.29– 0.56). In patients with normal karyotype and complete mutation status risk factors for RR were age ≥ 60y (2.00, 1.56– 2.63), and NPM1mut/FLT3-ITDneg (0.32, 0.23– 0.43). Testing the role of older age in favorable subgroups, the 198 patients with CBF leukemia show an OS at 5 years of 27.5 (95% CI 12.0– 43.0) % in the older versus 69.4 (60.7– 78.2) % in the younger age group, and a RR of 56.6 (35.7– 77.3) % versus 25.0 (15.6– 34.4) %. Comparatively, the 264 patients with a normal karyotype and NPM1mut/FLT3-ITDneg show an OS of 37.1 (26.6– 47.5) % in the older versus 71.9 (63.4– 80.4) % in the younger age group, and a RR of 61.0 (47.8– 74.2) % versus 23.0 (14.0– 32.0) %. There was no influence by randomized treatment variables on any therapeutic endpoint. Conclusion: Considering the prognostic spectrum of all major historic or genetic subgroups older age maintains its dominant role not explained by age related differences in risk profiles. Even within CBF leukemias and sole NPM1 mutation as the best prognostic categories older age predicts for markedly shorter OS and higher RR. Thus, understanding older age AML requires further genetic and epigenetic work.