A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60–87) years. CR/CRi status at 90 days was not significantly different between the CSA (54

SummaryRelapse of acute leukemia is a frequent complication with uncertain outcome and poorly defined risk factors. From 1621 patients entered into two prospective clinical trials (AML02; n = 740 and AML04; n = 881), 74.2% reached complete remission (CR) 1 after induction(s) and 59 patients after additional induction ± hematopoietic cell transplantation (HCT). Of the non-refractory patients, 48.4% with a median age of 63 (range 17–85) years relapsed. Relapses occurred within 6 months after CR in 46.5%, between 7 and 18 months in 38.7%, and after 18 months in 14.8% of patients. Relapse treatment resulted in CR2 in 39% of patients depending upon age (54.5% of ≤ 60 and 28.6% of > 60 years), duration of CR1, and treatment of relapse. Overall survival (OS) was 10.9 (7.4–16.2) %, but OS after HCT ± intensive chemotherapy (ICT) was 39.3% (31.8–48.6) at 5 years and not different in younger and older patients. Donor lymphocyte infusion ± chemotherapy and ICT alone resulted only in OS of 15.4% and of 5%, respectively. Independent favorable factors for OS were long CR1 duration, and HCT, while non-monosomal disease was beneficial for OS in elderly patients. Leukemia-free survival [LFS; 24.9 (19.5–31.7) % at 10 years] was affected by similar risk factors. In a competing risk model, the relapse incidence at 5 years was 53.5 ± 3.5% and the non-relapse mortality rate 21.7 ± 2.9%. Lower relapse incidence was observed in patents with HCT, long CR1 duration, and female gender. Risk factors for non-relapse mortality were HCT in younger and type of AML in elderly patients. In conclusion, allogeneic HCT ± IC improved the results in relapsed AML in younger and elderly patients. Increasing CR2 rates and HCT frequency will be the challenge for the next years. Relapse of the disease remains the major problem.

Abstract Despite recent advances, treatment of elderly patients with AML remains a challenge because of adverse disease biology, comorbidities and therapy related toxicities. The balance between effectivity and toxicity of treatment strategies play a key role. Since comparative studies are lacking, a prospective randomized trial was designed among German AML study groups with different treatment strategies to compare outcome. Patients ≥60 years with all AML subtypes except M3 were randomized up-front to a common standard arm (CSA) (10%) and to study specific arms (90%) of the AMLCG or the OSHO. The CSA consisted of one or two inductions of araC 100 mg/m2/d continuous IV (CI) d 1-7 d and daunorubicin (dauno) 60 mg/m2/d IV d 3, 4, 5 and two courses of araC 1 g/m2/d BID IV d 1, 3 and 5 as consolidation (Mayer RJ et al, NEJM 1994). The AMLCG study arm randomized TAD (araC 100 mg/m2/d CI d1-2 followed by BID d 3-8, dauno 60 mg/m2/d IV d 3-5 and 6-thioguanine 100 mg/m2/d po BID d 3-9) and HAM [araC 1 mg/m2/d IV BID d 1-3 and mitoxantrone (mito) 10 mg/m2/d IV d 3-5] versus two courses of HAM with any 2nd course only given if blasts persisted ± G-CSF. Two courses of TAD were given as consolidation followed by maintenance chemotherapy over three years. The OSHO study arm included araC 1 g/m²/d BID IV d 1 + 3 + 5 + 7 and mito 10 mg/m2/d IV d 1 - 3 for one or two induction courses and ara-C 500 mg/m² BID 1h IV d 1 + 3 + 5 in combination with mito10 mg/m2/d IV d 1 + 2 as consolidation. Pegfilgrastim 6 mg s.c. was applied on day 10 of induction and on d 8 of consolidation. The study was approved by the IRB and registered at clinicaltrials.gov (NCT01497002 and NCT00266136). Written informed consent was obtained from all patients prior to randomization. Between April 1st, 2005 and May 26th, 2015 1286 patients were assigned randomly to the CSA (n=132) or to the study groups arm (n=1154). After excluding 139 patients (10.8%), 1147 patients were eligible for analysis, 1120 with follow-up for overall survival (OS) and 1079 for complete remission (CR) analysis. Baseline characteristics of all eligible patients showed median ages of 68 (60-82) years for the CSA and 69 (60-87) and 70 (60-85) years in the study arms A and B, respectively (p=0.05). Proportions of patients with secondary AML differed significantly between study arms (A: 42%, B: 30%, CSA: 36%; p=0.003). The CSA had less flt3 wildtype/npm1 wildtype patients (31%) vs. arm A (51% p=0.040) and arm B (58%, p=0.0455). No differences were observed with respect to cytogenetic risk groups, white blood cell counts, LDH, and npm1 mutant/ flt3-wildtype or mutant. The primary endpoint event free survival (EFS) did not differ between the CSA and study group strategies. Three-year EFS was 12.4% (95% CI: 6.7 - 19.9%) in the CSA, 15.6% (95% CI: 13.1 - 18.3%) in group A and 11.4% (95% CI, 7.4% to 16.4%) in group B (n.s.;Fig.1). With a median follow-up of 67 months, OS did not differ significantly between CSA and study group regimens. The 3-year survival probability was 22.3% (95% CI: 14.7-30.9%) in the CSA, 24.7% (95% CI: 21.6-27.9%) in group A and 22.4% (95% CI, 16.7% - 18.3%) in group B (Fig.2). CR status after 90 days of therapy was evaluated as secondary endpoint. The proportion of patients in CR in the CSA [51% (95% CI: 42-61%)] was comparable to the 50% (95% CI: 47-54%) and 48% (95% CI: 41-55%) of the study group arms (p=n.s.). Persistent leukemia was seen in 16% (95% CI: 10-24%) in the CSA vs 17% (95% CI: 14-19%) and 12% (95% CI: 8-17%) in groups A and B, respectively (both p= n.s.). A total of 226 patients died within 90 days of treatment, 24% (95% CI: 17-33%) in CSA, 19% in group A (95% CI: 16-22%) and 27% (95% CI: 21-33%) in group B; CSA vs A p=0.1859, CSA vs B p=0.5902). Death without AML was 3% in CSA, 2% in group A and 3% in group B, death with AML was 9% in CSA, 6% in group A and 5% in group B and death from indeterminate cause was 12% in CSA, 11% in group A and 20% in group B. Three-year relapse free survival (RFS) was 21.3% (95% CI: 12.2 - 31.0) in the CSA, 28.9% (95% CI: 24.9 -33.0%) in group A and 24.0% (95% CI: 16.8 - 31.9) in group B (both p=n.s.; Fig.3). In multivariate analysis independent variables for EFS and OS were age, type of disease, cytogenetic group and WBC count, but not the allocation to one of the treatment arms. Age and cytogenetic group were determinants for RFS. Conclusion A strictly prospective comparison of different treatment strategies in patients with AML did not show clinically relevant outcome differences when compared to a common standard arm. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Niederwieser: Novartis Oncology Europe: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Hoffmann:Novartis Oncology Europe: Research Funding. Al-Ali:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hegenbart:Pfizer: Other: Travel grant; Janssen: Honoraria, Other: Travel grant. Sayer:Riemser Pharma: Consultancy. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Fischer:Novartis: Consultancy, Honoraria. Dreger:Novartis: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Gilead: Speakers Bureau; Roche: Consultancy; Novartis: Speakers Bureau. Hiddemann:Roche: Membership on an entity's Board of Directors or advisory committees; Genentech: Other: Grants; Roche: Other: Grants.

e18501 Background: HSCT has been reported to be a treatment option for elderly patients with AML. Here we analyze the outcome of CT compared to HSCT in elderly AML patients according to genetic risk groups defined by the European Leukemia Net. Methods: By May 2015, 492 of 789 eligible patients (62%) from the AML 2004 study group entered CR and were assigned to CT (n = 205), matched (n = 119) or one antigen/allele mismatched HSCT (n = 31) depending on donor availability. Median age was higher (68 vs 66 years; p < 0.0005) and intermediate risk (IR) II and high risk (HR) cytogenetics were less frequent (p = 0.002) in CT than in HSCT. The interval CR - CT was significantly shorter than CR - HSCT (43 vs 65 days; p < 0.0005]. AML type, NPM1 and FLT3 status were comparable. Results: Patients receiving matched HSCT had longer LFS than those receiving CT (25±5% vs. 14±3% at 9 years; p < 0.001). As expected, RI was lower (42±5% vs 78±3%; p < 0.0001) and NRM was higher (34±5% vs 8±2%; p < 0.0001) at 9 years in HSCT than in CT patients. LFS differed between HSCT and CT for IR I (28±8% vs. 16±4% at 9 years; p = .007), IR II (30±10% vs. 4±4% at 7 years; p = .08) and HR patients (12±7% vs. 0±0% at 7 years; p < .05). RI was decreased in HSCT vs. CT for IR I (35±7% vs. 74±4% at 9 years; p < .0001), IR II (38±10% vs. 96±5% at 7 years; p < .0001) and HR (59±11% vs. 96±7% at 9 years; p < .004). These effects outweigh the higher NRM in HSCT for IR I (37±9% vs. 10±3% at 9 years; p = .0005), IR II (33±10% vs. 0% at 7 years; p = .003) and HR (29±10% vs. 4±4% at 9 years; p = .11). HSCT was an independent prognostic factor for NRM (p < 0.005), LFS and RI (both p < 0.0005). Genetic risk group (p < 0.01) was the only factor associated with OS. Conclusions: HCT improves LFS in AML CR1 patients between 60 and 75 years of age in genetic risk groups from IR I to HR. Clinical trial information: NCT01497002.

Treatment of patients (pts) with acute myelogenous leukaemia (AML) above 60 years remains a challenge. We report long-term follow-up of the AML97 study, where pts were registered at diagnosis and received treatment dependent on their comorbidities: dose-intense cytarabine (AraC) and anthracycline in the curative arm, and low-dose chemotherapy in the palliative arm or best supportive care.

Background: For patients with primary refractory or relapsed acute myeloid leukemia (AML), no treatment of choice has until now been defined to date. Cytarabine (Ara- C) is a key drug in the treatment of AML patients, there is still uncertainly regarding its optimal dose and infusion schedule. The aim of this study is to examine the impact of the Ara- C infusion schedule used as part of an intensive salvage regimen, in patients with relapsed or refractory AML. Patients and Methods: A total of 252 adult patients (median age 59 years) with relapsed or refractory AML were randomly allocated to receive either Mito- FLAG with Ara- C as bolus (B) (1000 mg/m2 over 1 h, every 12 h, days 1- 5), or continuous infusion (CI) (150 mg/m2 over 24 h, days 1- 5) in combination with mitoxantrone, fludarabine, and granulocyte colony- stimulating factor (G- CSF). Autologous or allogeneic hematopoietic stem- cell transplantation was offered as consolidation therapy. Primary end point was the rate of complete remissions (CRs) after the first cycle of Mito- FLAG. Results: The CR rates after Mito- FLAG (B) and Mito- FLAG (CI) were 54% and 43%, respectively (P = 0.1). There was no statistical difference between rates of grade 3/4 neutropenia, thrombocytopenia, mucositis, renal, and liver toxicity. More infections occurred, however, after Mito- FLAG (B) compared with Mito- FLAG (CI) (80% versus 69%, P = 0.01). The early death rate by day 42 was 13% in both arms. Median disease- free survival was comparable in the two arms (7.8 versus 7.1 months, P = 0.53) as was overall survival (7.1 versus 6.6 months, P = 0.53). Conclusion: A 5- day course of Ara- C 2 x 1000 mg/m2 administered as bolus versus Ara- C 150 mg/m2 administered by CI (in combination with mitoxantrone, fludarabine, and G- CSF), resulted in a nonsignificant trend in response rates in favor of Mito- FLAG (B) at the selected dose levels, but no differences in the survival outcome in relapsed or refractory AML.

Abstract Background The German AML Intergroup conducted two randomized studies in younger (<60 years) and elderly (≥60 years) patients in which the study arms were compared to a common standard arm. Here, we compared the two studies in younger and elderly patients focusing on disease characteristics and outcome. Patients and Methods The East German Study Group (OSHO) and the Acute Myeloid Leukemia Cooperative Group (AMLCG) each entered patients from 18 to 59 years into one study and patients aged 60 years and older into another. Each study group randomized upfront 10% of all AML patients into a common standard arm and 90% in the study group specific arm. All patients with de novo AML or AML after myelodysplastic syndrome or cytotoxic treatment were eligible. Chi-squared and Mann-Whitney-U tests were used to detect significant differences between the age groups regarding demographic, clinical and cytogenetic characteristics at baseline. Complete Remission (CR) at 90 days and cumulative probabilities of death were determined for outcome. To avoid bias due to the higher probability of death in older patients, cumulative probabilities of death were calculated for relapsed patients or those who did not achieve CR after 90 days. Other deaths were considered as a competing risk. Results A total of 2435 AML patients were analyzed, 1132 in the study <60 years and 1303 in the study ≥60 years. Significant differences in patient characteristics were noted between the studies. The elderly patient group contained a higher proportion of males than the younger group (55% vs 49% respectively, p=0.0031) and a higher percentage of secondary AML (40% vs 21% respectively, p<0.0001). In contrast, younger patients had higher median WBC count [13x109/L (range 0.03-798) for <60 years and 6.9x109/L (range 0.23-450) for ≥60 years, p<0.0001] and higher median lactate dehydrogenase [442U/L (range 35-19,624) for <60 years and 350U/L (range 51-9,486) for ≥60 years, p<0.0001]. Cytogenetic risk was similarly distributed in both groups (favorable: 12% in both age groups, intermediate: 66% in <60 years and 63% in ≥60 years, adverse: 22% in <60 years and 25% in ≥60 years, p=0.1672). However, the favorable combination of FLT3-ITDwt and NPM1mut in normal karyotype was more common in the younger (35%) than in the older group (27%; p=0.0212). A higher rate of CR at 90 days was observed in the younger (66%) than in the older (51%) patients (p=<0.0001). Of the younger patients 14.8% died (3.8% with persisting AML, 3.3% without AML and 7.7% without evaluable disease status) while of the older patients 21.8% died (6.2% with persisting AML, 2.5% without AML and 13.1% without evaluable disease status) during this period (p=0.0001). Relapse at 90 days was seen in 1% of the younger and in 2% of the older patients. The cumulative probability of AML-related death was lower in younger patients than in older patients (p<0.0001). Of the younger patients 29% (95% CI: 26% to 31%) and 44% (95% CI: 40% to 46%) died after one and three years due to AML; in the older group the corresponding frequencies were 45% (95% CI: 42% to 48%) and 62% (95% CI: 59% to 65%; Figure 1a). The probability of dying from AML was lowest for the younger patients with de novo AML [27% (95% CI 24% to 29%) at 1 year and 41% (95% CI 38% to 44%) at 3 years] and highest for those with secondary AML [38% (95% CI 32% to 44%) at 1 year and 56% (95% CI 49% to 62%) at 3 years (p=0.0001)], with similar differences being observed in the older patients (p=0.0001, Figure 1b). In the younger patients, CR at 90 days was lower in the standard (58%) than in the study arm (66%, p=0.0558), while AML related death was 29% and 27% at 1 year and 44% and 39% at 3 years respectively. In the older patients CR at 90 days was 52% vs. 51%, AML related death at 1 year 45% and 45% and at 3 years 63% and 69% for study arm and standard arm, respectively (Figure 1c). Conclusion This analysis reveals significant differences in gender, laboratory characteristics and proportion of secondary AML in elderly compared to younger AML patients. While there was no clear difference in cytogenetic risk groups, favorable molecular markers were more frequent in younger patients. Clear differences in CR rates after 90 days of therapy and AML related death rate were seen in regard to age (<60 years and ≥60 years) and disease type (de novo and secondary AML). As the common standard arm in both of the studies was age adapted, the differences between the two age groups are likely to be related to disease biology. Disclosures Niederwieser: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hoffmann:Novartis Oncology Europe: Research Funding. Krug:Sunesis; Clavis Pharma; usa Pharma, Catapult Cell Therapy, Gilead, Roche: Membership on an entity's Board of Directors or advisory committees; Sunesis: Speakers Bureau; Boehringer Ingelheim: Research Funding; Novartis; BMS; Roche; Boehringer Ingelheim; Bayer: Honoraria. Hegenbart:Janssen: Honoraria, Other: travel support. Pfirrmann:Novartis Pharma: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Kraemer:TEVA: Other: travel support. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Treatment of elderly patients with AML remains challenging. While increasing doses of induction and consolidation chemotherapy have failed to improve outcome, efforts to decrease relapse rates using the graft-versus-leukemia effect have shown promising results in phase II studies. In the present analysis of the prospective OSHO 2004 study we evaluated the effect of post-induction hematopoietic cell transplantation (HCT) in comparison to conventional consolidation chemotherapy (CT) on outcome in elderly patients with AML.

The incidence of acute myeloid leukemia (AML) is age-dependent with the majority of patients (pts) being older than 60 years at diagnosis. Treatment of these pts needs to be well balanced between sufficient efficacy and tolerable toxicity. Here, we report long term follow-up of the OSHO AML97 study. Pts with AML older than 60 years were registered after informed consent and received age-adapted intensive chemotherapy treatment (curative arm; induction therapy with AraC 2 g/m2 iv day 1, 3, 5, 7 and mitoxantrone 10 mg/m2 iv day 1 to 3 to induce complete remission (CR), followed by 2 consolidation courses with AraC 240 mg/m2 iv day 1 to 5 and mitoxantrone 10 mg/m2 iv day 1 to 2), low dose chemotherapy (palliative arm; idarubicin 10 mg po day 1 and either thioguanine 40 mg po day 1-5, or AraC 80 mg sc day 1-5 or etoposide 100mg po day 1-5) or supportive therapy (best supportive care including transfusions). A total of 618 pts were enrolled (curative arm n=471, palliative treatment n=115 and supportive therapy n=32 pts). In the curative arm, CR was obtained in 66.8% of pts. Treatment related mortality (TRM) was 11.2% after induction and 4.5% after consolidation I, respectively. Median overall survival for all pts in the curative arm was 12 months, event free survival (EFS) at 12 years was 0.11±0.02%. In multivariate analysis, cytogenetics at diagnosis was the most important prognostic factor for CR (p=0.001). With a median follow up of 10 years (range 0.1 - 11.8) probability of overall survival (OS) at 5 years was 0.48±0.11; 0.13±0.03; 0.10±0.04 and 0.08±0.03 for pts with favorable, normal, other and unfavorable cytogenetics. Median survival for pts treated with palliative chemotherapy was 54 days.

Purpose: To define prognostic factors for overall survival in adult patients (pts) with relapsed acute myeloid leukemia (AML).

Abstract The optimal consolidation chemotherapy in AML patients >60 years has yet to be defined in detail. Although age-adjusted induction chemotherapy results in CR rates comparable to those in younger patients, relapse remains the major hurdle to successful treatment. While the role of stem cell transplantation (HSCT) in elderly patients is currently being evaluated in randomized studies, we focus here on the intensity of consolidation chemotherapy. Patients data from the elderly AML trials OSHO 1997 (n=410) and OSHO 2004 (n=733) were pooled and analyzed. These protocols have identical inclusion/exclusion criteria and induction chemotherapy, but differ in the intensity of consolidation therapy. In the OSHO 1997 trial, Ara-C 120 mg/m2 bid was given from day 1-5 and mitoxantrone 10 mg/m2 from day 1-2 as consolidation. In the OSHO 2004 an intensified consolidation using Ara-C 500 mg/m2 bid on day 1/3/5 was applied together with mitoxantrone as used in the OSHO 1997 study. Of the 1143 patients, 689 entered CR (60% in the OSHO 1997 and 61% in the OSHO 2004) and 536 (OSHO 1997, n=242, OSHO 2004, n=294) did not receive HSCT as consolidation. The analysis concentrated on the dose of AraC used in the consolidation for this elderly population and on the cycles of consolidation applied. Patient characteristics were compared using chi-square test for categorical data and Wilcoxon rank sum test for continuous data. OS was analyzed using the Kaplan-Meier method, and univariate comparisons were made by means of the log-rank test. Cox regression was used to find any association between consolidation chemotherapy considered as a time-dependent covariate on Overall Survival (OS) or Relapse Incidence (RI). RI and Non Relapse Mortality (NRM) were calculated using the competing risk method, and the Gray test was applied to compare differences. Multivariate modeling was performed by Cox regression analyses with a forward selection method. Median ages in the AML studies were 66 (60-81) years and 69 (60-85) years for the OSHO 1997 and OSHO 2004, respectively. Patients characteristics were balanced except for age and Karnofsky score (p< .0005) and a trend towards more intermediate and high risk karyotypes, more female and less WBC in the OSHO 2004 compared to the OSHO 1997 study (p=0.06). OS at 15 years was 14±2% in all patients with no difference between the two consolidations, but strong dependence on cytogenetic risk factors. In multivariate analyses risk factors for survival were high/intermediate risk karyotypes, male gender, non de-novo AML and less than two consolidations. Patients with two consolidations had better OS than patients with one or no consolidations in the pooled group and in each of the two protocols with no difference between OSHO 1997 and OSHO 2004. Relapse incidence amounted to 79±2% and NRM 10±04% at 15 years with no difference between the two protocols. Relapse incidence was dependent upon cytogenetic risk and the number of consolidations applied in a multivariate model. There were no risk factors predicting TRM in multivariate analysis. Our analysis of patient characteristics according to the number of consolidations showed the distribution of consolidation therapies to be 15.2%, 28.0%, 56.6% and 14.2%, 32.3% and 53.4% for 0, 1 and 2 consolidations in the OSHO 1997 and OSHO 2004 respectively (n.s.). Higher age, higher risk cytogenetics, non-de novo AML type, less CR after one induction cycle and lower WBC count at diagnosis were characteristic of patients receiving none or one as compared to two consolidation therapies. The multivariate analysis revealed cytogenetics and gender as independent risk factors, but not the application of one as opposed to two consolidation treatments. The increase of AraC dose in the OSHO 2004 was unable to either increase survival or improve relapse incidence in the cohort of elderly patients. TRM was not different between the OSHO 1997 and 2004 studies. However, the application of one or two consolidation cycles had a significant impact on survival that was not due to decreased relapse incidence after normalization for risk factors. Interestingly, just above 50% of patients received 2 consolidations as proposed in the protocol with no statistically significant difference between OSHO 1997 and OSHO 2004. Patients receiving fewer consolidation therapy cycles are older, have more non-de novo AML and lower WBC count. Disclosures: Hochhaus: Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria.

![Graphic][1] Purpose In patients with relapsed acute myeloid leukemia (AML) > 60 years of age we analyzed age at relapse, interval from first complete remission (CR1) to relapse, cytogenetic risk at initial diagnosis, prior allogeneic stem cell transplantation (alloSCT) and FLT3/NPM1 mutational status as possible prognostic factors for overall survival (OS). Introduction After achieving CR1 more than 50% of elderly AML patients eventually relapse. Prognostic factors for OS are poorly defined in this patient population. For younger patients with relapsed AML a risk score has been described including age at relapse, interval from CR1 to relapse, cytogenetic risk at initial diagnosis and prior stem cell transplantation (SCT) as prognostic factors. We sought to investigate whether these are also prognostic factors in elderly patients with relapsed AML. In addition, we assessed the prognostic impact of FLT3- and NPM1 mutational status (wild-type (wt) or mutated (mut)) at diagnosis. Patients and methods In the ongoing multicenter OSHO trial #69 for AML patients > 60 years we evaluated data of all relapsed patients. Overall survival was calculated from the day of first relapse until the day of death using the Kaplan Meier method. Univariate analysis was performed to test for the influence of age at relapse, interval from CR1 to relapse, cytogenetic risk at initial diagnosis, prior alloSCT and FLT3/NPM1 mutational status. Subsequently, independent prognostic factors were defined in a multivariate analysis with age at relapse, time from CR1 to relapse, cytogenetic risk at initial diagnosis and prior alloSCT as covariates. Results From April 2005 until April 2013 904 patients were registered. 733 of these received intensive induction chemotherapy which resulted in CR1 in 447 (61%) pts. In this patient group 260 relapses were observed after a median interval, calculated from the day of CR1, for living patients of 2.7 years (range 0.1 to 7.5). Median age at relapse was 69 years (range 60 – 85) with 129 (49.6%) pts. being 60 to 68 years old, 102 (39.2%) pts. being 69 to 74 years old and 29 (11.1%) pts. being 75 to 85 years old. Median interval from CR1 to relapse was 0.58 years (0.07 – 6.28). 114 (43.8%) relapses occurred up to 6 months after CR1, 119 (45.8%) between 7 and 18 months after CR1 and 27 (10.4%) later than 18 months after CR1. Only five (1.9%) relapsed pts. showed good risk cytogenetics at diagnosis, whereas it was of intermediate risk in 159 (61.1%) pts., of poor risk in 68 (26.2%) pts. and unknown in 28 (10.8%) pts. Forty-one (15.8%) pts. had received prior alloSCT in CR1. Information on FLT3- and NPM1 mutational status at diagnosis was available in 194 (74.6%) pts. 110 (42.3%) pts. had FLT3/NPM1 wt/wt, 48 (18.5%) pts. had FLT3/NPM1 wt/mut, 23 (8.8%) pts. had FLT3/NPM1 mut/wt and 13 (5.0%) pts. had FLT3/NPM1 mut/mut. OS rate at 2 years of all relapsed pts. was 13 ± 2%. For patients younger than 69 years and for those 69 years of age or older OS rate at 2 years was 17 ± 4% and 9 ± 3%, respectively (p=0.03). The interval between CR1 and first relapse also affected 2 year-OS with 7 ± 3%, 15 ± 4% and 36 ± 12% for pts. with relapse up to 6 months, 7 to 18 months and later than 18 months after CR1, respectively ( 18 months: p=0.009). OS rate at 2 years was also influenced by cytogenetic risk at initial diagnosis with 17 ± 3% for pts. having good or intermediate risk cytogenetics and 3 ± 2% for those with poor risk cytogenetics (p< 0.0005). Prior alloSCT had a negative influence on OS. Two-year OS rate was 10 ± 5 and 13 ± 3% (p= .015) for patients with prior alloSCT vs. those without prior alloSCT, respectively. FLT3/NPM1 mutational status at diagnosis had no impact on OS. In univariate analysis age at relapse (p<0.04), interval from CR1 to relapse (p< 0.0005), cytogenetic risk at initial diagnosis (p<0.02) and prior alloSCT (p<0.02) were shown to be prognostic factors for OS, whereas FLT3/NPM1 mutational status was not significant (p=0.82). In multivariate analysis the same factors remained significant but only interval from CR1 to relapse (p<0.0005) and prior alloSCT (p=0.003) were independent. Conclusion In AML patients >60 years in first relapse OS is poor. Longer interval from CR1 to relapse and no prior alloSCT are independent beneficial prognostic factors for OS. FLT3/NPM1 mutational status at diagnosis has no prognostic impact on OS. Disclosures: Wedding: Roche: Speakers Bureau; Amgen: Speakers Bureau; Chugai: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Novartis: Speakers Bureau; Cephalon: Speakers Bureau; Prostarkan: Speakers Bureau; Pfizer: Speakers Bureau. Niederwieser: Novartis: Consultancy. [1]: /embed/inline-graphic-1.gif

Abstract Abstract 128 The treatment of elderly patients (pts) with AML remains challenging. High treatment associated mortality using protocols developed for younger patients and high relapse rates for pts reaching CR are frequent causes of failure, while many pts are assessed as ineligible for intensive chemotherapy. Patient registration at diagnosis to check for patient allocation or the use of age-adjusted induction protocols to reduce treatment related mortality may improve the management of these pts. In a prospective German Intergroup Study for patients ≥ 60 years, comparable to a completed study for patients < 60 years (Büchner JCO 2012 in press), the outcomes from two study groups using specific induction and consolidation protocols were compared to a common standard arm (CSA). By October 2011, 1041 pts had been randomized to the study-specific regimens or CSA in a 9:1 ratio. Eighty four patients (8%) were excluded due to incorrect diagnosis, secondary neoplasias or other reasons. Treatment in the CSA consisted of araC [100 mg/m2 continuous infusion (c.i.) d1-7] and daunorubicin (60 mg/m2 i.v. on d3- 5). A second induction was given if marrow blasts ≥5% on d15. Pts in CR received two consolidations with araC (1 g/m2 i.v. bid on d1, 3 und 5). The OSHO study group (group A) investigated araC (1 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m2 d1-3) for induction and araC (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m2 d1-2) for consolidation, while the AMLCG (group B) analyzed TAD (ara-C 100 mg/m2 c.i. d1,2; ara-C 100 mg/m2 bid i.v. d3-8)-HAM (ara-C 1g/m2bid i.v. d1-3) vs HAM-HAM ± G-CSF in pts with ≥5% blasts and TAD as consolidation followed by maintenance. Of 957 eligible pts, the median age was 69 (range: 60–87) years (68, 70 and 67 years for A, B and CSA, respectively; p<0.03), 45% were female (with no imbalance between groups) and 61% had de novo AML. Significantly more secondary AML were present in group A than in group B or CSA (A 43%, B 28%, CSA 37%, p<0.0001). Risk factors were unevenly distributed with significantly more favorable cytogenetics in group A (15%) than in group B (7%; p=0.0139). There were fewer patients with favorable molecular markers (NPM1 mut/FLT3 wt) in group B than in group A or the CSA (CSA 36%, A 29%, B 16%, p=0.04). No difference was detected in baseline white blood cell counts (WBC) between the three arms, but there was a trend to a higher serum LDH in group A (p=0.06). Induction therapy led to CR in 71% and 68% of pts in the standard and study arms respectively with early death rates of 20% and 21%. Nine percent of pts in the CSA and 6% in the study group arms had persistent AML. The results after 90 days are available for 743 patients with a CR rate of 56% in the study arms and 50% in the CSA. At 90 days, 156 patients had died with no difference between CSA and study groups (22.0 vs. 21.0% respectively). Persistent AML was present in 21% of the patients in the CSA, but in only 16% of the study arms. Univariate (Χ2and Mann-Whitney U-test) and multivariate analyses (logistic regression, Wald test) were performed to identify risk factors. CR after 90 days was more frequent in pts with de novo AML than in those with secondary AML (60.7% vs. 47.9%; p=0.0007) and also higher in pts with favorable as compared with intermediate and unfavorable cytogenetics (68.1% vs 55.0% vs 48.4%; p=0.0107). Pts in CR after 90 days were younger (mean [95% CI]: 68.3 years [67.9; 68.8] vs 69.4 years [68.8; 70.0]; p=0.0067) and had a lower WBC than pts without CR (27.5 per μL [22.6; 32.3] vs 36.1 per μL [29.7; 42.6]; p=0.0077). LDH was higher in pts without CR after 90 days (641.0 U/l [537.1; 744.8] vs 536.0 U/l [461.3; 610.8]; p=0.0041). The percentage of bone marrow blasts, treatment groups, sex, FAB and NPM1/FLT3 mutation status had no significant influence on treatment outcome at 90 days. AML diagnosis (de novo or secondary; p=0.0002), cytogenetic risk (p=0.0114), age (p=0.0069) and WBC (p=0.0025) were independent factors influencing the CR rate. Adjusted overall survival (OS) and event free survival (EFS) showed no significant differences between the groups after a median follow up of 33 months. In conclusion, high CR rates can be achieved in elderly patients with AML. The CR-rate is dependent upon the type of AML (de novo or secondary), cytogenetic risk, age and WBC at diagnosis in a multivariate analysis. No differences have been detected in the CR rates between the three arms to date. Further follow up is needed to detect differences in OS and EFS. Disclosures: Hoffmann: Novartis Pharma: Research Funding.

Between 1996 and 2004, a total of 708 patients were enrolled in the acute myeloid leukaemia (AML) '96 and '02 studies of the East German Study Group (OSHO). Of these, 138 patients (19.5%) had unfavourable cytogenetics defined as complex karyotype, del (5q)/-5, del (7q)/-7, abn (3q26) and abn (11q23). In all, 77 (56%) achieved complete remission 1 (CR1) after induction chemotherapy and were eligible for haematopoietic cell transplantation (HCT). HCT was performed after a median of two cycles of consolidation chemotherapy (CT) in the AML '96 and one cycle in the AML '02 study (P=0.03). After a median follow-up of 19 months, overall survival (OS) at two years was significantly better in the donor group (52+/-9%) versus the no-donor group (24+/-8%; P=0.005). Differences in outcomes were mainly because of a lower relapse incidence in patients after HCT (39+/-11%) compared with a higher relapse incidence in patients undergoing CT (77+/-10%; P=0.0005). Treatment-related mortality was low and not statistically significantly different between the two treatment groups (15+/-7 and 5+/-5% for HCT and chemotherapy, respectively; P=0.49).We conclude that early HCT from related or unrelated donors led to significantly better OS and leukaemia-free survival compared with chemotherapy in patients with unfavourable karyotype.

Clinical trials on different cytarabine doses for treatment of AML provide evidence of a dose response effect, but also for increase toxicity after high dose AraC (HDAC). Pharmacokinetic measurements of cytarabine-triphosphate (AraC-CTP), which is the most relevant cytotoxic metabolite of AraC, have revealed its formation in leukemic cells to be saturated with infusion rates above 250 mg/m2/h, this being significantly lower than used in HDAC schedules.

The incidence of AML increases with age. More than half of the patients (pts) are over 60 years (y) at time of diagnosis. On the other hand, elderly pts are clearly under-represented in the literature. The AML 97 study was designed to register all pts aged 60 and more with newly diagnosed AML. Subsequently, pts were allocated to one of the 3 parts of protocol dependent on Karnofsky's index (KI).

7003 Background: Even after reaching initial CR, most AML patients > 60 years relapse within 2 years of diagnosis. Cytogenetic high risk AML (abn 3q26, abn 11q23, -5/5q-, -7/7q- and complex) has an even worse prognosis. Attempts to improve survival by intensifying consolidation chemotherapy have so far failed. We investigated the role of allogeneic HCT in comparison to chemotherapy among patients with high risk cytogenetics entered into the OSHO AML 97 protocol. Methods: Initial treatment consisted of a course of induction therapy (AraC 2 g/m2 iv on day 1,3,5,7 + mitoxantrone 10 mg/m2 iv day 1 –3, repeated once in case of PR) followed by one consolidation course (AraC 240 mg/m2 iv day 1 –5 + mitoxantrone 10 mg/m2 iv day 1 –2). Patients in CR1 after the consolidation I were either treated with an additional consolidation therapy or with an allogeneic HCT from related (n=2) or unrelated (n=10) donors. Transplant patients were conditioned with fludarabine and TBI 200 cGy and immunosuppressed with cyclosporine and mycofenolate mofetil. Results: A total of 347 patients are evaluable. Of 105 (33%) patients with high-risk cytogenetics, 53 (50%) went into remission after one or two cycles of induction chemotherapy. Of these 53 patients, 42 received consolidation I and 35 patients were available for either consolidation II (n=23) or HCT (n=12). Median age of the patients receiving chemotherapy was 64 (range 61–77) years and that of the transplant patients was 64 (range 61–68) years. LFS at 4 years was 42 ± 14% after HCT and 15 ± 8% after chemotherapy. Major differences in relapse incidences were seen between the two groups, with the lowest RI at 4 years after HCT (36 ± 15%) followed by chemotherapy (85±8%, p<0.04). Treatment related mortality at 4 years was 35±17% and 0±0% for patients receiving HCT and chemotherapy, respectively (p<0.05). Conclusions: From these results, we conclude that consolidation with allogeneic HCT after minimal conditioning is superior to chemotherapy even in older patients with high risk cytogenetics. While differences in TRM were seen between the treatment arms, a lower relapse incidence after related and unrelated HCT contributed to the improved LFS. No significant financial relationships to disclose.

Purpose: The purpose of this study was to compare the efficacy and toxicity of bendamustine, vincristine+prednisone (BOP) with a standard regimen of cyclophosphamide, vincristine+prednisone ( COP) in patients with previously untreated advanced indolent non-Hodgkin's lymphoma (NHL) and mantle cell lymphoma. Methods: A total of 164 patients with follicular lymphoma (grade 1/2), mantle cell lymphoma or lymphoplasmacytic lymphoma (immunocytoma) was randomised to treatment with vincristine 2 mg (day 1) and prednisone 100 mg/m(2) (days 1-5) + bendamustine 60 mg/m(2) (days 1-5) or + cyclophosphamide 400 mg/m(2) (days 1-5) for a total of eight 21-day cycles. Results: The rate of complete remission was 22% with BOP and 20% with COP. The projected 5-year survival rate was 61% with BOP and 46% with COP. The BOP-associated 5-year survival advantage almost reached significance in the subgroup of patients who responded to therapy (74% vs. 56%; P=0.05), and did reach significance in responders who did not receive interferon maintenance therapy (70% vs. 47%; P=0.03). Toxicity was acceptable in both treatment groups, although alopecia and leucopenia were more severe with COP. Conclusions: Bendamustine can efficaciously and safely replace cyclophosphamide, as used in standard COP therapy, for the treatment of patients with indolent NHL and mantle cell lymphoma. Long-term survival data suggest a clinically significant benefit for patients treated with BOP.

Purpose : This randomized phase III study compared bendamustine and prednisone (BP) to standard melphalan and prednisone (MP) treatment in previously untreated patients with multiple Myeloma (MM). Patients and Methods : To be included, patients had to have histologically and cytologically proven stage II with progressive diseases or stage III MM. They were randomly assigned to receive BP ( n =68) or MP ( n =63). The primary endpoint was the time to treatment failure (TTF). Secondary endpoints included survival, remission rate, toxicity and quality of life. Results : The overall response rate was 75% in the BP and 70% in the MP group. A significantly higher number of patients treated with BP achieved a complete remission than did patients receiving MP (32 vs. 13%; P =0.007), and the maximum response was achieved more rapidly in patients treated with BP compared to those receiving MP (6.8 vs. 8.7 cycles; P <0.02). TTF and remission duration were significantly longer in the BP group. Patients receiving BP had higher QoL scores and reported pain less frequently than patients receiving MP. Conclusion : BP is superior to MP with respect to complete remission rate, TTF, cycles needed to achieve maximum remission and quality of life and should be considered the new standard in first-line treatment of MM patients not eligible for transplantation.

AML patients with unfavourable cytogenetics generally have a poor outcome. Over the last decade a number of strategies to improving survival have been assessed by the East German Study Group (OSHO). Here, we analyse the results of three protocols (AML 93, AML 96 and AML 2002) for effects on outcome in younger patients (<60 years) with unfavourable cytogenetics.