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.

Abstract: 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.

Abstract: 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. Methods: Based on a pharmacological model and encouraging results of a phase II study we conducted a prospective randomized multicenter clinical trial comparing the effects of two different application modes of AraC in patients up to 60 years with untreated newly diagnosed AML. Patients were randomized to receive AraC at two different infusion rates (IR) during induction and consolidation treatment: arm A/experimental: 1 × 2 g/m2/d AraC over 8 hours (IR 250 mg/m2/h) arm B/standard: 2 × 1 g/m2/d AraC over 3 hours (IR 333 mg/m2/h). Induction and first consolidation consisted of AraC (days 1, 3, 5, 7) in combination with an anthracycline (Idarubicine 12 mg/m2 or Mitoxantrone 10 mg/m2, days 1–3). The final dosage points (AraC day 7 and anthracycline day 3) were excluded from the second consolidation. The third consolidation consisted of either allogeneic or autologous stem cell transplantation or of chemotherapy identical to second consolidation. Results: From 02/97 to 04/02 419 patients were enrolled in the study. The present analysis is based on 361 eligible and evaluable patients with a median follow up of 7 years. CR was reached in 249/361 (69%; 95%CI: 65%–74%) patients. No statistically significant differences were detected between arms A and B with regard to CR-rate (69% vs 69%) or early death rate (11% vs 8%). Hematological recovery of median white blood cell count (WBC) & gt; 109/l and median platelets (plt) & gt; 50 × 109/l revealed no difference between arms A and B after induction (WBC day 22 vs 22, p=0,68; plt day 25 vs 26, p=0,41) and consolidation (WBC day 28 vs 27, p=0,07; plt day 42 vs 40, p= 0,58). The event free survival (EFS) after 5 years is 0,25 ± 0,03 % for all patients with an overall survival of 0,31 ± 0,03 % after 5 years. For the purposes of analysis, the 83 transplant patients (23 allogeneic MRD, 14 allogeneic MUD and 46 autologous) were censored at time of transplant. No statistically significant difference between arms A and B in regard to EFS (0,25 ± 0,04 vs 0,25 ± 0,04, p=0,99), relapse incidence (0,63 ± 0,06 vs 0,60 ± 0,06, p=0,89), overall survival (0,32 ± 0,04 vs 0,30 ± 0,04, p=0,44) and therapy associated mortality (0,18 ± 0,04 vs 0,17 ± 0,03, p=0,95) were detectable after adjustment of prognostic factors. An analysis of risk factors by multivariate cox regression model confirmed cytogenetics at diagnosis to be the most important risk factor for CR rate (p & lt;10−6) and for EFS (p & lt;10−6). Other significant prognostic factors for EFS evaluated in the multivariate analysis were de novo vs secondary AML (p=0,0001), WBC (continuous) (p=0,001), LDH ( & gt;1–4 × vs other ULN) (p=0,008) and FAB classification (FAB M0,6,7 vs FAB M1,2,4,5) (p=0,0005). EFS after 5 years shows a significant correlation to cytogenetics (p & lt;10−6) with 0,71±0,1, 0,27±0,05, 0,20±0,06 and 0,03±0,03 for favorable, normal, other and unfavorable cytogenetic karyotype, respectively. Conclusion: We conclude that the application of AraC at the presumptive saturating infusion rate of 250 mg/m2/h results in comparable remission rates, toxicity, event free survival and overall survival as compared to the standard IR with 333 mg/m2/h.

Abstract: 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. Methods: Unfavourable cytogenetics, defined as abn 3q26, -5/5q-, -7/7q-, abn 11q23 or a multiaberrant clone were present in 20 (12,3%), 76 (20,5%) and 60 (26,3%) patients from the AML 93/96/2002 respectively. In the AML 93 protocol, therapy consisted of double induction (Idarubicin and standard dose AraC 3+7), followed by consolidation (Mitoxantron, Etoposide) and re-induction (Idarubicine + high dose AraC). In both AML 96 and AML 2002, a single course of induction therapy (intermediate dose AraC and Idarubicine 3+7) was repeated as the first consolidation for all patients achieving CR. In AML 96, patients in PR after the first induction received intermediate dose AraC and Mitoxantrone as a 2nd induction therapy. In AML 2002, both non-responders and those achieving PR were randomized between the same induction therapy or a more intensive regime (Mitoxantrone, Fludarabin and intermediate dose AraC). Results: Of all patients with unfavourable cytogenetics (n=156), 40%, 50%, and 65% achieved CR in the AML 93, 96 and 2002 studies respectively, with no statistically significant difference between the CR rates in the three studies (p=0,19). OS and EFS were analyzed both with and without censoring HCT. OS and EFS in patients censored at the time of transplant was not different between the three AML studies although intensity of chemotherapy differed widely (standard, intermediate and high dose AraC). The same analysis performed without censoring allogenic HCT revealed OS at 3 years of 10% for the AML 93, 14% for the AML 96 and 34% for the AML 2002 study (log rank p 〈 10 −2). EFS at 3 years was 9%, 10% and 32% in the AML 93, 96 and 2002 respectively (log rank p 〈 0,10−3). In AML 96, 32% of the patients with unfavourable karyotype underwent HCT, 40 % of these in CR1. In AML 2002, 60% of such patients were transplanted and 75% of them were in CR1. The interval from diagnosis to HCT decreased from median 204 (range 142–329) days in the AML 96 to median 125 (range 47–321) days in the AML 2002 (p=0,001). This decrease was associated with fewer cycles of chemotherapy prior to transplant: Patients in the AML 96 protocol received a median of 3 courses (range 2–4) and those in AML 2002 a median of 2 courses (p= 0,002). Conclusion: We conclude that intensity of induction and consolidation chemotherapy is not crucial for CR rate, OS or EFS in patients with unfavourable karyotype,. Improvement in OS and EFS was observed only using HCT as early as possible after CR1.

Abstract: Cytogenetic high risk AML (abn 3q26, abn 11q23, −5/5q-, −7/7q- and complex) has a dismal prognosis with a two year overall survival (OS) below 20% even in young patients. Attempts to improve survival by intensifying consolidation chemotherapy have so far failed. In the two OSHO protocols AML 96 and AML 2002, we investigated the role of allogeneic HCT in these patients. A total of 708 patients have been entered into the two studies between 1997 and the present. The first protocol (AML 96) compared two different schedules employing identical total dosages of intermediate AraC and Idarubicin. The second protocol (AML 2002) studied the role of two different induction therapies in patients failing to reach CR after the first induction therapy. In patients with cytogenetic high risk AML, the search for a donor (either familial or, if none available, then unrelated) was initiated as soon as possible. Allogeneic HCT was scheduled either after induction or after first consolidation therapy. HCT was performed after conditioning with cytoxan and 1200 cGy total body irradiation followed by GvH-D prophylaxis with cyclosporine and methotrexate. Of the 708 patients, 138 (19,5%) had high risk cytogenetics and 77 (55,8%) of these went into remission after one or two cycles of induction chemotherapy. Of these 77 patients, 54 were alive and in CR after the first consolidation therapy and were allocated to either related (n=12) or unrelated (n=21) HCT or, if no compatible donor was available, to a two courses of chemotherapy (n=21). Median age of the patients was 36 (range 17–51) years, 46 years (range 23–59) years and 49 (range 16–60) years for patients receiving related HCT, unrelated HCT and chemotherapy respectively. Data were analysed as intention to treat.LFS at 3 years was 67 ± 14% after related and 44 ± 14 % after unrelated HCT, but decreased to 11 ± 7% in patients receiving chemotherapy. Allogeneic HCT results were significantly better than the results of chemotherapy with p-values of 0.005 and 0.002 for related vs. chemotherapy and unrelated vs. chemotherapy respectively. Major differences in relapse incidences were seen between the three groups, with the lowest RI at 3 years after related HCT 26±0.13%, followed by unrelated HCT 48±15% and by chemotherapy 89±8% (p=0.003 and p=0,0006 for chemotherapy vs. related or unrelated HCT). Transplant related mortality at 3 years was 10±9%, 14±10% and 6±6% for patients receiving HCT from related donors, from unrelated donors and chemotherapy, respectively. Conclusions: From the results observed in the two prospective, multicenter studies we conclude that consolidation with allogeneic HCT is superior to chemotherapy in younger patients with high risk cytogenetics. While no differences in TRM were seen between the three treatment arms, a lower relapse incidence after related and unrelated HCT contributed to the improved OS.

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.

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.

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.

Abstract: Peripheral T-cell lymphomas (PTCL) - especially angioimmunoblastic (AITL) and follicular TCL - have a dismal prognosis due to lack of efficient therapies, and patients` symptoms are often dominated by an inflammatory phenotype including fever, night sweats, weight loss and skin rash. In this study, we investigated the role of inflammatory granulocytes and activated cytokine signaling on PTCL-TFH (T-follicular helper type) disease progression and symptoms. We show, that ITK-SYK driven murine PTCLs and primary human PTCL-TFH xenografts both induce inflammation in mice including murine neutrophil expansion and massive cytokine release. Granulocyte/lymphoma interactions were mediated by positive autoregulatory cytokine loops involving INF-γ (CD4+malignant T-cells) and IL-6 (activated granulocytes), ultimately inducing broad JAK kinase activation (Jak1/2/3, Tyk2) in both cell types. Depletion of inflammatory granulocytes via antibodies (Ly6G), genetic granulocyte depletion (LyzM-Cre/MCL1flox/flox) or the deletion of IL-6 within microenvironmental cells blocked inflammatory symptoms, reduced lymphoma infiltration and enhanced mouse survival. Furthermore, unselective JAK kinase inhibitors (ruxolitinib) inhibited both, TCL progression and granulocyte activation in various PTCL mouse models. Our results support the important role of granulocyte-driven inflammation, cytokine-induced granulocyte/CD4+ TCL interactions and the requirement of an intact JAK/STAT signaling pathway for PTCL-TFH development, and support broad JAK kinase inhibition as an effective treatment strategy in early disease stages.

Abstract: 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 OSHO 2004 study is part of the German intergroup study. Upon achieving complete remission (CR) after induction, patients were assigned to CT or HCT depending on the availability of a matched related or unrelated donor. Unrelated, single antigen mismatched donors were accepted in high risk situations. By April 2014 from 817 eligible patients, 505 entered CR (62%) after one or two induction therapies. From the 452 patients who received consolidation in CR 1, 31 patients (7%) relapsed and 10 (2%) died of complications during consolidation. No further therapy for medical reasons was given to 73 patients, 206 patients received second consolidation with cytarabine (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m² d1-2) and 132 patients underwent HCT. Most frequent conditioning regimens for HCT were low dose TBI (83%) and treosulfan/fludarabine (12%). Most of the patients received HCT from unrelated (80%) donors and the majority received grafts from HLA-identical (78%) donors. Our analysis was restricted to the 315 patients 〈 75 years receiving either CT or HCT. Probabilities for overall survival (OS) and leukemia free survival (LFS) were estimated according to the Kaplan-Meier method and differences tested by the log-rank test. Relapse incidence (RI) and non relapse mortality (NRM) were described by estimating the cumulative incidence and testing the differences using the Gray's test. Multivariate Cox regression models and competing risks regression models were used to identify independent prognostic variables for outcomes. The median age was 67 (60-74) and 65 (60-74) years in the CT and the HCT groups (p 〈 0.0005), respectively. There were no differences between CT and HCT regarding gender, AML type (de novo, secondary or therapy related) and FLT3 mutation status. However more patients with mutated NPM1 were observed in the CT as compared to the HCT group (39% vs 28%; p=0.07) and more patients entered into remission after one induction in the CT as compared to the HCT group (89% vs. 81%; p=0.05). Low risk cytogenetics and normal karyotype were present more frequently in the CT than in the HCT arm (p 〈 0.0005). The interval from CR to CT was 50 days and from CR to HCT 72 days (p 〈 0.0005). Patients receiving related or unrelated matched/mismatched HCT had superior LFS than those receiving CT (32±5% vs. 13±4% at 8 years, respectively; p 〈 0.0005). The difference was more distinct when only those patients with matched related or unrelated donors were compared to those receiving CT (36±6% vs. 13±4% at 8 years; p 〈 0.0005). Similar figures were obtained for overall survival [OS, 35±5% matched/mismatched HCT vs. 24±4% for CT (p=0.18) and 41±6% for matched HCT patients vs. 24±4% for CT (p=0.09)]. RI was lower after HCT (40±5%) than after CT (79±5%; p 〈 0.0001). In contrast, NRM was higher in HCT patients (28±7%) than in CT patients (9±11%; p 〈 0.0001). Subpopulation analyses identified no difference in LFS and OS between matched related versus unrelated HCT. The difference in LFS between HCT and CT was highest in patients with normal karyotype, high risk cytogenetics and patients with non-monosomal karyotyp. Prognostic factors for LFS, OS, RI and NRM were analyzed in a multivariate analysis. Significant prognostic factors for LFS were cytogenetic risk (p=0.04), HCT (p=0.01) and FLT3 mutation status (p=0.07). OS was determined by cytogenetics p 〈 0.01) with a trend for lower age (p=0.07) and HCT (p=0.14). Prognostic factors for RI were cytogenetics (p 〈 0.0006), FLT3 mutation status (p 〈 0.03) and HCT (p 〈 0.0005). NRM was influenced by HCT (p=0.002). Conclusions: HCT from related or unrelated donors improved LFS and OS in patients with AML over the age of 60 years and in particular in those with high risk cytogenetics or normal karyotype disease. The LFS of over 30% after 8 years achieved by HCT represents a marked improvement in the prognosis of patients with AML aged 60-75 years in CR1. Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Maschmeyer:Celgene: Consultancy.