Abstract: Progress in the treatment of acute myeloid leukemia (AML) in older patients (pts) is still limited with poor complete remission (CR) rate and overall survival (OS). This is attributed to a variety of reasons including an inherently poor biology, especially a higher incidence of poor-risk karyotypes, co-morbidities, and an age-related functional impairment. In our randomized AML HD98B trial, the addition of all-trans retinoic acid (ATRA) to intensive chemotherapy resulted in an increased CR rate, event-free (EFS) and OS (Schlenk et al Leukemia 2004). More recent reports on in vitro studies indicated a synergistic action of the histone deacetylase inhibitor valproic acid (VPA) when associated with ATRA plus cytarabine and anthracyclines. In the randomized AMLSG 06-04 trial, therefore, VPA was evaluated in combination with intensive induction therapy plus ATRA in older pts ( 〉 60 years) with newly diagnosed AML. In first analyses, the addition of VPA did not provide a significant advantage in OS and EFS after a median follow-up of 47 months (Tassara et al, ASH 2010, abstract #185). This was mainly due to increased hematological toxicity by VPA after the second induction therapy. Here we provide updated analyses especially on survival outcome data based on mature follow-up. Aims To evaluate VPA in combination with intensive induction therapy and ATRA in older patients with newly diagnosed AML. Methods Between August 2004 and February 2006 186 patients were randomized (standard-arm, n=93; experimental-arm, n=93) in the AMLSG 06-04 study (ClinicalTrials.gov Identifier: NCT00151255); median age was 68 years (60-84). The first 77 pts were randomized to receive 2 induction cycles (idarubicin 12 mg/m2 i.v. days 1-3, cytarabine 100 mg/m2 cont. i.v. days 1-5, ATRA 45 mg/m2 days 3-5 and 15 mg/m2 days 6-28) with or without VPA (days 1-28; started at 400 mg bid and then adapted in order to obtain a serum level of 60-150 mg/l). After an interim analysis the study was amended; for the following 109 patients idarubicin was dose-reduced to day 1 and 3 and VPA only added during the first induction cycle. All patients were intended for consolidation. Molecular diagnostics were performed as previously published (Schlenk et al, Haematologica 2009) Results Details of the response rate and toxicity of the induction treatment have already been presented (Tassara et al, ASH 2010, abstract #185). To summarize, CR rates after double induction were in trend higher in the standard-arm (52% vs. 40%; p=0.10), and early death rate higher in the experimental-arm (14% vs. 26%; p=0.06). The main toxicities attributed to VPA were grade 3/4 infections and delayed hematologic recovery (leukocytes, neutrophils and platelets) observed after the second induction cycle. Therapy (i.e. double induction and consolidation) was completed by 37/93 (40%) of patients in the standard arm and 19/93 (20%) in the experimental arm (p=0.01) After a median follow up of 84 months, analysis of the primary endpoint EFS revealed no differences between the two arms (EFS at 5 years, standard arm 2.3%, experimental arm 7.6%; p=0.95); similarly OS was not different (OS at 5 years, standard arm 11.7%, experimental arm 11.4%; p=0.57). However, pts in the experimental arm had a significantly better relapse-free survival (RFS at 5 years, standard arm 6.4%, experimental arm 24.0%, p=0.02). In explorative subset analyses superior RFS (p=0.03) and OS (p=0.03) of CR-patients were observed in AML patients with mutated NPM1 randomized into the experimental arm (RFS at 5 years, standard arm 8%, experimental arm 42%; OS at 5 years, standard arm 37%, experimental arm 52%). In contrast no differences were seen in AML patients with NPM1 wild-type for RFS (p=0.13) and OS (p=0.87) of CR-patients (RFS at 5 years, standard arm 7%, experimental arm 20%; OS at 5 years, standard arm 15%, experimental arm 22%). Due to a low frequency of FLT3-ITD (9/72) in this patient subset meaningful analyses were not possible. Conclusion In older patients with AML, the addition of VPA to standard induction treatment was associated with severe hematological toxicity as well as higher rates of infections and did not improve EFS and OS. However, after a long follow-up VPA was associated with a significantly improved RFS, which might be related to the mutated NPM1 genotype. Disclosures: Schlenk: Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Ambit: Honoraria.

Abstract: Background: Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in roughly 25% of younger adult patients (pts) with acute myeloid leukemia (AML). The multi-targeted kinase inhibitor midostaurin combined with intensive chemotherapy has shown activity against AML with FLT3 mutations. However, toxicity and potential drug-drug interactions with strong CYP3A4 inhibitors such as posaconazole may necessitate dose reduction. Aims: To evaluate the impact of age and midostaurin dose-adaptation after intensive induction chemotherapy on response and outcome in AML with FLT3-ITD within the AMLSG 16-10 trial (NCT01477606). Methods: The study included adult pts (age 18-70 years (yrs)) with newly diagnosed FLT3-ITD positive AML enrolled in the ongoing single-arm phase-II AMLSG 16-10 trial. Pts with acute promyelocytic leukemia were not eligible. The presence of FLT3-ITD was analyzed within our diagnostic study AMLSG-BiO (NCT01252485) by Genescan-based DNA fragment-length analysis. Induction therapy consisted of daunorubicin (60 mg/m², d1-3) and cytarabine (200 mg/m², continuously, d1-7); midostaurin 50 mg bid was applied from day 8 until 48h before start of the next treatment cycle. A second cycle was allowed in case of partial remission (PR). For consolidation therapy, pts proceeded to allogeneic hematopoietic-cell transplantation (HCT) as first priority; if alloHCT was not feasible, pts received three cycles of age-adapted high-dose cytarabine (HDAC) in combination with midostaurin starting on day 6. In all pts one-year maintenance therapy with midostaurin was intended. The first patient entered the study in June 2012 and in April 2014, after recruitment of n=147 pts, the study was amended including a sample size increase to 284 pts and a dose reduction to 12.5% of the initial dose of midostaurin in case of co-medication with strong CYP3A4 inhibitors (e.g. posaconazole). This report focuses on age and the comparison between the first (n=147) and the second cohort (n=137) of the study in terms midostaurin dose-adaptation. Results: Patient characteristics were as follows: median age 54 yrs (range, 18-70; younger, 68% 〈 60 yrs; older, 32% ≥ 60 yrs); median white cell count 44.7G/l (range 1.1-1543 G/l); karyotype, n=161 normal, n=16 high-risk according to ELN recommendations; mutated NPM1 n=174 (59%). Data on response to first induction therapy were available in 277 pts; complete remission (CR) including CR with incomplete hematological recovery (CRi) 60%, PR 20%, refractory disease (RD) 15%, and death 5%. A second induction cycle was given in 54 pts. Overall response (CR/CRi) after induction therapy was 76% (76%, younger; 76%, older) and death 6% (4%, younger; 10% older). The dose of midostaurin during first induction therapy was reduced in 53% and 71% of patients in cohort-1 and cohort-2, respectively. Reasons for dose reduction were in 58% and 49% toxicity, and in 9% and 23% co-medication in cohort-1 and cohort-2, respectively. No difference in response to induction therapy was noted between cohorts (p=0.81). Median follow-up was 18 months. Overall 146 pts received an alloHCT, 128 in first CR (n=94 younger, n=34 older; n=92 from a matched unrelated and n=36 from a matched related donor). In pts receiving an alloHCT within the protocol in median two chemotherapy cycles were applied before transplant (range 1-4). The cumulative incidence of relapse (CIR) and death after transplant were 13% (SE 3.2%) and 16% (SE 3.5%) without differences (p=0.97, p=0.41, respectively) between younger and older patients. So far maintenance therapy was started in 86 pts, 61 pts after alloHCT and 25 pts after HDAC. Fifty-five adverse events 3°/4° were reported being attributed to midostaurin; cytopenias after alloHCT were the most frequent (29%). CIR in patients starting maintenance therapy was 20% one year after start of maintenance without difference between alloHCT and HiDAC (p=0.99). In addition, no difference in CIR was identified in patients after consolidation with alloHCT or HDAC according to dose reduction of midostaurin during first induction therapy (p=0.43, p=0.98, respectively). Median overall survival was 25 months (younger, 26 months; older 23 months; p=0.15). Conclusions: The addition of midostaurin to intensive induction therapy and as maintenance after alloHCT or HDAC is feasible and effective without an impact of age and dose adaptation on outcome. Disclosures Schlenk: Amgen: Research Funding; Pfizer: Honoraria, Research Funding. Fiedler:GSO: Other: Travel; Pfizer: Research Funding; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; Gilead: Other: Travel; Ariad/Incyte: Consultancy; Novartis: Consultancy; Teva: Other: Travel. Lübbert:Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding; Ratiopharm: Other: Study drug valproic acid. Greil:Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; AstraZeneca: Honoraria; Boehringer-Ingelheim: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Eisai: Honoraria; Amgen: Honoraria, Research Funding. Greiner:BMS: Research Funding. Paschka:ASTEX Pharmaceuticals: Consultancy; Novartis: Consultancy; Medupdate GmbH: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer Pharma GmbH: Honoraria; Celgene: Honoraria. Heuser:Bayer Pharma AG: Research Funding; Karyopharm Therapeutics Inc: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Honoraria; Pfizer: Research Funding; BerGenBio: Research Funding; Tetralogic: Research Funding.

Abstract: Background: The concept of intensive post-remission chemotherapy in acute myeloid leukemia (AML) is based on the observation that despite achievement of a first complete remission (CR) after intensive induction therapy virtually all patients relapse in the absence of further treatment. Moreover, randomized studies showed that intensive post-remission consolidation chemotherapy was superior to prolonged low-dose maintenance therapy in younger patients. With regard to consolidation therapy, the landmark study conducted by the Cancer and Leukemia Group B established the current standard for patients aged 60 years and younger with high-dose cytarabine (HDAC) 3g/m² bidaily on days days 1, 3, and 5. Aims: to compare a compressed schedule of high-dose cytarabine (HDAC) on days 1, 2, and 3 with the standard HDAC given on days 1, 3, and 5 as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in patients in first CR receiving repetitive consolidation cycles for acute myeloid leukemia. Methods: Patients (18 to 60 years) were accrued between 2004 and 2009. They were randomized up-front 1:10 between the standard German intergroup-arm (Büchner et al. J Clin Oncol. 2012;30:3604-10) and the AMLSG 07-04 study (NCT00151242). Induction therapy in the AMLSG 07-04 study consisted of two cycles of idarubicin, cytarabine and etoposide +/- all-trans retionoic acid (ATRA) and +/- valproic acid (VPA) in a 2 by 2 factorial design. After recruitment of 392 patients the randomization for VPA was stopped due to toxicity. For consolidation therapy, patients with high-risk AML, defined either by high-risk cytogenetics or induction failure, were assigned to receive allogeneic hematopoietic cell transplantation from a matched related or unrelated donor. All other patients were assigned to 3 cycles of HDAC from 2004 to November 2006 with cytarabine 3g/m² bidaily, on days 1, 3, 5 and pegfilgrastim on day 10 (HDAC-135) and from December 2006 to 2009 patients were treated with a condensed schedule with cytarabine 3g/m², bidaily, on days 1,2,3 and pegfilgrastim on day 8 (HDAC-123). Patients randomized into the German AML intergroup arm were treated for consolidation therapy with cytarabine 3g/m² bid on days 1, 3, 5 (HDAC-135) without prophylactic growth-factor support. Results:Overall 568 patients receiving 1376 consolidation cycles were included into the study. According to up-front randomization 41 were treated with HDAC-135 without prophylactic growth factor support in the German AML Intergroup protocol, 135 with HDAC-135 and 392 with HDAC-123 with intended prophylactic pegfilgrastim at day 10 and 8, respectively, in the AMLSG 07-04 protocol. Time from start to chemotherapy until hematological recovery with leukocytes 〉 1.0G/l and neutrophils 〉 0.5G/l was significantly (p 〈 0.0001, each) and in median 4 days shorter in patients receiving HDAC-123 compared to HDAC-135, and further reduced by 2 days (p 〈 0.0001) by the addition of pegfilgrastim. Treatment with ATRA and VPA according to initial randomization had no impac on hematological recovery times. Rates of infections were significantly reduced by HDAC-123 compared to HDAC-135 (p 〈 0.0001) and pegfilgrastim yes versus no (p=0.002). Days in hospital and platelet transfusions were also significantly reduced in patients receiving HDAC-123 compared to HDAC-135. Relapse-free and overall survival were similar with HDAC-123 and HDAC-135 (p=0.48, p=0.90, respectively). Conclusion: Data from our study suggest that consolidation therapy with a condensed schedule of HDAC-123 is superior to that of standard HDAC-135 in terms of faster hematological recovery, lower infection rate and fever days in hospital. In addition, the administration of one dose of pegfilgrastim after chemotherapy further shortened hematological recovery and reduced infection rate. Importantly, similar efficacy in terms of relapse-free and overall survival rates after HDAC-123 and HDAC-135 were observed. Disclosures Lübbert: Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding. Fiedler:GSO: Other: Travel; Pfizer: Research Funding; Teva: Other: Travel; Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding.

Abstract: Trisomy 8 (+8) occurs in about 8–13% of patients with acute myeloid leukemia (AML). However, so far the prognostic impact of this recurrent aberration is unclear. Additional prognostic factors and different consolidation therapies may influence prognosis in this disease entity. Therefore, the German AML Intergroup analyzed 198 adult patients (median age 49 (17–60) years; 172 de novo and 26 secondary AML) with trisomy 8 treated between 1993 and 2002 in eight prospective German AML treatment trials. Patients with t(8;21), inv(16) or abn11q23 and an additional +8 were not included in the study. Clinical, diagnostic and laboratory data were reviewed for consistency and completeness before analysis by a central coordination center. Ninety-two (46%) patients had +8 as a sole aberration, 39 (20%) had one additional secondary aberration and 67 (34%) had +8 within complex karyotypes with at least three independent abnormalities. Trisomy 8 was frequently accompanied by other trisomies (53/198), especially by +21 (16/198) or +22 (13/198). Complete remission rate after two induction therapies was 62% for all patients. An additional +21 (odds ratio 0.17; 95% CI 0.05–0.57) and a secondary AML (odds ratio 0.38; 95% CI 0.16–0.90) were negative prognostic factors for treatment response. Only 25% of patients with an additional +21 reached CR criteria. Disease free survival (DFS) was 18% and overall survival (OS) 19% after 5 years for all patients, respectively. Patients with +8 as a sole aberration had a 5-year OS of 20%, with one additional secondary aberration of 32% and with a complex karyotype of only 8% (p=0.005). All but one patient with an additional +21 died within the first two years (p & lt;0.001). Multivariate analysis revealed age (difference 10 years hazard ratio (HR) 1.30; p & lt;0.001), an additional +21 (HR 2.32; p=0.004), a complex karyotype (HR 1.58; p=0.02) and logarithm of white blood cell count (WBC) (HR 1.41; p=0.01) as prognostic factors for overall survival and age (difference of 10 years HR 1.22; p=0.01) and a complex karyotype (HR 1.63; p=0.04) for disease free survival in all patients. Post remission therapy (i.e. high-dose Ara-C vs. autologous transplantation vs. conventional allogeneic transplantation) did not enter in the multivariate models. Looking on the group of patients with +8 as sole aberration only extramedullary disease (HR 2.05; p=0.02) influenced survival. In conclusion, the data of this large cohort of patients indicate that AML with trisomy 8 is a heterogeneous entity. Neither allogeneic nor autologous transplantation proved superiority compared to high-dose cytarabine based consolidation therapy. For the majority of patients alternative therapeutic approaches are needed to achieve durable remissions in the future.

Abstract: The MLL gene on chromosome 11q23 is translocated to a variety of fusion partners in about 5–10% of adults with acute myeloid leukemia (AML). The heterogeneity of these genetic aberrations hampers risk stratification of the patients. To identify prognostic parameters in AML patients up to 60 years with 11q23 aberrations, a pooled data analysis of 8 trials for the treatment of adults with AML was performed. All patients (pts) received double induction with araC and an anthracycline followed by intensive consolidation with either a high dose araC based chemotherapy or an autologous or allogeneic stem cell transplantation (alloSCT). 180 pts with 11q23 translocations were identified by cytogenetics and/or molecular techniques. 76 pts (42%) had a t(9;11), 35 (19%) a t(6;11), 17 (9%) a t(11;19), 14 (8%) a t(10;11) and 10 (6%) a t(11;17). 28 pts (16%) had other translocation partners. 77 pts (43%) had secondary chromosomal aberrations. Median age was 39 years (range 16–60). Median platelet and PB blast count was 45G/l and 7.5G/l. Median follow up is 53 months. Complete remission rate was 71%. Logistic regression identified t(9;11) (OR 2.6; 95% CI 1.2–5.9), secondary chromosomal aberrations (OR 0.4; 95% CI 0.2–0.8) and secondary leukemia (OR 0.3; 95% CI 0.1–0.6) as significant factors for induction success. Four year overall survival (OS) was 29% (95% CI 25–33%). Multivariate analysis identified presence of a t(9;11) (HR 0.6; 95% CI 0.4–0.9), platelets above the median (HR 0.6; 95% CI 0.4–0.9), secondary leukemia (HR 1.9; 95% CI 1.2–2.9) and PB blasts above the median (HR 1.9 95% CI 1.3–2.8) as significant factors for OS. Combination of these factors separated three risk groups for OS (p=0.0001): Good, pts with de novo AML, t(9;11) and PB blasts below median (4y OS 61%); intermediate, remaining pts with platelets above median (4y OS 32%); poor, remaining pts with platelets below median (4y OS 15%). Four year relapse-free survival (RFS) was 29% (95% CI 24–34%). Cox regression analysis identified the presence of a t(6;11) (HR 1.8; 95% CI 1.1–3.0) and PB blasts above the median (HR 1.7; 95% CI 1.0–2.6) as independent risk factors for RFS. By combination of these factors, three risk groups for RFS were defined: Good, pts without t(6;11) with PB blasts below median (4y RFS 63%); intermediate, pts without t(6;11) with PB blasts above median (4y RFS 23%); poor, pts with t(6;11) (4y RFS 9%). The effect of different consolidation strategies was analyzed “as treated” in CR-pts who had received at least one cycle of consolidation. In these pts, RFS was improved by an alloSCT (MRD or MUD) in first CR (p=0.04). However, this effect was restricted to the RFS-intermediate risk group (p=0.029), whereas pts in the good or poor risk group did not benefit from an alloSCT in first CR. In conclusion, the prognosis of patients with translocations of chromosome 11q23 is heterogenous. Risk stratification of these patients is feasible based on the MLL-fusion partner and clinical parameters. This prognostic model can be used as a basis for the selection of consolidation therapy.

Abstract: To identify risk factors for induction success and overall survival (OS) and relapse-free survival (RFS) and to evaluate the impact of allogeneic stem-cell transplantation (alloSCT) in adult patients up to 60 years old with acute myeloid leukemia (AML) and reciprocal translocations involving chromosome band 11q23 [t(11q23)]. Patients and Methods An individual patient data-based meta-analysis was performed on 180 adult patients with AML and t(11q23). These patients were identified by cytogenetics and/or molecular techniques and treated within eight prospective multicenter trials of the German AML Intergroup. The median follow-up time was 53 months. Results Complete remission rate was 71%. Favorable factors for induction success were the presence of a t(9;11), t(11q23) as a sole aberration, and de novo leukemia. OS rate at 4 years was 29%. Translocations other than t(9;11), platelets less than the median, secondary leukemia, and peripheral blasts greater than the median were adverse risk factors for OS. RFS rate at 4 years was 29%. The presence of a t(6;11) and peripheral blasts greater than the median had a negative impact on RFS. Three risk groups for OS and RFS could be defined by the combination of these factors with 4-year OS rates of 50%, 28%, and 5% and 4-year RFS rates of 37%, 26%, and 5%. An alloSCT from matched related or unrelated donors in first complete remission was beneficial, especially in t(6;11)-negative patients. Conclusion Risk stratification of AML patients with reciprocal translocations of chromosome band 11q23 is feasible based on the translocation partner and clinical parameters.

Abstract: Aberrations of the MLL gene on chromosome 11q23 occur in about 5–10% of adult patients with acute myeloid leukemia (AML). Most commonly, fusion of the MLL gene to the genes AF9 on chromosome 9 or AF6 on chromosome 6 are found resulting in the translocation t(9;11) and t(6;11), respectively. The remaining patients with aberrations of chromosome 11q23 constitute a heterogeneous group with numerous fusion partners. This genetic heterogeneity hampers risk stratification of these patients. Accordingly, AML patients with 11q23 aberrations have varyingly been stratified as intermediate or high risk patients by different study groups. To analyze the impact of different 11q23 aberrations on the prognosis of AML patients up to 60 years, a pooled data analysis of 5 consecutive studies for the treatment of adult AML patients was performed. All patients received double induction treatment with araC and an anthracycline followed by an intensive consolidation with either a high dose araC based chemotherapy regimen or an autologous or allogeneic stem cell transplantation. In total, 137 patients with 11q23 aberrations were identified by cytogenetics and/or molecular techniques. 51 patients (37%) had a t(9;11), 19 patients (14%) a t(6;11), 8 patients (6%) a t(11;19), 6 patients (4%) a t(11;17) and 5 patients (4%) a t(10;11). 48 patients (35%) hold other fusion partners or deletions of 11q23. For further evaluation, patients harbouring other 11q23 aberrations than t(9;11) and t(6;11) were grouped together. Median age of all patients was 39 years (range 16–60). Overall complete remission rate was 75% with no significant difference between the groups (82% for t(9;11), 74% for t(6;11) and 70% for others). Altogether, 9% of the patients had treatment failure and 8% died during induction. Relapse-free survival (RFS) and overall survival (OS) at 5 years for the entire group was 34% and 28%, respectively. RFS and OS of the t(6;11) group was 0% and 11% respectively and thus was significantly inferior to patients with t(9;11) (RFS: 48%, OS: 33%) and patients with other 11q23 aberrations (RFS: 32%, OS: 28%). Within the t(9;11) group there was no difference in RFS or OS between patients who had a t(9;11) as a sole aberration (n=35) and patients with additional aberrations (n=16). Moreover, in t(9;11) no difference in RFS was observed between treatment with high dose araC, autologous or allogeneic stem cell transplantation as late consolidation. In conclusion, these data demonstrate that prognosis of patients with 11q23 is heterogeneous. Patients with t(9;11) have a relatively good outcome independent of the consolidation therapy used. In contrast, the prognosis of patients with t(6;11) is extremely poor. Therefore, patients with t(6;11) should be regarded as high risk and alternative treatment strategies for this subgroup are required.

Abstract: The addition of valproic acid to intensive induction therapy in combination with all-trans retinoic acid did not result in an improvement of clinical outcome. Valproic acid-related hematologic toxicity and higher death rates were observed when valproic acid and idarubicin were given in parallel.