Abstract: The presence of a mutated nucleophosmin-1 gene (NPM1 mut ) in acute myeloid leukemia (AML) is associated with a favorable prognosis. To assess the predictive value with regard to allogeneic stem-cell transplantation (SCT), we compared the clinical course of patients with NPM1 mut AML eligible for allogeneic SCT in a donor versus no-donor analysis. Patients and Methods Of 1,179 patients with AML (age 18 to 60 years) treated in the Study Alliance Leukemia AML 2003 trial, we identified all NPM1 mut patients with an intermediate-risk karyotype. According to the trial protocol, patients were intended to receive an allogeneic SCT if an HLA-identical sibling donor was available. Patients with no available donor received consolidation or autologous SCT. We compared relapse-free survival (RFS) and overall survival (OS) depending on the availability of a suitable donor. Results Of 304 eligible patients, 77 patients had a sibling donor and 227 had no available matched family donor. The 3-year RFS rates in the donor and no-donor groups were 71% and 47%, respectively (P = .005); OS rates were 70% and 60%, respectively (P = .114). In patients with normal karyotype and no FLT3 internal tandem duplication (n = 148), the 3-year RFS rates in the donor and no-donor groups were 83% and 53%, respectively (P = .004); and the 3-year OS rates were 81% and 75%, respectively (P = .300). Conclusion Allogeneic SCT led to a significantly prolonged RFS in patients with NPM1 mut AML. The absence of a statistically significant difference in OS is most likely a result of the fact that NPM1 mut patients who experienced relapse responded well to salvage treatment. Allogeneic SCT in first remission has potent antileukemic efficacy and is a valuable treatment option in patients with NPM1 mut AML with a sibling donor.

Abstract: Evaluate the impact of BAALC (brain and acute leukemia, cytoplasmic), a gene whose expression has been associated with adverse outcome in acute myeloid leukemia (AML) with normal cytogenetics, and FLT3 internal tandem duplication (ITD) mutations as independent prognostic factors in a larger study. Patients and Methods BAALC expression was determined by real-time reverse transcriptase polymerase chain reaction in pretreatment blood samples of 307 adults ≤ 60 years of age with AML with normal cytogenetics. Patients were dichotomized at BAALC's median expression into low and high expressers. The FLT3 ITD mutant:wild-type ratio was determined by fragment analysis. Results Compared with low-BAALC patients, high-BAALC patients had a higher rate of primary resistant leukemia (16% v 6%; P = .006). High BAALC expression was associated with a higher cumulative incidence of relapse (CIR; P = .018) and an inferior overall survival (OS; 3-year OS, 36% v 54%; P = .001). On multivariable analysis, high BAALC was independently predictive of resistant disease (P = .019), and high BAALC as well as a high FLT3 mutant:wild-type ratio were confirmed as the only factors predicting a high CIR (BAALC, P = .03; FLT3, P = .01) and inferior OS (BAALC, P = .001; FLT3, P = .012). Conclusion This study strengthens BAALC expression as one of the most important prognostic factors in AML patients with normal cytogenetics. BAALC expression and FLT3 mutation status should assist in tailoring induction and postremission therapies.

Abstract: Background: Trisomy 4 is a recurrent but rare cytogenetic abnormality reported in patients with acute myeloid leukemia (AML). The prognostic significance of this abnormality in AML patients is not clear. Prognosis of AML patients with trisomy 4 seems to be poor as compared to that of patients with intermediate-risk cytogenetics. Allogeneic hematopoietic stem cell transplantation (allo-HCT) may improve survival if applied early in first complete remission (CR). However, neither prospective clinical nor larger retrospective cohort studies are available to support these results from small series. Aims: To characterize AML patients with trisomy 4 and compare outcomes according to different treatment strategies. Methods: We retrospectively studied 123 AML patients with trisomy 4 (median age at diagnosis, 58 years; range, 16-76 years) treated between 2000 and 2019 within 2 large study groups. Standard statistical methods were applied. Results: Median white blood cell count at diagnosis was 4.8/nl (range, 0.4-255/nl) and platelets 46/nl (range, 2-330/nl). Type of AML was de novo in 97 (79%), secondary after myelodysplastic syndrome/myeloproliferative neoplasm in 18 (15%), and therapy-related in 8 (6%) patients. Sixty-two (50%) patients were female. Cytogenetic analysis revealed trisomy 4 as the sole abnormality in 28 (23%), additional abnormalities in 95 (77%) patients, most frequently ≥3 (n=66) abnormalities, trisomy 8 (n=41), karyotypes characterized by trisomies only (n=21) and t(8;21) or inv(16) (CBF; n=10). A total of 98 patients (80%) had NPM1 and FLT3-ITD mutation testing. Of those, 21 (21%) and 15 (15%) harbored NPM1 and FLT3-ITD mutations. Only 2 (3%) of 72 patients were CEBPA double mutated. Data on response to intensive anthracycline-based induction therapy were available in 117 patients. Early death rate was 5% (n=6). CR was achieved in 68% (n=79) with 22 (19%) requiring an intensive salvage treatment cycle. Notably, patients with trisomy 4 as sole abnormality had a CR rate of 89% (n=25/28). There was no difference in the CR rate in FLT3-ITD positive (n=10/15) as compared to FLT3 wild type (n=56/83) patients (67% each, P=0.99). Univariable analysis revealed trisomy 4 as sole abnormality (OR, 5.76; P=0.007) and NPM1 (OR, 12.08; P=0.02) as favorable factors. An allo-HCT was performed in 40 (34%) patients, of whom 19 patients were transplanted in first CR after induction therapy. Nine patients achieved CR after salvage chemotherapy and went on to allo-HCT; another 12 patients received allo-HCT with active disease. Type of donor was matched-related in 8, matched-unrelated in 30, and unknown in 2 of the 40 patients, respectively. Median follow-up of the intensively treated cohort was 73 months (95%-CI, 36-91 months). Five-year overall survival (OS) and relapse-free survival (RFS) were 31% (95%-CI, 23-42%) and 27% (95%-CI, 18-42%). OS rates were significantly higher in patients with CBF leukemia or patients with trisomy 4 as compared to all other abnormalities (Figure 1; P & lt;0.001). Cox regression analysis on OS revealed CBF/CEBPA (HR, 0.75; P=0.02) and trisomy 4 as sole abnormality (HR, 0.63; P=0.04) as favorable factors; age with a difference of ten years was an in trend adverse factor (HR, 1.15; P=0.06; not significant: NPM1, FLT3-ITD, complex karyotype with ≥3 abnormalities). There was no difference on OS if patients proceeded to allo-HCT in CR1 or with active disease (P=0.8). Five-year RFS was 26% (95%-CI, 14-50%) in patients proceeding to allo-HCT after induction therapy (n=40), as compared to 28% (95%-CI, 17-46%; P=0.99) in those who received consolidation chemotherapy (n=49). Conclusions: Clinically, patients with trisomy 4 are very heterogeneous in particular with respect to cytogenetic and molecular abnormalities. In our cohort, patients with trisomy 4 as a sole abnormality had a high CR rate and favorable clinical outcome. In the total cohort, allo-HCT did not improve RFS. Figure 1 Figure 1. Disclosures Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Haenel: Takeda: Consultancy, Honoraria; Bayer Vital: Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Fransecky: Medac: Honoraria; Amgen: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria. Martinez-Lopez: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Platzbecker: AbbVie: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Takeda: Honoraria. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Müller-Tidow: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding. Levis: Astellas and FujiFilm: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Takeda: Honoraria. Montesinos: Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Röllig: Roche: Honoraria, Research Funding; Bristol-Meyer-Squibb: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria; AbbVie: Honoraria, Research Funding. Schlenk: Novartis: Honoraria; Pfizer: Honoraria, Research Funding, Speakers Bureau; Hexal: Honoraria; Neovio Biotech: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Celgene: Honoraria; Astellas: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria; Agios: Honoraria; Roche: Honoraria, Research Funding; AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding.

Abstract: High mRNA expression levels of the human gene BAALC (Brain And Acute Leukemia, Cytoplasmic) have been shown to be an adverse risk factor in newly diagnosed AML patients (pts; Blood2003;102:1613). The first study included 86 de novo AML pts under the age of 60 with normal cytogenetics and a more favorable FLT3 mutation status, which were uniformly treated on the Cancer And Leukemia Group B protocol 9621. An independent confirmation of these data is necessary, to confirm the impact of BAALC expression in intermediate risk AML pts. Here we present the results of a Süddeutschen Hämoblastosegruppe (SHG) study including 309 adult pts diagnosed with de novo (n=280) and secondary AML (n=29), normal cytogenetics, age 〈 60 years that were uniformly treated on the SHG’96 protocol. Treatment consisted of 2 cycles of induction therapy followed by intensive consolidation including autologous as well as allogeneic stem cell transplantation. Median follow-up for patients alive was 28.7 months (range: 0–86 months). BAALC expression was measured in pretreatment peripheral blood blasts by comparative real-time RT-PCR. Pts having BAALC expression values within the lower 50% were classified as low BAALC and pts having BAALC expression values within the upper 50% were classified as high BAALC. Whereas no correlation was seen between BAALC expression and the prevalence of FLT3 internal tandem duplications (ITD; P=0.16), high BAALC patients had a significantly higher FLT3 mutant/wild-type (wt) ratio as determined by Genescan analysis (mean mutant/wt ratio: 0.59 vs. 0.17; P=0.012). There was no significant difference in the prevalence of MLL partial tandem duplications between the high and the low BAALC group. High BAALC expression was significantly more frequent in FAB groups M0/M1 as compared to the other subtypes (P=0.002). Pts with high BAALC expression levels had a significantly lower CR rate (62.3% vs. 73.5%; P=0.039) and a higher relapse rate (43.8% vs. 28.9%; P=0.030). The overall survival (OS) was significantly shorter for pts with high BAALC expression (OS at 4 years: 29.8% vs. 53.3%; P=0.0018), event-free survival (EFS, at 4 years: 21.6% vs. 45.8%; P=0.0001), and disease-free survival (DFS, at 4 years: 30.4% vs. 57.6%; P=0.0018). Pts with a high FLT3 mutant/wt ratio (greater than 0.8) had a significantly shorter OS and DFS. For patients with a low FLT3 mutant/wt ratio, high BAALC expression allowed identification of pts with a high risk of treatment failure. A multivariate analysis confirmed high BAALC expression and a high mutant/wt FLT3 ratio as the only independent adverse risk factors. For pts with high BAALC expression the hazard ratio of death was 1.7 (95% CI 1.18–2.48; P=0.005), and the hazard ratios for EFS and DFS were 1.8 (95% CI 1.3–2.6; P=0.0003) and 2.0 (95% CI 1.2–3.3; P=0.004), respectively. In conclusion, this independent and larger study strengthens high BAALC expression as one of the most relevant adverse prognostic risk factors in intermediate risk AML pts with normal cytogenetics. Thus, determination of BAALC expression should be considered for risk adaptive treatment strategies.

Abstract: Abstract 229 Background: The optimal timing of hematopoietic cell transplantation (HCT) in AML and its use in risk groups defined by genetic markers or early blast clearance is still under debate. We addressed this question in the AML 2003 study, a large multicenter, randomized, open-label study within the German SAL group. All patients received one cycle of induction therapy (IT) with a 3+7 regimen combining daunorubicin and continuous infusion cytarabine. Upfront cytogenetic and molecular characterization, HLA typing, related donor search and a preliminary search for an unrelated donor were performed for all patients. The subsequent transplant strategy was tailored to the biological risk and donor availability. Patients and Methods: Patients aged 18–60 years were randomly assigned upfront 1:1 to either of two transplant strategies: In the control arm allogeneic HCT was scheduled in first complete remission for patients with intermediate risk cytogenetics and an HLA-identical sibling and for patients with a complex karyotype (CK) and a related or unrelated HLA-compatible unrelated donor. In the experimental arm the indication for allogeneic HCT was extended to patients with an FLT3-ITD allelic ratio 〉 0.8 (mutant/wild type), 〉 10% marrow blasts on day 15 after IT1 and patients with adverse karyotypes, including: −7, −5, del(5q), inv(3q), t(3;3), t(6;9), t(6;11), t(11;19)(q23;p13.1). Furthermore, allogeneic HCT was scheduled at an early time-point, i.e. in aplasia after the first or the second cycle of IT in the experimental arm. Patients without an HLA-compatible donor assigned to the transplant strategy were scheduled for high-dose busulfan and cyclophosphamide followed by autologous SCT. Here, we present the final analysis of this study according to the intent-to-treat principle. Results: Between December, 1, 2003 and November, 26, 2009 1179 patients were randomized between the experimental (N=598) and the control intervention (N=581). The median age was 48 years (range, 18 to 60 years). The distribution of age, ECOG performance status, type of AML, cytogenetic risk groups, NPM1- and FLT3-ITD-mutations, LDH, white blood cell and platelet count was not statistically different between the two treatment arms. However, more males and patients with higher marrow blast counts at diagnosis were randomized to the experimental treatment arm. The median observation time for all patients was 52 months. The hazard ratio of the treatment effect (experimental versus control) was 0.92 (95% CI, 0.75 to 1.14; p=0.45) for primary endpoint overall survival and 0.85 (95% CI, 0.71 to 1.02; p=0.08) for the secondary endpoint event-free survival. Patients in both arms had an excellent long-term overall survival of 50% (95% CI, 46% to 54%) at 5 years after enrollment in the experimental arm and 47% (95% CI, 42% to 51%) in the control arm (see Figure). Across all risk groups the rate of early allogeneic HCT performed per protocol was 22% in the experimental arm and 8% in the control arm. Among patients with high risk cytogenetics this rate was 48% and 17%, respectively. These numbers point at the difficulty to deliver allogeneic HCT within two months after diagnosis of AML in the context of a multicenter trial. However, since HLA-typing and preliminary donor search was done for all patients and allogeneic HCT was standard for relapsed or refractory AML in both arms, the rates of allogeneic HCT as first post remission therapy or after induction failure/relapse were substantially higher than in previous studies and almost equal in the experimental and control arm (63% versus 56%). Conclusions: Although a survival benefit by early allogeneic HCT could not be demonstrated in this large randomized study in newly diagnosed AML, the study treatment resulted in excellent overall survival rates in both arms. Relatively small differences between the per-protocol transplantation rates and crossover effects may partially explain why a benefit of early allogeneic HCT could not be demonstrated. Early awareness of donor availability and the option of allogeneic HCT in patients with primary induction failure or AML relapse resulted in a high overall rate of allogeneic transplantation. This may have contributed to the excellent overall survival in both arms. Disclosures: No relevant conflicts of interest to declare.

Abstract: Treatment success in patients with acute myeloid leukaemia ( AML ) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP 53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation ( HSCT ). Samples of 97 patients with AML and adverse‐risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP 53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP 53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three‐year probabilities of overall survival ( OS ) and event‐free survival for patients with TP 53 wild type were 33% [95% confidence interval ( CI ), 21% to 45%] and 24% (95% CI , 13% to 35%) compared to 10% (95% CI , 0% to 19%) and 8% (95% CI , 0% to 16%) ( P  =   0·002 and P  =   0·007) for those with mutated TP 53, respectively. In multivariate analysis, the TP 53 ‐mutation status had a negative impact on OS (Hazard Ratio = 1·7; P  =   0·066). Mutational analysis of TP 53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML .

Abstract: To assess the treatment outcome benefit of multiagent consolidation in young adults with acute myeloid leukemia (AML) in a prospective, randomized, multicenter trial. Patients and Methods Between December 2003 and November 2009, 1,179 patients (median age, 48 years; range, 16 to 60 years) with untreated AML were randomly assigned at diagnosis to receive either standard high-dose cytarabine consolidation with three cycles of 18 g/m 2 (3× HD-AraC) or multiagent consolidation with two cycles of mitoxantrone (30 mg/m 2 ) plus cytarabine (12 g/m 2 ) and one cycle of amsacrine (500 mg/m 2 ) plus cytarabine (10 g/m 2 ; MAC/MAMAC/MAC). Allogeneic and autologous hematopoietic stem-cell transplantations were performed in a risk-adapted and priority-based manner. Results After double induction therapy using a 3 + 7 regimen including standard-dose cytarabine and daunorubicin, complete remission was achieved in 65% of patients. In the primary efficacy population of patients evaluable for consolidation outcomes, consolidation with either 3× HD-AraC or MAC/MAMC/MAC did not result in any significant difference in 3-year overall (69% v 64%; P = .18) or disease-free survival (46% v 48%; P = .99) according to the intention-to-treat analysis. Furthermore, MAC/MAMAC/MAC led to additional GI and hepatic toxicity and a higher rate of infection and bleeding, resulting in significantly shorter 3-year overall survival in the per-protocol analysis compared with 3× HD-AraC (63% v 72%; P = .04). Conclusion In younger adults with AML, multiagent consolidation using mitoxantrone and amsacrine in combination with high-dose cytarabine does not improve treatment outcome and confers additional toxicity.

Abstract: Increasingly large and complex biomedical data sets challenge conventional hypothesis-driven analytical approaches, however, data-driven unsupervised learning can detect inherent patterns in such data sets. Methods While unsupervised analysis in the medical literature commonly only utilizes a single clustering algorithm for a given data set, we developed a large-scale model with 605 different combinations of target dimensionalities as well as transformation and clustering algorithms and subsequent meta-clustering of individual results. With this model, we investigated a large cohort of 1383 patients from 59 centers in Germany with newly diagnosed acute myeloid leukemia for whom 212 clinical, laboratory, cytogenetic and molecular genetic parameters were available. Results Unsupervised learning identifies four distinct patient clusters, and statistical analysis shows significant differences in rate of complete remissions, event-free, relapse-free and overall survival between the four clusters. In comparison to the standard-of-care hypothesis-driven European Leukemia Net (ELN2017) risk stratification model, we find all three ELN2017 risk categories being represented in all four clusters in varying proportions indicating unappreciated complexity of AML biology in current established risk stratification models. Further, by using assigned clusters as labels we subsequently train a supervised model to validate cluster assignments on a large external multicenter cohort of 664 intensively treated AML patients. Conclusions Dynamic data-driven models are likely more suitable for risk stratification in the context of increasingly complex medical data than rigid hypothesis-driven models to allow for a more personalized treatment allocation and gain novel insights into disease biology.