allo-HSCT In CR1 Research Articles

Mutation patterns and prognostic implications in acute myeloid leukemia with chromosomal 7 deletions.

6547 Background: Chromosomal 7 deletions (del7/7q) are the most common adverse cytogenetic event in acute myeloid leukemia and are associated with high rate of relapse. We analyzed gene mutation profiles in del7/7q AML patients who relapsed after initial remission to identify molecular patterns associated with clinical outcomes. Methods: Out of 351 newly diagnosed AML patients with del7/7q, 115 (32%) achieved complete remission after first-line treatment between 2012-2023. Of the 115 patients, 77 (67%) patients relapsed during the study follow-up. Kaplan-Meier and Cox regression were used to analyze survival outcomes. Next-generation sequencing was performed on a targeted panel of 81 genes for 59 patients who relapsed on bone marrow samples at diagnosis and relapse for paired analysis. Results: The median age of the 115 patients at diagnosis was 74 (41-93). Thirty-four patients (30%) received intensive treatment. With 30.8-month median follow-up, the median overall survival (OS) was 10.4 months, with improved survival in patients without TP53 mutation (13.04 vs. 8.6 months, p=0.005) or complex karyotype (12.4 vs. 8.6 months, p=0.03). The median duration of response for the 77 patients who relapsed was 5 months (2-7). Allo-HSCT significantly improved median OS (not reached vs. 8.5 months, P=6e-06), and was identified as the key variable impacting survival in multivariate analysis. TP53 was the most commonly mutated gene at diagnosis (67%) and relapse (71%). Mutations in CBLC and KDM6A were cleared after induction therapy, while BCOR and BCORL1 were commonly acquired at relapse (Table). At diagnosis, a lower co-mutation burden was observed in TP53 mutant patients as compared with wild type (average 1.84 vs. 3.65 respectively, p=0.0001). Patients with mutated TP53 and coexisting mutations in GATA2, NF1, BCORL1, or RUNX1 at diagnosis had shorter relapse free survival (RFS, 2 vs. 5 months, p=0.01) and OS (7.2 vs. 10.4 months, p=0.01) compared to patients with solely mutated TP53 (HR 2.2; 95% CI 1.2-4; P = 0.004). Allo-HSCT significantly improved the OS in patients with mutated TP53 (13 vs. 8 months, p=0.01). Conclusions: Mutated TP53 clones persist from diagnosis to relapse in patients with del7/7q AML. In patients with mutated TP53, co-occurring mutations in GATA2, NF1, BCORL1or RUNX1 at diagnosis were linked to a shorter RFS and indicate a particularly high-risk subgroup that require proceeding to allo-HSCT in CR1 without delay. [Table: see text]

Comparison of long-term outcomes between imatinib and dasatinib prophylaxis after allogeneic stem cell transplantation in patients with Philadelphia-positive acute lymphoblastic leukemia: A multicenter retrospective study.

Although the prognosis of Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) has improved with the introduction of tyrosine kinase inhibitors (TKIs) and stem cell transplantation, prevention of relapse after transplantation remains a concern. The aim of this study was to compare the impact of TKI prophylaxis with imatinib and dasatinib on long-term outcomes after transplantation. Patients with Ph+ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) and received TKI prophylaxis after allo-HSCT were included in this retrospective analysis. Two cohorts were established based on the choice of TKI prophylaxis: the imatinib (Ima) and dasatinib (Das) cohorts. The survival and safety outcomes of these cohorts were compared. Ninety-one patients in the Ima cohort and 50 in the Das cohort were included. After a median follow-up of 50.6months, the 5-year cumulative incidence of relapse, nonrelapse mortality rate, and overall survival in the Ima and Das cohorts were 16.1% and 12.5%, 5.2% and 9.8%, and 86.5% and 77.6%, respectively, with no statistical differences. The cumulative incidence of mild chronic graft-versus-host disease was higher in the Das cohort. The most common adverse event was neutropenia (64.7% vs. 69.5%). The Das cohort had a higher incidence of gastrointestinal bleeding (25.5% vs. 2.3%) and gastrointestinal reaction (48.9% vs. 31.4%) than the Ima cohort. The proportion of patients treated on schedule was significantly lower in the Das cohort than in the Ima cohort, and drug intolerance was the main reason for protocol violation. For patients with Ph+ALL undergoing allo-HSCT in CR1, imatinib prophylaxis achieved long-term outcomes similar to those of dasatinib.

Comparison of Long-Term Outcome between Imatinib and Dasatinib Prophylaxis after Allogeneic Stem Cell Transplantation in Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia-a Multi-Center Retrospective Study

Background: Though the prognosis of Philadelphia-positive (Ph-positive) acute lymphoblastic leukemia (ALL) has been improved since the introduction of tyrosine kinase inhibitors (TKIs) and combined with allogeneic stem cell transplantation (allo-HSCT), relapse after HSCT remains a concern. Prophylactic TKIs after allo-HSCT seemed a promising strategy to prevent relapse. But the optimal choice of the agent is still obscure.Methods: We retrospectively analyzed the clinical data of Ph-positive ALL patients who underwent allo-HSCT in CR1 from 6 medical centers in China between September 2010 and October 2021. Patients were divided into two cohorts according to different choice of TKI after allo-HSCT, namely Ima cohort with imatinib prophylaxis and Das cohort with dasatinib prophylaxis. Survival and safety outcomes of two cohorts were compared, and prognostic factors were determined by univariate and multivariate analyses.Results: One hundred and forty-one patients, with median age of 37 years (range, 14-61 years), were included, of whom 91 were in Ima cohort and 50 were in Das cohort. After median follow-up of 50.6 months, 5-year cumulative relapse rate (CIR), non-relapse mortality rate (NMR), leukemia-free time (LFS) and overall survival (OS) in Ima and Das cohort were 16.1% and 12.5%; 5.2% and 9.8%; 78.8% and 77.6%; 86.5% and 77.6%, respectively, with no significant difference. Mild cGVHD was higher in Das cohort compared to Ima cohort, while the total, moderate or severe cGVHD were similar. The most common adverse event was neutropenia (66.4%). Das cohort owned higher incidence of gastrointestinal bleeding and gastrointestinal reaction than Ima cohort. The proportion of patients treated on schedule was 30% in Das cohort, lower than that of in Ima cohort (p<0.001). Drug intolerance was the main reason for not completed treatment as intended.Conclusions: For patients with Ph-positive ALL receiving allo-HSCT in CR1, imatinib prophylaxis after transplantation could obtain the same long-term outcome compared to dasatinib, showing better tolerance.

Machine Learning Provides Individualized Prediction of Outcomes after First Complete Remission in Adult AML Patients - Results from the Harmony Platform

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with high disease-related mortality and allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for a large proportion of patients. However, allo-HSCT has a significant transplant-related mortality (TRM), so a careful evaluation between risk of disease relapse and TRM is needed for the challenging decision of whom to transplant in first complete remission (CR1). The European LeukemiaNet (ELN) provides a 3-tier static risk classification which is already a useful guidance, although dynamic risk assessment using measurable residual disease (MRD) information should also be taken into account. However, the intermediate-risk group is characterized by a wide heterogeneity and there are also some favorable-risk patients who require allo-HSCT because of early relapses after CR1. Therefore, more precise prediction tools are warranted to provide additional information valuable for clinical decision-making. Aims: To develop and validate a model that provides individualized outcome estimations in adult AML patients achieving CR1 with intensive treatment approaches. Methods: From the HARMONY Platform including 7467 AML patients at the time of the analysis, we selected patients aged 18-70 years old who received intensive treatment, achieved CR and were not consolidated with allo-HSCT in CR1. Patients who were refractory to first line chemotherapy or who had a relapse-free survival (RFS) of less than two months after achieving CR were excluded. A Bayesian Additive Regression Trees (BART) nonparametric machine learning model was used to predict the individualized likelihood of RFS, cumulative incidence of relapse (CIR) and overall survival (OS) in 1863 AML patients who were also selected based on the availability of comprehensive mutational information by next-generation sequencing analysis. Genomic aberrations that were present in at least 10 patients were included in the model. In order to test the accuracy of the model, a 10-fold cross-validation was applied using the area under receiver operating curve (AUC) at predefined time points (1, 2, 3, 4 and 5 years). Subsequently, the model was validated using an external publicly available database (Tazi et al, Nat. Commun. 2022) which included 722 patients based on identical inclusion criteria. Results: The study population of 1863 adult AML patients in CR1 included 51.2% of males and median age was 50 years. Regarding ELN2022 classification, 52% of patients were classified as favorable, 30% as intermediate and 18% as adverse risk. Most frequently mutated genes were NPM1 (35.9%), DNMT3A (25.6%) and NRAS (21.6%). The HARMONY model was able to estimate individualized likelihood of RFS, CIR and OS for all patients, providing confidence intervals for all estimations. Moreover, we could predict outcomes with increased accuracy over ELN2022 at all predefined time points. At 5 years, the AUC value was significantly better for the HARMONY model than ELN2022 in predicting RFS (0.729 vs 0.679, p=0.003), CIR (0.729 vs 0.680, p=0.002) and OS (0.733 vs 0.675, p<0.001) ( figure 1A). Validation in an external independent AML cohort confirmed superiority of the HARMONY model in predicting RFS (5-year AUC 0.714 vs 0.609, p <0.001), CIR (0.713 vs 0.610, p <0.001) and OS (0.737 vs 0.638, p <0.001) as compared to the ELN2022 risk stratification ( figure 1B), despite the fact that there was a different distribution of risk categories (28% favorable, 45% intermediate and 27% adverse risk). Conclusions: Analysis of large well-defined AML cohorts allows the development of increasingly precise predictive models for clinically relevant scenarios. The HARMONY machine learning model provides individualized outcome prediction for patients aged 18-70 years in CR1 consolidated without allo-HSCT and might be used in the future for clinical decision-making. The model can be accessed online via an interactive web calculator () and, while it has been validated using a large independent AML cohort, future studies are required focusing on prospective validation. Furthermore, the incorporation of additional variables such as MRD and the inclusion of patients treated with targeted therapies and non-intensive approaches will provide more accurate risk predictions.

Muticenter Retrospective Comparable Study of Prophylactic Versus Preemptive Modified Donor Lymphocyte Infusion for Patients with High-Risk Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Objective: To compare the efficacy and safety of prophylactic modified DLI (pro-DLI) and preemptive modified DLI (pre-DLI) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with high-risk acute leukemia Method: Patients with high-risk acute leukemia who received myeloablative conditioning and allo-HSCT during August 1, 2014 to August 30, 2020 were eligible for this study. Pro-DLI was scheduled at three months after HSCT for patients in pro-DLI cohort. In the pre-DLI cohort, patients would stop immunosuppressive drugs and receive pre-DLI immediately after MRD turning positive with morphology remission. Result: Pro-DLI was performed in ninty-five patients while two hundred and six patients were included in the pre-DLI cohort. Thirty-eight patients in the pre-DLI cohort became positive MRD and received pre-DLI. Patients in the pro-DLI cohort achieved a lower cumulative incidence of relapse (CIR) (27.6% versus 37.1%, p=0.027) and comparable overall survival (OS) (65.2% versus 59.3%, p=0.303) comparing with patients in the pre-DLI cohort. The 100-days cumulative incidence of grade III-IV acute graft-versus-host-disease (aGVHD) and chronic graft-versus-host-disease (cGVHD) were comparable between cohorts. Further subgroup analysis of patients who received allo-HSCT at CR1, pro-DLI achieved lower 3-year cumulative incidence of relapse (CIR) (27.6% versus 37.1%, p=0.027) while no benefit in OS (72.2% versus 69.2%, p=0.864) comparing with pre-DLI cohort. On the other hand, pro-DLI significantly decreased the CIR (13.25% versus 28.77%, p=0.044) and increased OS (60.7% versus 42.3%, p=0.022) when compared with pre-DLI in patients who received HSCT beyond CR1. Multivariate analysis demonstrated the strong protective effect of pro-DLI on long-term OS and PFS in patients who received HSCT beyond CR1. Conclusion: From these date, pro-DLI was highly recommended for patients with high-risk features who received allo-HSCT beyond CR1 with significantly decreased incidence of relapse and increased survival rates. Pre-DLI could be chosen by those who received allo-HSCT in CR1 in view of comparable survival rates regardless of higher relapse rates compared with pro-DLI.

Allogeneic hematopoietic stem cell transplantation for pediatric acute myeloid leukemia in first complete remission: a meta-analysis

Identification of pediatric patients with acute myeloid leukemia (AML) candidates to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) is still a matter of debate. Currently, transplantation is reserved to patients considered at high risk of relapse based on cytogenetics, molecular biology, and minimal residual disease (MRD) assessment. However, no randomized clinical trial exists in the literature comparing transplantation with other types of consolidation therapy. Here, we provide an up-to-date meta-analysis of studies comparing allo-HSCT in CR1 with chemotherapy alone as a post-remission treatment in high-risk pediatric AML. The literature search strategy identified 10 cohorts from 9 studies performing as-treated analysis. The quantitative synthesis showed improved overall survival (OS) (relative risk, 1.15; 95% confidence interval [CI], 1.06–1.24; P = 0.0006) and disease-free survival (relative risk, 1.31; 95% CI, 1.17–1.47; P = 0.0001) in the allo-HSCT group, with increased relapse rate in the chemotherapy group (relative risk, 1.26; 95% CI, 1.07–1.49; P = 0.006). Sensitivity analysis including prospective studies alone and excluding studies that reported the comparison only on intermediate-risk patients confirmed the benefit of allo-HSCT on OS. Further research should focus on individualizing allo-HSCT indications based on molecular stratification and MRD monitoring.

Combination of KIT and FLT3-ITD mutation status with minimal residual disease levels guides treatment strategy for adult patients with inv(16) acute myeloid leukemia in first complete remission.

Although several studies have investigated the benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with inv (16) acute myeloid leukemia (AML) in first complete remission (CR1) individually stratified by KIT or FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation status or minimal residual disease (MRD) levels, evaluation based on the combination of mutation status and MRD levels remains absent. This study included 157 adult patients with inv (16) AML who were consecutively diagnosed and receiving treatment at our center. A total of 50 (31.6%) patients had KIT mutations (KITMU ), and the risk of relapse was significantly higher in patients with KITMU than in patients with KITWT (p<0.001). A total of 12 patients (7.6%) had FLT3-ITD, and FLT3-ITD+ tended to be related to a higher risk of relapse (p=0.14). KITMU , FLT3-ITD and MRD3-H (beta subunit of core binding factor-myosin heavy chain 11 levels >0.2% after course 2 of consolidation therapy) were independent adverse prognostic factors for relapse with patients who received allo-HSCT at CR1 were censored at the time of transplantation. After combination, patients were categorized into molecularly defined high-risk (M-HR; KITMU or FLT3-ITD+ with MRD3-H; n=30), low-risk (M-LR; KITWT and FLT3-ITD- with MRD3-L; n=45) and intermediate-risk (M-IR; others; n=70) groups. For the M-HR group, allo-HSCT significantly improved both cumulative incidence of relapse cumulative incidence of relapse (CIR) and overall survival (OS) (11.1% vs. 92.6%, p<0.001; 90.0% vs. 34.1%, p=0.019). For the M-IR group, allo-HSCT significantly improved CIR but did not affect OS (14.1% vs. 62.2%, p=0.0004; 73.3% vs. 68.3%, p=0.43). For the M-LR group, allo-HSCT had no significant effect on both CIR and OS (0% vs. 35.1%, p=0.31; 100% vs. 78.8%, p=0.22). Therefore, the combination of KIT and FLT3-ITD mutation status with MRD levels may identify inv (16) AML patients with high-risk who can benefit from allo-HSCT in CR1.

Pretransplant Consolidation Therapies Improve the Outcome of Myeloablative Allogeneic Transplantation in Adults with Ph-negative Acute Lymphoblastic Leukemia

The benefit of pre-transplant consolidation in patients with acute lymphoblastic leukemia (ALL) who achieved first complete remission (CR1) has not yet been clearly demonstrated. Here, we aimed to investigate the relationship between the treatments received before transplantation and transplant outcome in Ph-ALL patients who underwent myeloablative allo-HSCT in CR1. A total of 55, 32 (58.2%) men and 23 (41.8%) women, who underwent allo-HSCT with the diagnosis of Ph-ALL were evaluated retrospectively. All patients underwent to allo-HSCT with myeloablative conditioning regimen in the 1st CR from the available donor. In patients who received >2 consolidation, the 2-year and 3-year OS was 69% and 65%, respectively, while the 2-year and 3-year OS was 39% and 26%, respectively, in those who received < 2 consolidation (P =.03). RFS was similar in both groups (P=.8). One year- NRM was found 28% in patients who received ≥ 2 consolidations, and 37% in patients who received <2 consolidation (P =.06). L-asparaginase, high dose methotrexate, and cranial treatments given before transplantation had no effect on transplant outcomes (P > .05). Contrary to the belief that pre-transplant consolidation is not beneficial in ALL patients who proceed with allo-HCST in CR1, our results showed that consolidation treatments reduce NRM and improve the survival.

Impact of Allogeneic Hematopoietic Stem Cell Transplantation in First Complete Remission and Additional Cytogenetic Aberrations at Diagnosis on Prognosis in 1256 Pediatric Patients with KMT2A-Rearranged Acute Myeloid Leukemia: A Retrospective Study By the I-BFM-SG

IntroductionKMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) is a heterogeneous genetic subgroup with a frequency of about 25% in children with AML. At the 62 nd ASH annual meeting last year, we reported on the differences in outcome of various KMT2A subgroups based on translocation partner and the significance of minimal residual disease (MRD) status during and after induction as a follow-up study of Balgobind et al., Blood 2009. The impact of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) and the presence of additional cytogenetic aberrations (ACAs) on prognosis have not yet been described for our cohort.MethodsData on allo-HSCT in CR1 and the presence of ACAs of 1256 KMT2A-r de novo pediatric AML patients from 15 AML study groups affiliated with the I-BFM Study Group, diagnosed between 2005 and 2016, were retrospectively collected and studied. Karyotypes were reviewed and classified by two of the authors (RW&CH). Based on translocation partners, patients were classified to the KMT2A high-risk subgroup (6q27, 10p11.2, 10p12, 4q21, and 19p13.3) or non-high-risk subgroup (9p22, 19p13, 19p13.1, 1q21, Xq24, 17q21, 1p32, and 17q12). These two categories have been used to estimate a Cox model. Patients with unknown translocation partners were excluded from these analyses (n=126). Flow cytometry MRD levels at the end of induction course 1 (EOI1) and 2 (EOI2) <0.1% were considered negative, and levels ≥0.1% positive. Kaplan-Meier's methodology was used to estimate disease-free survival (DFS) and overall survival (OS). DFS was calculated from EOI1 for patients in CR to date of relapse or death/last follow-up. OS was calculated from the time of diagnosis to date of death/last follow-up. Two-sided P-values of ≤ .01 were considered statistically significant. Covariates with P-values ≤ .05 in univariate analyses were included in multivariate analyses; allo-HSCT in CR1 was included as a time-dependent covariate in the Cox model. MRD status at EOI2 was excluded from multivariate analyses as therapy could have been adjusted to the MRD status and the number of MRD positive patients was small.ResultsOf 1256 pediatric patients with KMT2A-r AML, data on HSCT in CR1 and ACAs were available for 1186 (94.4%) and 1204 patients (95.9%), respectively; 211 (17.8%) patients received HSCT in CR1 and ACAs were present in 601 (49.9%) patients. Compared with the KMT2A non-high-risk subgroup, patients in the KMT2A high-risk subgroup underwent HSCT in CR1 more often (23.8% vs 15.0%; P < .001). ACAs were borderline significantly more common in the KMT2A high-risk subgroup (54.1% vs 46.4%; P = .015).Univariate analysis of the probability of DFS (Table 1) showed that the KMT2A high-risk subgroup (HR 2.1; 95% CI, 1.7-2.5), age ≥10 years (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 1.5; 95% CI, 1.1-1.9) were associated with DFS. HSCT in CR1 was a borderline significant prognostic factor (HR 0.7; 95% CI, 0.6-0.9).In a multivariate analysis for DFS (n=515) (Table 1), the KMT2A high-risk subgroup (HR 2.0; 95% CI, 1.6-2.6), MRD ≥0.1 at EOI1 (HR 1.7; 95% CI, 1.2-2.3), and HSCT in CR1 (HR 0.6; 95% CI, 0.4-0.9) were associated with DFS.Univariate analysis of the probability of OS (Table 1) showed that the KMT2A high-risk subgroup (HR 1.8; 95% CI, 1.5-2.2), age ≥10 years (HR 1.6; 95% CI 1.3-2.0), WBC ≥100 x10 9/L (HR 1.4; 95% CI, 1.1-1.7), the presence of ACAs (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 2.1; 95% CI, 1.6-2.7) were associated with OS. HSCT in CR1 was not associated with OS. The effect of HSCT in CR1 was not significantly different between the KMT2A high-risk and non-high-risk subgroups.In a multivariate analysis for OS (n=557) (Table 1), the KMT2A high-risk subgroup (HR 1.9; 95% CI, 1.4-2.5), age ≥10 years (HR 1.5; 95% CI, 1.1-1.9), the presence of ACAs (HR 1.6; 95% CI, 1.2-2.1), and MRD positivity at EOI1 (HR 1.9; 95% CI, 1.4-2.5) were associated with OS.ConclusionsIn this cohort of KMT2A-r pediatric AML patients, the presence of ACAs at diagnosis was independently associated with inferior OS, but not with DFS. This may be due to the exclusion of refractory patients in DFS analysis, who were significantly more common in the group of patients with ACAs. Analysis has yet to be performed to distinguish karyotype complexity. In addition, allo-HSCT in CR1 was an independent predictor of improved DFS, but was not a prognostic factor for OS. [Display omitted] DisclosuresAbrahamsson: wedish Children´s Cancer Foundation. Research grants and 50% senior research position for clinical research on pediatric leukemia: Research Funding. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau.

Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission.

The mutant burden of FLT3-ITD modulates its prognostic impact on patients with acute myeloid leukemia (AML). However, for patients with low allelic ratio(AR) FLT3-ITD (FLT3-ITDlow, AR < 0.5), clinical features, as well as genomic and transcriptomic profiles remain unclear, and evidence supporting allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) remains controversial. This study aimed to elucidate the genomic features, prognosis, and transplantation outcome of FLT3-ITDIow in AML patients with intermediate-risk cytogenetics. FLT3-ITDlow was associated with a negative enrichment of the leukemic stem cell signature, a marked enrichment of the RAS pathway, and with higher frequencies of RAS pathway mutations, different from those with FLT3-ITDhigh. Concurrent CEBPA double mutations were favorable prognostic factors, whereas MLL-PTD, and mutations in splicing factors were unfavorable prognostic factors in FLT3-ITDlow patients. Patients with FLT3-ITDlow hada shorter overall survival (OS) and event-free survival (EFS) than those with FLT3wt. Allo-HSCT in CR1 was associated with a significantly longer OS and EFS compared with postremission chemotherapy in patients with FLT3-ITDlow. In conclusion, FLT3-ITDlow is associated with different mutational and transcriptomic profiles compared with FLT3-ITDhigh. The presence of concomitant poor-risk mutations exert negative prognostic impacts in patients with FLT3-ITDlow, who markedly benefit from allo-HSCT in CR1.

In-depth time-dependent analysis of the benefit of allo-HSCT for elderly patients with CR1 AML: a FILO study

AbstractThe benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with acute myeloid leukemia (AML) aged >60 years remains a matter of debate, notably when performed in first complete remission (CR1). To clarify this issue, the French Innovative Leukemia Organization (FILO) performed a 10-year real-world time-dependent analysis. The study enrolled patients between 60 and 70 years of age with AML in CR1 after intensive chemotherapy with intermediate (IR) or unfavorable (UR) risk according to the European LeukemiaNet (ELN) 2010 classification. The impact of allo-HSCT was analyzed through three models: (1) time-dependent Cox; (2) multistate for dynamic prediction; and (3) super landmark. The study enrolled 369 (73%) IR and 138 (27%) UR patients with AML, 203 of whom received an allo-HSCT. Classical multivariate analysis showed that allo-HSCT significantly improved relapse-free survival (RFS; hazard ratio [HR] [95% confidence interval (CI)], 0.47 [0.35-0.62]; P < .001) and overall survival (OS; HR [95% CI], 0.56 [0.42-0.76]; P < .001), independently of the ELN risk group. With the multistate model, the predicted 5-year probability for IR and UR patients to remain in CR1 without allo-HSCT was 8% and 1%, respectively. Dynamic predictions confirmed that patients without allo-HSCT continue to relapse over time. Finally, the super landmark model showed that allo-HSCT significantly improved RFS (HR [95% CI], 0.47 [0.36-0.62]; P < .001) and OS (HR [95% CI], 0.54 [0.40-0.72]; P < .001). allo-HSCT in CR1 is reported here as significantly improving the outcome of fit older patients with AML. Long-term RFS without allo-HSCT is very low (<10%), supporting allo-HSCT as being the best curative option for these patients.

Is the Outcome of Patients with High Risk T-Cell Acute Lymphoblastic Leukemia Improving in the Era of Pediatric—Inspired Protocols? a Comparison of 2 Consecutive Pethema Trials

BACKGROUND: Pediatric-inspired regimens have been adopted by several groups as the treatment strategy for adult patients with acute lymphoblastic leukemia (ALL). Whether subsequent modifications of these protocols have led to an improvement in the outcome of patients is uncertain. This is especially relevant in T-cell ALL, where barely no new drugs have been approved in recent years. The aim of the study was to compare the outcome of patients with high risk T-cell ALL included in 2 consecutive trials of the Spanish PETHEMA Group (ALL-HR03 [NCT00853008] and the more contemporary ALL-HR11 [NCT NCT01540812]).METHODS: Both ALL-HR03 and ALL-HR11 trials included pediatric-inspired regimens and have been published. Modifications in the ALL-HR11 protocol included a lower dose of daunorubicin in the induction phase, lower intensity of chemotherapy in the consolidation phase (except for a higher dose of MTX: 3g/m2 vs. 5g/m2) and a centralized review of minimal residual disease (MRD) by flow cytometry according to EuroFlow recommendations. In both trials, patients with poor clearance of MRD after induction or consolidation were assigned to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) in CR1 while patients with good clearance of MRD underwent subsequent delayed consolidation and maintenance with reinductions phases without allo-HSCT.RESULTS: One-hundred and sixty-nine patients with T-cell ALL were included (104 in the HR03 and 65 in the HR11). Patient- and disease-characteristics were balanced between both groups except for a longer follow-up time in patients included in the HR03 than in the HR11 (5.2 years [range 0.1-9.1] vs. 1.8 years [0.2-4.7], p<0.001).In terms of efficacy, the results are summarized in table 1. We observed a similar risk of slow cytologic response on day +14 of induction, complete remission (CR) rate and relapse in both protocols. Disease-free survival (DFS) in patients achieving CR was also similar in both groups. Patients included in the HR11 protocol had better 4-yr overall survival (OS) compared with the HR03 protocol (61% [95% CI 46%-76%] vs. 40% [95% CI 30%-50%], p = 0.026) (Figure 1).Regarding toxicity and after censoring the follow-up at the time of transplantation, the cumulative incidence of treatment-related mortality (TRM) at 5 years for all patients was 7% (95% CI 3%-12%). More patients died of TRM during induction (7% vs. 3%) and consolidation (6% vs. 0%) in the HR03 protocol than in the HR11, respectively (p = 0.05).Of the 152 patients achieving CR1 in both trials, 109 reached the time point for allocation to allo-HSCT in CR1 or chemotherapy (35 were assigned to allo-HSCT and 74 to chemotherapy). Patients assigned to allo-HSCT showed lower risk of relapse at 4-yrs (20% [95% CI 8%-37%] vs. 50% [95% CI 37%-62%], p = 0.005) but higher risk of TRM at 4-yrs (28% [95% CI 14%-45%] vs. 1% [95% CI 0%-7%], p < 0.001) than patients treated with chemotherapy alone. DFS at 4 years (52% [95% CI 34%-70%] vs. 49% [95% CI 36%-62%], p = 0.97) and OS at 4 years (51% [95% CI 31%-71%] vs. 67% [95% CI 55%-79%], p = 0.14) were similar in patients undergoing transplantation and chemotherapy (Figure 2).CONCLUSIONS: Patients with T-ALL included in the HR-11 trial showed better OS than patients in the HR-03 mainly due to lower treatment-related deaths. CR rate and DFS were similar in both protocols. Promising long-term survival can be achieved in patients with T-cell ALL and good MRD clearance throughout the treatment without the need of allo-HSCT in CR1. [Display omitted] DisclosuresMontesinos:Celgene Corporation: Honoraria, Research Funding. Ribera:Celgene: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Pfizer: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; Roche: Honoraria; Amgen Inc.: Research Funding, Speakers Bureau.

Comparison of Frontline Induction Therapy Using Idarubicin in Combination with High-Dose (HDAC3) Versus Intermediate-Dose Cytarabine (IDAC3) in Adult Acute Myeloid Leukemia

BackgroundThe utility of high-dose cytarabine during induction chemotherapy for adult acute myeloid leukemia (AML) remains contentious. Intermediate-dose cytarabine may maintain a high first-cycle complete remission (CR) rate, whilst reducing treatment-related toxicity.AimWe examined the outcomes of adult AML patients treated with idarubicin (12 mg/m2 days 1-3) in combination with high-dose (3 g/m2; HDAC3) or intermediate-dose cytarabine (1.5 g/m2; IDAC3) given twice daily on days 1, 3, 5, and 7.MethodsConsecutive AML patients aged ≤60 years at 2 major tertiary referral centers, the Alfred and Austin Hospitals, were treated with sequential protocols of HDAC3 (n=52; 2010-2014) and then IDAC3 (n=58; 2014-2017). Planned consolidation chemotherapy consisted of up to 2 cycles of idarubicin 9 mg/m2 days 1-2, cytarabine 100 mg/m2 days 1-5, and etoposide 75 mg/m2 days 1-5 (IcE). Favorable-risk karyotype was excluded from this analysis. We assessed treatment responses (2017 European LeukaemiaNet recommendations), 30 and 60-day mortality, ability to deliver consolidation therapy (number of cycles and days from induction to first consolidation chemotherapy), rates of allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission (CR1), rates of total parenteral nutrition (TPN) usage, haematologic toxicities (days to platelet and neutrophil recovery), and relapse-free (RFS) and overall survival (OS) censored for allo-HSCT or loss to follow-up. Statistical analysis was performed using R version 3.3.2.ResultsIDAC3-treated patients were younger than those receiving HDAC3 (median 44 vs 48 years) but had a higher frequency of secondary AML (16% vs 4%); (Table 1). Other baseline characteristics were balanced between both groups. No significant differences were observed for any outcome (Table 2), except the use of TPN which is most likely a result of change in practice over time rather than a true reflection of mucositis. Response rates including CR or CR with incomplete haematologic recovery (CRi) were similar: 79% (HDAC3) vs 83% (IDAC3) after 1 cycle of induction. There was no death at 30 days and only 1 death at 60 days. Allo-HSCT in CR1 was similar; among patients with adverse-risk karyotype, allo-HSCT in CR1 was performed for 9/15 (60%) after IDAC3 and 7/11 (64%) after HDAC3. Days to neutrophil and platelet recovery were also similar.Delivery of consolidation chemotherapy was similar between both groups. After excluding treatment failure and partial remission (PR), 94 patients were eligible for first consolidation chemotherapy (3 patients with PR were considered near CR), of which 14 (15%) did not receive further consolidation therapy with the following reasons: allo-HSCT in CR1 (n=10); prolonged cytopenias (n=3); and maintenance clinical trial (n=1). Twenty-nine patients (31%) received only 1 consolidation therapy due to the following reasons: allo-HSCT in CR1 (n=14); prolonged cytopenias (n=10); non-hematologic toxicities (n=2); relapse (n=2); and unknown (n=1). IcE chemotherapy was administered in all except 2 cases: one received high-dose cytarabine for 1 cycle, and another had reduced idarubicin dose for 1 cycle.Survivors were followed up for a median of 8 (IDAC3) and 37 months (HDAC3), respectively. Median OS were 11.5 and 18.6 months for IDAC3 and HDAC3 (p=0.3), respectively (Figure 1A), and the corresponding median RFS were 8.4 and 9.4 months (p=0.5), respectively (Figure 1B). Overall, the median OS for adverse-risk karyotype remained significantly inferior compared to intermediate-risk (5.6 vs 20.9 months, p=0.009 by log-rank test); among adverse-risk karyotype, this was 5.1 vs 6.5 months for IDAC3 and HDAC3, respectively. Similarly, patients with FLT3 -ITDpos/ NPM1WT had inferior median OS (n=7, 6.1 months) when compared with FLT3 -ITDneg/ NPM1WT (n=55, 15.9 months), FLT3 -ITDpos/ NPM1MUT (n=14, 20.9 months), and FLT3 -ITDneg/ NPM1MUT (n=16, 40.6 months, p=0.06 by log-rank test).ConclusionIDAC3 and HDAC3 were both well tolerated in adult patients with AML with high first-cycle CR/CRi rates observed and low early mortality. No significant differences in hematopoietic recovery or delivery of post-remission therapy was apparent. With the caveat of limited sample size and follow-up duration, survival outcomes appeared equivalent. [Display omitted] DisclosuresGrigg:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees. Wei:AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria.

Allogeneic hematopoietic stem cell transplantation for adult patients with t(4;11)(q21;q23) KMT2A/AFF1 B-cell precursor acute lymphoblastic leukemia in first complete remission: impact of pretransplantmeasurable residual disease (MRD) status. An analysis from the Acute Leukemia Working Party of the EBMT.

Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p < 0.001), OS (HR = 0.14, p < 0.001), RI (HR = 0.23, p = 0.001), and NRM (HR = 0.16, p = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.

Mixed phenotype acute leukemia: Biological profile, clinical characteristic and treatment outcomes: Report of the population-based study.

The aim of this population-based, retrospective study was to analyze biological and clinical features and treatment results in children diagnosed with MPAL in all Polish pediatric oncology centers between 2007 and 2018. Among 2893 children and adolescents diagnosed and treated for acute leukemia, 39 (1.35%) patients fulfilled the WHO criteria of MPAL. The T/myeloid phenotype was most prevalent. Cytogenetics findings were seen in 2 (5.1%), while chromosomal abnormalities were found in 14 (35.9%) patients. Thirty-two patients achieved CR-1, including 23 (92.0%) treated with ALL-directed chemotherapy and 9 (64.3%) treated with AML-type induction regimens. Within these patients, 4 (12.5%) died due to treatment-related complications and 11 (34.4%) relapsed. Nineteen (63.3%) patients underwent allo-HSCT in CR-1 and 14 (73.7%) of them have been in CR-1. In total, 17 (43.6%) patients remain in CR-1 for 1-12years, including 14 (58.3%) with T/myeloid MPAL. The 5-year pOS and pEFS were 51.8% and 44.2%, respectively. The overall survival for ALL-directed therapy was significantly better than the one for AML-type chemotherapy (P=.001). It was also better for patients who underwent HSCT in CR-1 (P=.001). The prognosis of MPAL is unsatisfactory, but initial treatment with ALL-directed chemotherapy consolidated with allo-HSCT improves the outcomes in MPAL.

Haploidentical Hematopoietic Stem Cell Transplantation May Improve Prognosis in Non-Infant Children with t(v;11q23)/MLL-Rearranged B-Acute Lymphoblastic Leukemia

Background: B-acute lymphoblastic leukemia (B-ALL) with t(v;11q23)/MLL-rearrangement (MLL-r) in children (1 year or older) is rare, and its outcome and optimal treatment options remain controversial. This study aimed to analyze the clinical characteristics and outcomes of these patients, and to explore the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially haploidentical HSCT (haplo-HSCT) in the treatment of these patients. Methods: At the time of the last follow-up (July 1, 2019), we retrospectively analyzed clinical data of 42 non-infant children with t(v;11q23)/MLL-r B-ALL. Comparison of outcomes was made between patients received allo-HSCT in the first complete remission (CR1) and chemotherapy only. Results: The median follow-up was 41 (1-106) months. The median age at diagnosis was 4.5(1-14) years and the median leukocyte count was 56.0 (2.2-735.2)×109/L. One was excluded for death during induction. For the remaining 41 patients, the complete remission rate after induction therapy was 40/41 (97.6%), the estimated 4-year probabilities of overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 59.7%, 51.6% and 43.4%, respectively. 19 patients received allo-HSCT in CR1 (HSCT in CR1 cohort), notably, 18/19 cases in this cohort received haplo-HSCT, and the remaining 22 patients continued the consolidation therapy (Non-HSCT in CR1 cohort). The estimated 4-year probabilities of OS, EFS and CIR in the HSCT in CR1 cohort were 86.6%, 89.2% and 5.3%, respectively. Meanwhile, the estimated 4-year probabilities of OS, EFS and CIR in the Non-HSCT in CR1 cohort were 37.5%, 19.9% and 75.6%, respectively. They were considered to be statistically significant. Of the 17 patients who relapsed during consolidation chemotherapy, 9 patients who underwent chemotherapy only (Non-HSCT after relapse cohort) all died within 44 months. For the remaining 8 patients who chose allo-HSCT (HSCT in CR2 cohort) when they achieved the second complete remission (CR2), the estimated 4-year probability of OS was 47.6% (P=0.002). Multivariate analysis showed that HSCT in CR1 was the only independent protective factor for OS, EFS and CIR, and age at diagnosis (≥10 years) was an independent risk factor of OS. Conclusions: Allo-HSCT (especially haplo-HSCT) in CR1 may reduce the risk of relapse and improve prognosis in non-infant children with MLL-r B-ALL. In addition, allo-HSCT also seemed to be an effective approach to improve the prognosis of relapsed patients. Thus, haplo-HSCT could be an alternative approach for non-infant children with MLL-r B-ALL. Disclosures No relevant conflicts of interest to declare.

Prospective Evaluation of Allogeneic HSCT at the First Remission for Younger Adults with FLT3-ITD Positive Acute Myeloid Leukemia: The JALSG AML209-FLT3-SCT Study

Prospective Evaluation of Allogeneic HSCT at the First Remission for Younger Adults with FLT3-ITD Positive Acute Myeloid Leukemia: The JALSG AML209-FLT3-SCT Study

Acute myeloid leukemia patient with FLT3-ITD and NPM1 double mutation should undergo allogeneic hematopoietic stem cell transplantation in CR1 for better prognosis.

Background: According to the recent National Comprehensive Cancer Network (NCCN) guidelines, the risk level in acute myeloid leukemia (AML) patients with FLT3-ITD and NPM1 double mutation (AMLFLT3-ITD+/NPM1+) depends on the allelic ratio of FLT3-ITD. But despite a low or high allelic ratio of FLT3-ITD, AMLFLT3-ITD+/NPM1+ patients belong to the favorable or intermediate risk, for whom allogeneic stem cell transplantation is not obligated. However, some latest studies pointing out that NPM1 and FLT3-ITD double mutation patients showed an inferior prognosis, which have raised concern about the risk categorization and more effective treatment of AMLFLT3-ITD+/NPM1+ patients.Methods: A total of 76 patients were selected for coexisting FLT3 and NPM1 mutations with normal cytogenetics. The prognostic risk factors were analyzed, and treatment strategies including allogeneic stem cell transplantati1on and chemotherapy were compared.Results: In 76 AMLFLT3-ITD+/NPM1+ patients, 36.8% of patients had hyperleukocytosis (HL) and DNMT3A R882 mutation was the most common concomitant gene (23.7%). For 53 patients in the complete remission (CR), 22 had received allogeneic hematopoietic stem cell transplantation (allo-HSCT) on first complete remission (CR1). Patients in transplantation group had better overall survival (OS) and disease-free survival (DFS) than chemotherapy only (P=0.002 and 0.001, respectively). In multivariable Cox model analyses, HL and DNMT3A R882 mutation were independent adverse prognostic factors (all P<0.05) for AMLFLT3-ITD+/NPM1+ patients. Nevertheless, allo-HSCT was an independent good factor of OS and DFS (P=0.001 and 0.000; HR =0.173 and 0.138; 95% CI were 0.062–0.483 and 0.049–0.389). And allo-HSCT could moderately improve the poor prognosis of AML FLT3-ITD+/NPM1+/DNMT3A R882+.Conclusion: Although, AMLFLT3-ITD+/NPM1+ patients are categorized as favorable or intermediate risk levels according to recent NCCN and ELN guidelines, these patients should receive allo-HSCT in CR1 for a longer survival. AMLFLT3-ITD+/NPM1+ patients with DNMT3A R882 mutation had a very poor prognosis, and allo-HSCT could moderately improve their survival.

Prognostic Impact of the Interaction between DNMT3A mutation and Internal Tandem Duplication of the FLT3 Gene (FLT3-ITD) in Patients with De Novo Mutated NPM1 (NPM1mut) acute Myeloid Leukemia

IntroductionThe association of NPM1mut and FLT3-ITD in de novo acute myeloid leukemia (AML) with intermediate-risk cytogenetics has different prognostic impact depending on the FLT3 allelic burden. Previous studies published by our cooperative group showed that patients with de novo AML of intermediate-risk cytogenetics with NPM1mut and FLT3-ITD low ratio (<0.5, FLT3low) at diagnosis presented an overall survival and relapse rate similar to those with NPM1mut and FLT3wt. Therefore, in the CETLAM-2012 protocol, patients with FLT3low NPM1mut AML are not considered for allogenic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1). Recent studies suggest that the co-occurrence of DNMT3A mutation in FLT3-ITD NPM1mut AML patients confers a worse prognosis regardless of FLT3-ITD ratio.We analysed our data to determine whether these findings were confirmed in our cohort, specifically in the low FLT3-ITD ratio patients, since this could have therapeutic implications.Methods and patientsA total of 163 patients with de novo AML, intermediate-risk cytogenetics and NPM1mut were analysed (median age 53 years (18-72); male:female 72:91 (0.79)). Eighty patients (49%) harboured an FLT3-ITD, with a high allelic ratio in 42 of 76 patients with available ITD/wt ratio (55%). They were included in the AML-2003 (n=49) and AML-2012 (n=114) CETLAM protocols. Proportion of patients undergoing alloHSCT in CR1 is detailed in table 1.Bone marrow samples from diagnosis were studied for DNMT3A mutations as previously described. The definition of complete remission (CR), overall survival (OS), leukemia-free survival (LFS) and risk of relapse (RR) followed recommended ELN criteria. The Kaplan-Meier method was used to estimate the distribution of LFS and OS, for RR cumulative incidence was used.ResultsOut of the 163 patients with AML of intermediate risk cytogenetics and NPM1mut, 78 presented DNMT3A mutations (48%). Of these, 62 (79%) presented mutations in codon R882 or corresponded to DNA insertions/deletions while 16 (21%) harboured missense mutations. Presence of DNMT3A mutation did not associate with FLT3-ITD (ITD/85 DNMT3Awt vs ITD/78 DNMT3Amut, p=0.394). In the entire cohort, 5-year OS, LFS and RR were 58±4.5%, 59±4.6% and 27±13.9%. FLT3-ITD ratio confirmed its prognostic impact when analysing FLT3wt (n=83) vs FLT3low (n=34) vs FLT3high (n=42) patients (5-year OS of 68±6% vs 62±8.7% vs 37±8.6%; p=0.002; and 5-year RR of 18±9.4% vs 27±16.1% vs 41±23.2%; p=0.023). On the contrary, DNMT3Amut did not exert any effect on overall outcome (5-yr OS DNMT3Awt vs DNMT3Amut 61±6.2% vs 55±6.2%; p=0.234)When DNTM3A mutational status was considered, the impact of FLT3-ITD on outcome was mitigated in wild-type DNMT3A population. Thus, we found that DNMT3Awt patients presented no statistical differences in OS according to FLT3 mutational status or ratio: FLT3wt (n=46) vs FLT3-ITD (n=39) was 67±8.5% vs 57±8.2%; p=0.122, whereas FLT3wt (n=46) vs FLT3low (n=18) vs. FLT3high (n=19) was 67±8.5% vs. 66±11.5% vs 46±11.8%; p=0.088 (image 1A).This was also seen in relation to LFS and RR according to FLT3 ratio: 5-yr LFS of FLT3wt vs FLT3low vs FLT3high was 72±7.9% vs 61±12.6% vs 51±13.4%; p=0.244 and 5-year RR of the same groups: 19±8.8% vs 26±12.5% vs 27±21.9%; p=0.724 (image 2A).In the DNMT3Amut group, patients with FLT3-ITD (n=41) presented shorter OS than those with FLT3wt (n=37) with an OS of 37±10.7% vs 69±7.8%; p=0.028. When FLT3 ratio was considered, FLT3wt (n=37) vs FLT3low (n=16) vs FLT3high (n=23) showed an OS of 69±7.8% vs. 58±13.2% vs 27±13.1%; p=0.038 (image 1B).Similar results were seen in LFS according to FLT3 ratio (FLT3wt (n=29) vs FLT3low (n=16) vs FLT3high (n=20) 71±8.6% vs 53±12.9% vs 18±13.8%; p=0.012).Finally, we observed significant differences in the 5-year RR when considering DNMT3Amut patients in relation to FLT3 ratio (FLT3wt vs FLT3low vs FLT3high 18±10.6% vs 27±20% vs 54±28.8%; p=0.021)(image 2B).ConclusionsIn this study, patients with NPM1mut and FLT3-ITDlow presented a similar outcome to patients with NPM1mut and FLT3wt regardless of DNMT3A mutational status. These results support the modification of alloHCST policy in CR1 in CETLAM-2012, which do not consider alloHSCT for patients with FLT3low. On the other hand, concurrence of DNMT3A mutation may have an added negative effect in patients with NPM1mut and FLT3-ITDhigh, which should be further confirmed in larger studies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Comparison of High-Dose Cytarabine During Induction Versus Consolidation Therapy in Newly Diagnosed AML.

The proportion of patients with acute myeloid leukemia (AML) cured is increased by administering high-dose cytarabine (HiDAC). It remains uncertain whether to administer HiDAC as induction or consolidation, and whether ≥1 cycle of HiDAC is required. Our retrospective study of 416 adult AML patients, excluding good risk cytogenetics, compared a single cycle of HiDAC-based therapy followed by 2 cycles of standard-dose cytarabine (SDAC) (HiDAC induction cohort) with SDAC-based chemotherapy followed by 2 cycles of HiDAC-based chemotherapy (HiDAC consolidation cohort). Complete remission (CR) rate was greater in the HiDAC induction cohort (90% vs 78%, P < 0.01) which did not lead to an improved overall survival (48% vs 43%, P = 0.18) or disease-free survival (DFS) (39% vs 45%, P = 0.95). We noted that, after censoring for allogeneic hematopoetic stem cell transplant (alloHSCT) in CR1, the cumulative incidence of relapse was lower in the HiDAC consolidation cohort in patients with intermediate risk cytogenetics (68% vs 44%, P = 0.01), which lead to a greater DFS (30% vs 47%, P = 0.095). In the patients with adverse risk cytogenetics, the RR was numerically greater in the HiDAC consolidation cohort (52% vs 80%, P = 0.60) which lead to a lower DFS (27% vs 4%, P = 0.11). Our data show that, although the HiDAC induction cohort (1 cycle of HiDAC) achieved a greater CR rate, there were no overall survival differences between the 2 cohorts, and that the HiDAC consolidation cohort (2 cycles of HiDAC) had a lower RR and greater DFS in those patients with intermediate risk cytogenetics who did not undergo alloHSCT in CR1.