Cohort Of Acute Myeloid Leukemia Pts Research Articles

Impact of KMT2A-PTD Mutational Subgroups on Outcome of AML Patients after Induction Therapy and Allogeneic Hematopoietic Cell Transplantation

Introduction Genetic profiling of acute myeloid leukemia (AML) has increasingly revealed the possibility of adjusted therapeutic options. Recently, updates in genetic risk classifications introduced novel molecular features, but also excluded aberrations like partial tandem duplications in the lysine (K)-specific methyltransferase 2A ( KMT2A-PTD), formerly associated with adverse prognosis. Furthermore, there is growing evidence that molecular subtypes confer differential prognosis. Therefore, we analyzed a large cohort of AML pts to decipher the prognostic impact of KMT2A-PTD mutations ( KMT2A-PTD mut) including variants e9e3, e10e3 and e11e3 and their role in allogeneic hematopoietic cell transplantation (alloHCT). Methods Genomic DNA and total RNA of pts enrolled within the SAL registry (NCT03188874) was extracted at diagnosis. Samples were screened for KMT2A-PTD mut using the Mentype AMLplexQS Kit (Biotype, Dresden, Germany). Statistical as-treated analyses included standard statistical methods for categorial and continuous variables. Effects of alloHCT modeled as a time dependent covariate were estimated using Cox regression. Complete remission (CR) and survival rates were defined according to the current European Leukemia Net criteria. Logistic regression was used to evaluate CR rates and Cox regression to estimate hazard ratios (HR). The significance level was set at 0.05. All patients gave written informed consent. The study was conducted in accordance to the Declaration of Helsinki and was approved by the responsible ethics committees. Results Among 1409 pts, 206 pts harbored KMT2A-PTD mut, while 1203 pts showed wildtype (WT) alleles. KMT2A-PTD mut status was more often associated with secondary AML (p = .001) and less likely with concomitant NPM1 mutations (p < .001).Variants e9e3 (40.8%) and e10e3 (36.6%) were more frequently detected than e11e3 (22.6%). A total of 136 KMT2A-PTD mut and 859 WT pts received intensive induction therapy (IT). Rates of first complete remission (CR1) did not differ (p = .14). However, 5-year RFS was significantly lower in KMT2A-PTD mut pts compared to WT pts (15% vs. 25%), with median RFS of 23 vs. 29 months (HR = 1.4, p = .008). Accordingly, median OS was shorter (29 vs. 61 months; HR = 1.6, p = .002) and 5-year OS was lower for KMT2A-PTD mut pts compared to the WT counterparts (28% vs. 51%). In CR1, 81.6% of KMT2A-PTD mut pts proceeded to alloHCT and 18.4% of KMT2A-PTD mut pts received chemotherapy-based consolidation only. Median RFS improved from 15 to 37 months (HR = 0.5, p = .13) and chance of 5-year RFS enhanced from 17% to 21% when KMT2A-PTD mut pts underwent alloHCT in CR1 compared to KMT2A-PTD mut pts receiving chemo-consolidation.Median OS increased from 30 to 43 months when being allografted (HR = 0.5, p = .2), paralleled by increased rates of 5-year OS (33% chemo-consolidation vs. 47% alloHCT). Concerning KMT2A-PTD variants, there was no difference in likelihood to achieve CR1 between the three variants (p = .4). However, a trend towards shorter median OS ( e9e3: 41 months, e10e3:27 months, e11e3:27 months) and worse median RFS ( e9e3: 24 months, e10e3:23 months, e11e3:23 months) compared to WT pts (median OS: 61 months, median RFS: 29 months) could be revealed. Variant e10e3 was associated with worst prognosis (OS: HR = 2.1, p = .006; RFS: HR = 1.6, p = .06) and e9e3 with best prognosis (OS: HR = 1, p = .9; RFS: HR = 1.1, p = .7). e9e3 demonstrated best prognosis for both consolidation strategies. Median OS was not reached until last follow-up. Median RFS was higher in alloHCT pts (15 vs. 38 months, HR = 0.5, p = .3). e10e3 and e11e3 also had a higher median OS (12 vs. 43 months, HR = 0.3, p = .3 and 12 months vs. median survival not reached, HR = 0.2, p = .3, respectively) and RFS (11 vs. 41 months, HR = 0.3, p = .3 and 11 months vs. median survival not reached, HR = 0.2, p = .3, respectively) when allografted. Conclusions Based on our retrospective analysis, KMT2A-PTD mut are associated with reduced prognosis and survival in AML patients compared to WT pts. However, poor prognosis was effectively mitigated by alloHCT. Concerning KMT2A-PTD variants, we hypothesize alloHCT to be beneficial for improved survival. This effect seemed to be less pronounced for variant e9e3and more distinct for variant e11e3. Therefore, some KMT2A-PTD variants could be potentially implemented in AML risk stratification. However, prospective studies and larger patient numbers are needed.

Real World Data on Decitabine Treatment in 296 Patients with Acute Myeloid Leukemia: Outcome and Impact of TP53 Mutations

Real World Data on Decitabine Treatment in 296 Patients with Acute Myeloid Leukemia: Outcome and Impact of TP53 Mutations

Prognostic Impact of Clonal Diversity in Acute Myeloid Leukemia (AML) Treated with Intensive Chemotherapy (IC)

Prognostic Impact of Clonal Diversity in Acute Myeloid Leukemia (AML) Treated with Intensive Chemotherapy (IC)

Impact of DNMT3A mutations on Clinical Response to the Hypomethylating Agent Decitabine in Older Patients (pts) with Acute Myeloid Leukemia (AML)

Abstract 944Loss of function mutations of the DNA methyltransferase 3A (DNMT3A) gene have been associated with a negative impact on outcome in AML pts treated with conventional chemotherapy and/or stem cell transplantation. DNA methyltransferases (DNMTs) such as DNMT3A are responsible for catalyzing the addition of methyl groups to CpG dinucleotides. In AML, aberrant DNMT activity plays a role in epigenetic silencing of genes involved in hematopoiesis, and inhibition of DNMT activity by hypomethylating agents such as azacitidine and decitabine has been explored as a way to reverse hypermethylated gene silencing and induce clinical response. However, whether DNMT3A mutations influence response to hypomethylating agents is unknown. We studied the frequency and impact of DNMT3A mutations in a cohort of AML pts similarly treated with low dose decitabine. Genomic DNA from pretreatment bone marrow specimens from 46 pts (age 32–85) with untreated or relapsed AML who received decitabine 20mg/m2/d for 10 days every 28 days alone (n=39) or in combination with escalating doses of bortezomib (1.3mg/m2/d on days 5, 8, 12 & 15; n=7) were evaluated. DNMT3A was studied for mutations in the “hot spot” regions, and the mutational status of NPM1, CEBPA, IDH1/IDH2 and TET2 was assessed using polymerase chain reaction (PCR) and direct sequencing. Mutations within FLT3 were determined by quantitative fluorescence-based PCR capillary electrophoresis. Of the 46 pts, 17 had cytogenetically normal (CN) AML. Ten pts belonged to the Favorable genetic group as defined by the European LeukemiaNet (ELN) reporting system, nine pts fell into the ELN Intermediate-I, 11 were in the Intermediate-II, and 16 in the Adverse. Of the 46 pts, eight (17%) carried a DNMT3A mutation: six had codon R882 missense mutations, one nonsense (c.1729A>T; p.K576X) and one splice-site (c.2322+1G>A) mutation. DNMT3A mutations were distributed across all ELN genetic groups: three in the ELN Favorable, one in the ELN Intermediate-I, one in the ELN Intermediate-II, and three in the ELN Adverse group. Among the other molecular markers, only NPM1 mutations were significantly associated with DNMT3A mutations (P=.004). The complete remission (CR) rate for the entire cohort was 41% (19/46, 95% CI: 27% to 57%). Six of eight DNMT3A-mutated pts (75%) reached CR, compared to 13 of 38 with wild-type DNMT3A (34%; P=.05). All five pts with mutated DNMT3A and mutated NPM1 achieved CR, a significantly better response rate than that observed among the remaining pts (P=.008). The median overall survival of DNMT3A-mutated pts was longer than that of DNMT3A-wild-type pts (16.8 vs 11.0 months), but the difference did not reach statistical significance, likely due to the relatively small number of pts. Our group has shown that high levels of microRNA miR-29b, which targets and downregulates DNMT3A, are significantly associated with response to decitabine. (Blum W et al, PNAS 107:7473) Among the pts achieving CR, DNMT3A mutations were present in the pts with the lowest miR-29b expression levels (Wilcoxon’s P=.02 for the comparison of miR-29b expression between CR pts with and without DNMT3A mutations). Indeed, the miR-29b expression levels in these three pts was similar to that of pts who did not achieve CR, thereby supporting an impact of the mutation independent from that of the miR. These initial findings, while based on a small sample size, suggest a potential link between DNMT3A mutations and response to decitabine. If confirmed in a larger cohort, screening for DNMT3A mutation status could be used for risk-adapted stratification of AML pts to decitabine-based regimens.Supported by NIH/NCI grants NO1 CM62207; UO1 CA76576; K23CA120708 (WB); R01 CA102031 (GM), K12CA133250 (JCB, AW); AW is an ASH-AMFDP Scholar.Table 1:Pt Characteristics and Response to Decitabine TreatmentCR n=19No CR n=27PAge (years) median (range)72 (62 – 85)76 (32 – 84).09WBC (×103/μl) median (range)2.7 (1.1 – 119.5)2.2 (0.6 – 150).74Bone marrow blast count median (range)35 (20 – 87)39 (18 – 92).23ELN genetic category no..77favorable55intermediate-I45intermediate-II38adverse79DNMT3A mutated no.62.05NPM1 mutated no.63.13DNMT3A mutated &NPM1mutated no.50.008IDH1 or IDH2 mutated no.341.0TET2 mutated no.351.0FLT3-ITD no.21.56FLT3-TKD no.011.0CEBPA mutated no.14.39P values are from the Wilcoxon test for continuous data or Fisher's exact test for count data and not adjusted for multiple comparisons Disclosures:Off Label Use: Decitabine alone or in combination with bortezomib is not approved for the treatment of AML.

Impact of Chronic Graft-Versus-Host disease (GVHD) After Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) As Treatment for Acute Myeloid Leukemia (AML): A Survey From the Acute Leukemia Working Party of the EBMT

Abstract 321▪▪This icon denotes a clinically relevant abstractThe goal of RIC allo-SCT is to harness the graft-versus-leukemia (GVL) effect, while minimizing toxicities and the risk of GVHD. However, prior studies have shown a lower risk of relapse in AML patients (pts) who experienced chronic GVHD after RIC allo-SCT versus in those who did not. Here, we investigated the impact of occurrence of GVHD on transplantation outcomes in a large cohort of AML pts given allogeneic PBSC after RIC conditioning. Data from 1859 AML pts in first (n=1439) or second (n=420) CR transplanted between 2000 and 2009 following a RIC regimen at EBMT affiliated centres were analyzed. Pts were given PBSC from HLA-identical sibling (MRD, n=1208), or from HLA-matched unrelated donors (MUD, n=651). Median pt age at transplantation was 56 y (range, 18–77). 338 male pts were given grafts from female donors. RIC was based on low-dose TBI in 520 (28%) pts, while the remaining pts received chemotherapy-based RIC. ATG was given in 269 (22%) MRD and in 267 (41%) MUD recipients, respectively, while 151 (13%) MRD and 165 (25%) MUD recipients received in-vivo T cell depletion with alemtuzumab. The impact of chronic GVHD on relapse risk, non-relapse mortality (NRM), leukemia-free survival (LFS), and overall survival (OS) was assessed using time-dependent multivariate Cox models and in a landmark analysis at 18 months after transplant. Three-year incidences of relapse, NRM, LFS and OS were 34±1%, 15±1%, 51±2% and 60±2% in MRD recipients, respectively, and 34±2% (p=NS), 24±2% (P<0.001), 42±2% (P=0.001) and 47±2% (P=0.001) in MUD recipients, respectively. Grade II, III and IV acute GVHD were observed in 133 (11%), 61 (5%) and 30 (2%) MRD recipients and in 119 (18%), 41 (6%) and 24 (4%) MUD recipients, respectively. The 3-y cumulative incidence of chronic GVHD was 47%. Fifty-three percent of patients with chronic GVHD had extensive chronic GVHD, while the remaining 47% had limited chronic GVHD. In multivariate analyses, occurrence of grade II-IV acute GVHD was associated with a lower risk of relapse (HR=0.8; P=0.04), a higher risk of chronic (HR=2.2; P<0.001) and extensive chronic GVHD (HR=2.8; P<0.001), a higher risk of NRM (HR=2.4 P<0.001), a worsened LFS (HR=1.3; P=0.01), and a worsened OS (HR=1.5; P<0.001). In multivariate time-dependent analyses, occurrence of limited chronic GVHD was associated with a lower risk of relapse (HR=0.7; P=0.05), comparable NRM (HR=1.4; P=0.16), comparable LFS (HR=0.9; P=0.29) and better OS (HR=0.5; P<0.001), while occurrence of extensive chronic GVHD was associated with a lower risk of relapse (HR=0.6; P=0.01), higher NRM (HR=3.2; P<0.001), a trend for worsened LFS (HR=1.3; P=0.06) and comparable OS (HR=0.9; P=0.34). The median interval from transplantation to occurrence of chronic GVHD was 163 (range, 100–1545) days. To further assess the graft-versus-leukemia effect of chronic GVHD, we performed a landmark analysis in patients who were leukemia-free at 18 months after transplantation (n=776). Median follow-up from this landmark time-point was 24 (range, 0.1–112) months. Two-year relapse, NRM, LFS and OS were 16±2%, 2.5±1%, 82±2%, and 89±2%, respectively, in patients without chronic GVHD before the landmark time-point, versus 9±1% (P=0.001), 8±1% (P<0.001), 83±2% (P=0.65), and 86±2% (P=0.38), respectively, in patients with chronic GVHD before the landmark time-point.In conclusion, in this cohort of AML patients transplanted in remission, occurrence of chronic GVHD was associated with a lower risk of relapse that translated to better OS in patients with limited chronic GVHD but not in those with extensive chronic GVHD who experienced higher long term NRM, highlighting the need for long term prospective assessment of long term effects and quality of life in patients receiving RIC allo-SCT. Disclosures:No relevant conflicts of interest to declare.