The prognostic value of multilineage dysplasia in de novo acute myeloid leukemia patients with intermediate-risk cytogenetics is dependent on NPM1 mutational status

Blood ◽  
2010 ◽  
Vol 116 (26) ◽  
pp. 6147-6148 ◽  
Author(s):  
Marina Díaz-Beyá ◽  
María Rozman ◽  
Marta Pratcorona ◽  
Montserrat Torrebadell ◽  
Mireia Camós ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
De Novo ◽  
Intermediate Risk ◽  
Multilineage Dysplasia ◽  
Mutational Status ◽  
Acute Myeloid

scholarly journals 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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1492-1492
Author(s):  
Guadalupe Oñate ◽  
Ana Garrido ◽  
Jordi Esteve ◽  
Rosa Coll ◽  
Montserrat Arnan Sangerman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Mutational Status ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction The 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 patients A 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. Results Out 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). Conclusions In 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. Disclosures No relevant conflicts of interest to declare.

scholarly journals Pattern and prognostic value of FLT 3 ‐ ITD mutations in Chinese de novo adult acute myeloid leukemia

2018 ◽  
Vol 109 (12) ◽  
pp. 3981-3992
Author(s):  
Song‐Bai Liu ◽  
Qiao‐Cheng Qiu ◽  
Xie‐Bing Bao ◽  
Xiao Ma ◽  
Hong‐Zhi Li ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
De Novo ◽  
Acute Myeloid

scholarly journals Addition of the Anti-CD33 Monoclonal Antibody Mylotarg to Fludarabine/High Dose Cytarabine - Based Induction Significantly Improves Outcome in Patient Affected By FLT3-ITD Positive Cytogenetically Normal Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1365-1365
Author(s):  
Paola Minetto ◽  
Anna Candoni ◽  
Fabio Guolo ◽  
Marino Clavio ◽  
Maria Elena Zannier ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Favorable Effect ◽  
High Dose ◽  
Intermediate Risk ◽  
Npm1 Mutation ◽  
Mutational Status ◽  
High Dose Cytarabine ◽  
Risk Patients ◽  
Acute Myeloid

Background: The addition of the anti-CD33 targeting antibody Mylotarg (MY) to conventional "3+7" induction has been shown to improve the outcome of patients affected by acute myeloid leukemia (AML) without adverse cytogenetic alterations. Early reports suggested that MY was particularly effective among low risk patients, such as core binding factor AML, particularly if included in a high dose cytarabine-based induction therapy. The role of MY for intermediate risk patients appears to be less clear. Cytogenetically defined intermediate risk patients may be further stratified considering two frequent molecular aberrations: FLT3 "internal tandem duplication" (FLT3-ITD) mutation, associated with poor prognosis and NPM1 mutation (NPM1-mut), associated with a good prognosis. The concomitant presence of NPM1-mutpartially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild type allelic ratio. NPM1 and FLT3 mutational status assessment is strongly recommended for risk stratification at diagnosis by the last ELN 2017 guidelines. Aims: To investigate the efficacy of MY added to an intensive fludarabine, high dose cytarabine and Idarubicin-based induction regimen (FLAI) as frontline treatment for younger (&lt;65 years), cytogenetically normal AML patients according to NPM1 and FLT3-ITD mutational status. Methods:One-hundred and forty eight consecutive AML patients, treated in 3 Italian Hematology centersbetween 2008 and 2018and harboring at least one molecular alteration among NPM1-mut and FLT3-ITD, were included in the analysis. Thirty three patients carried isolated FLT3-ITD, 50patients showed concomitant FLT3-ITD and NPM1-mut and 65 isolated mutated NPM-1.Median age was 50 years(range: 18-65). All patients received FLAI induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm on days1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5), with or without low dose MY(3 mg/sqm, added in 42 patients), followed by a second induction without fludarabine and with idarubicin at the increased dose of 12 mg/sqm. Before 2017, patients with isolated FLT3-ITD mutation were scheduled for allogeneic stem cell transplantation (HSCT), if an HLA-matched sibling donor was available, whereas after 2017 only patients with high allelic burden isolated FLT3-ITD mutation received HSCT in first CR. The other patients received conventional high dose cytarabine consolidation for a total of 3 cycles. Results: Overall, 60-days mortality was 3%, and was not significantly influenced by receiving or not MY during induction. After one induction cycle, 126 patients achieved CR (85%) with no difference between patients receiving or not MY. After a median follow up of 70months, 3-year overall survival (OS) was 59.5% (median not reached). OS duration was significantly longer in NPM1 mutated patients (p &lt;0.05).Patients with isolated FLT3-ITD mutation had a significantly worse prognosis (3-year OS 38.3%, p&lt;0.05). The addiction of MY did not significantly improve outcome in the whole cohort but did show a significant positive effect on survival among FLT3-ITD patients (3-year OS 66.7% vs 46.6% for FLT3-ITD patients receiving or not MY, respectively, p&lt;0.03, Fig. 1). This effect was more evident among the 33 NPM1 negative/FLT3-ITD patients: in this subgroup, patients who received MY had an overall good outcome that was similar to patients with double mutation who received the same therapy(median OS not reached in both groups, p=n.s.). On the contrary, among patients who did not receive MY, NPM1 negative/FLT3-ITD positive patients had a poor outcome, significantly inferior to double positive patients receiving the same regimen(3-Year OS 39.8% and 57.3%, respectively, p&lt;0.05). The favorable effect of MY among FLT3-ITD patients was not influenced by FLT3-ITD allelic burden.Of note, the proportion of patients receiving HSCT in first CR, as expected, was higher among patients harboring isolated FLT3-ITD mutation, but there was no significant difference among patients receiving or not MY. Conclusions: Despite the potential bias due to the retrospective nature of the analysis, our data seem to indicate that Mylotarg, added to an intensive fludarabine/high dose cytarabine-based induction, provides a significant improvement in anti-leukemic efficacy in patients carrying FLT3-ITD mutation, especially if concomitant NPM1 mutation is not present. Disclosures Candoni: Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Merck SD: Honoraria, Speakers Bureau. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria.

Mutations In the DNA Methyltransferase Gene DNMT3A Are Highly Recurrent In Patients with Intermediate Risk Acute Myeloid Leukemia, and Predict Poor Outcomes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 99-99
Author(s):  
Timothy J Ley ◽  
Li Ding ◽  
Matthew J. Walter ◽  
Michael D. McLellan ◽  
Tamara Lamprecht ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Intermediate Risk ◽  
Next Generation ◽  
De Novo Aml ◽  
Poor Outcomes ◽  
Acute Myeloid

Abstract Abstract 99 Whole genome sequencing with next generation technologies represents a new, unbiased approach for discovering somatic variations in cancer genomes. Our group recently reported the DNA sequence and analysis of the genomes of two patients with normal karyotype acute myeloid leukemia (AML). Improvements in next generation sequencing technologies (principally, paired-end sequencing) led us to reevaluate the first case (Ley et al, Nature 456:66–72, 2008) with deeper sequence coverage. We discovered a novel frameshift mutation in DNMT3A, one of the three genes in humans (DNMT1, DNMT3A, and DNMT3B) that encodes a DNA methyltransferase that catalyzes the addition of methyl groups to cytosine within CpG dinucleotides. We then sequenced all the coding exons of this gene in 280 additional de novo cases of AML to define recurring mutations. 62/281 de novo AML cases (22%) had mutations with translational effects in the DNMT3A gene. 18 different missense mutations were identified, the most common of which was at amino acid R882 (37 cases). Frameshifts (n=6), nonsense mutations (n=6), splice site mutations (n=3), and a 1.5 Mbp deletion that included the DNMT3A gene were also identified. DNMT3A mutations were highly enriched in cases with intermediate risk cytogenetics (56/166=33.7%; p<0.0001) and were not found in any cases with favorable cytogenetics (0/79; p<0.0001). Genomic 5-methylcytosine content, the general pattern of CpG island methylation, and gene expression patterns were essentially unaltered in genomes with DNMT3A mutations. The median overall survival of all AML patients with DNMT3A mutations was strikingly reduced, regardless of whether the mutation was at R882 or any other site (12.3 vs. 41.1 months, p<0.0001, Figure A). Patients with a FLT3 ITD mutation and no DNMT3A mutation (n=39) had a median survival of 33.5 months, but patients with a FLT3 ITD mutation and any DNMT3A mutation (n=18) had a median survival of 7.7 months (p=0.003, Figure B). Finally, DNMT3A mutation status independently predicted poor outcomes in a Cox Proportional Hazards analysis. In sum, DNMT3A mutations are highly recurrent in de novo AML cases with intermediate risk cytogenetics, and are independently associated with poor survival. These mutations may be valuable for identifying patients who need early intensification of therapy (allogeneic stem cell transplantation and/or innovative early phase clinical trials in first remission or consolidation). Disclosures: Westervelt: Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau. DiPersio:Genzyme: Honoraria.

Multilineage Dysplasia Confers Poor Prognosis to Patients with De Novo Acute Myeloid Leukemia with Intermediate-Risk Cytognetics and Wild-Type NPM1.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2551-2551
Author(s):  
Jose Tomas Navarro ◽  
Maria Rozman ◽  
Leonor Arenillas ◽  
Ana Aventin ◽  
Teresa Gimenez ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Leucocyte Count ◽  
Tandem Duplication ◽  
De Novo ◽  
Normal Karyotype ◽  
Intermediate Risk ◽  
Wild Type ◽  
Who Criteria ◽  
Multilineage Dysplasia

Abstract Abstract 2551 Background: The presence of multilineage dysplasia (MLD) is the hallmark to define acute myeloid leukemia (AML) with myelodysplasia-related changes. The recognition by the WHO classification of this category as a separate entity implies the presence of differential biological and clinical features. While this seems to be confirmed for patients with AML and MLD associated with high risk cytogenetic abnormalities, the prognostic significance of MLD in cases with intermediate risk karyotype is unclear. Recent studies have shown that MLD has no prognostic impact in patients with mutated NPM1, but the prognosis of patients with intermediate-risk cytogenetics and MLD harboring a wild-type configuration of NPM1 is uncertain. Objective: The aim of this study was to analyze the presence of MLD and its prognostic value in AML patients with intermediate risk cytogenetics (IR-AML) and wild-type NPM1. Patients and methods: One-hundred eighty-two patients diagnosed with de novo IR-AML and wild-type NPM1 treated with the same chemotherapy protocol (CETLAM-2003) were included (M/F:101/81; median age: 55.5, 18–73). Bone marrow aspirate smears performed at diagnosis were reviewed by a panel of expert cytologists, and the cases were categorized as having MLD by applying strictly the WHO criteria (Harris et al, WHO 2008, MLD-1). Additionally, cases with dysplasia in ≥50% of the cells in one cell line, and between 30% and 50% in another cell line, were classified as having significant dysplasia (MLD-2). Results: The degree of dysplasia was evaluable in 139 of the 182 cases, observing strictly WHO-defined multilineage dysplasia (MLD-1) in 45 (25%), significant dysplasia (MLD-2) in 17 additional patients (9%), and absence of MLD in 80 (44%). In 43 (30%) cases dysplasia could not be thoroughly quantified in all hematopoietic lines, mostly due to the lack of enough evaluable precursors in a context of massive blast infiltration. No major differences concerning main characteristics were observed between patients with or without MLD, including age, leucocyte count at presentation, degree of BM involvement, proportion of normal karyotype, and frequency of mutations of FLT3 (internal tandem duplication), CEBPA, and partial tandem duplication of MLL gene. Since the outcome of patients with MLD-2 was similar to that of patients with stringent WHO MLD, and markedly inferior to patients lacking MLD (table 1), these two groups were merged in a unique MLD group (MLD-1+MLD-2). Thus, MLD was associated with a lower probability to achieve complete remission (CR) after frontline induction chemotherapy (66% vs. 80%, p=0.033). In addition, patients with MLD showed a trend to an inferior overall survival (OS at 5 years: 39.2±5% vs. 22.9±8.1%, p=0.064). Of note, a multivariate analysis identified increasing age, higher leucocyte count at presentation, and presence of MLD (hazard ratio, 95% CI: 1.569,1.056–2.331; p=0.026) as the only variables associated with a shortened survival; this analysis also included presence of FLT3-ITD and cytogenetics (normal karyotype vs. other intermediate-risk abnormalities). Age was the only variable with independent prognostic value on leukemia-free survival in this cohort of patients, whereas MLD did not reach statistical significance. Interestingly, the outcome of patients with MLD-AML with a minimum CR duration of 3 months was significantly better after allogeneic stem cell transplantation in first CR compared to other post-remission treatments (5-year OS: 82±12% vs. 31±9%, p=0.006), suggesting that alloHSCT could partially overcome the adverse prognosis associated with this AML category. Conclusions: The presence of MLD confers adverse prognosis to patients with IR-AML and wild-type NPM1. Presence of significant dysplasia in two hematopoietic cell lines without fulfilling stringent WHO criteria was associated to an outcome similar to that of patients with WHO-defined criteria, an observation that leads to a wider interpretation of significant MLD in AML. These results have an important clinical relevance and should lead to the search of new genetic and epigenetic markers associated with MLD in this setting. This study has been partially supported by grant n° 03/0423 from Instituto de Salud Carlos III/FIS0. Disclosures: No relevant conflicts of interest to declare.

Prognostic value of p53 gene mutations and the product expression in de novo acute myeloid leukemia

2000 ◽  
Vol 65 (1) ◽  
pp. 23-31 ◽  
Author(s):  
Yasuyuki Nakano ◽  
Tomoki Naoe ◽  
Hitoshi Kiyoi ◽  
Kunio Kitamura ◽  
Saburo Minami ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
De Novo ◽  
Gene Mutations ◽  
P53 Gene ◽  
Product Expression ◽  
P53 Gene Mutations ◽  
Acute Myeloid

scholarly journals Response to Venetoclax and Hypomethylating Agents Among Prognostic Risk Groups and Genetic Subtypes of Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 334-334 ◽  
Author(s):  
Ibrahim Aldoss ◽  
Dongyun Yang ◽  
Raju Pillai ◽  
James F Sanchez ◽  
Ahmed Aribi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
De Novo ◽  
Recursive Partitioning ◽  
Response To Therapy ◽  
Intermediate Risk ◽  
Hypomethylating Agents ◽  
Newly Diagnosed ◽  
Acute Myeloid

Abstract The combination of venetoclax and hypomethylating agents (HMA) has demonstrated potent activity in acute myeloid leukemia (AML), both in newly diagnosed patients (pts) and those with relapsed/refractory (r/r) disease. We analyzed the association between response to therapy and leukemic somatic mutations, cytogenetics, and other pertinent patient- and leukemia-related features in a large series of newly diagnosed and r/r AML in adults treated with venetoclax in combination with HMA at City of Hope between October 2016 and May 2018. We identified 107 evaluable adults with AML treated with the combination of venetoclax and HMA. Sixty-one (57%) pts had r/r AML at the time of initiating treatment (median prior lines of therapy: 2; range: 1-10), while 46 (43%) were treated in the frontline setting. The median age of pts was 68 years (range: 19-86). AML was de novo in 57 (53%), therapy-related in 23 (21%) and secondary in 27 (25%) pts. Thirty-six (34%) pts had prior exposure to HMA, and 21 (20%) pts had relapsed following prior allogeneic hematopoietic cell transplantation (HCT). The majority of treated pts had unfavorable (52%) or intermediate-risk (39%) AML based on combined cytogenetics and molecular profiles. The most common detected somatic mutations (majority by next generation sequencing) were FLT3 (17%), followed by DNMT3A (15%), RAS and TET2 (each 14%), RUNX1 (13%), TP53 (12%), and IDH1/2 (11%). Most pts received decitabine in combination with venetoclax (N=97, 91%); only 10 (9%) pts received 5-azacitidine together with venetoclax. Complete remission (CR)/CR with incomplete hematologic recovery (CRi) was achieved in 57 (53%) pts after a median of 2 (range 1-4) cycles. For 36 pts who achieved CR/CRi and had available minimal residual disease (MRD) assessment by multicolor flow cytometry (MFC), 23 (64%) became MRD-. CR/CRi was higher in pts carrying favorable- or intermediate-risk AML compared to poor-risk AML (100% vs. 60% vs. 45%, P=0.029). CR/CRi was 48% in those with complex cytogenetics (N = 31), 45% in monosomal karyotype (N = 22), 36% in KMT2A gene rearrangement (N = 11), 74% in normal karyotype (N = 19), and 25% in inversion 3 (N =4). The CR/CRi rate was not significantly different between newly diagnosed or r/r AML (61% vs. 48%, P = 0.17), nor was there a difference associated with AML type (de novo vs. therapy-related vs. secondary, P= 0.26), patient age (> or ≤ 65 years) at time of therapy (P = 0.13), prior allogeneic HCT (P = 0.29), prior administration of HMA (P = 0.37) and the type or schedule (5- or 10-day decitabine) of HMA (P = 0.52). In multivariate analysis, only favorable- or intermediate-risk cytogenetics was associated with better CR/CRi (P = 0.036). CR/CRi was also comparable regardless of the presence or absence of various analyzed somatic AML mutations. However, in recursive partitioning analysis of detectable somatic mutations and response to therapy, the combined lack of RAS, TP53 and RUNX1 mutations was linked to an improved rate of CR/CRi. When AML cases were stratified into functional gene alteration subgroups (according to the TCGA data set), there was no significant difference in CR/CRi according to the presence or absence of certain functional genes/fusions. Median overall survival (OS) for all pts was 12.5 months and was 14.6 months for pts who achieved CR/CRi, in contrast to 4.6 months for non-responders (P <0.001). Only AML subtype (de novo vs. therapy-related vs. secondary) (P <0.001) and AML genetic risk (favorable/intermediate vs. high) (P = 0.042) independently impacted OS in multivariate analysis. None of the AML individual somatic mutations influenced OS for this cohort, however, in recursive partitioning analysis of detectable mutations, the presence of any of SRSF2, IDH1/2 or RUNX1 were associated with improved OS. Furthermore, the presence of myeloid transcription factor (P = 0.033) and spliceosome complex mutations (P = 0.004) predicted superior OS, whereas the presence of a chromatin modifying mutation predicted inferior OS (P = 0.004). Thirteen (23%) responders subsequently underwent allogeneic HCT. We report remarkable activity with venetoclax and HMA across various high-risk genetics and clinical features in AML patients. Prospective studies are warranted to compare this combination directly with chemotherapy in all AML subsets. This is particularly true for high risk AML where response to conventional chemotherapy is poor. Disclosures Ali: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Khaled:Alexion: Consultancy, Speakers Bureau; Juno: Other: Travel Funding; Daiichi: Consultancy. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

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