Serum 2-Hydroxyglutarate Levels Predict Isocitrate Dehydrogenase Mutations and Clinical Outcome in Acute Myeloid Leukemia.

Abstract Abstract 2481 Purpose: Cancer-associated IDH mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of serum 2HG measurements has not been previously established. We studied whether 2HG measurements in AML patients correlate with the presence of IDH mutations and whether diagnostic or remission 2HG measurements predict survival. Patients and Methods: Serum samples from 223 previously untreated adults (≤ 60 years of age) with de novo AML from the Eastern Cooperative Oncology Group E1900 clinical trial (62 IDH mutated, 161 IDH wild-type) were analyzed for 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry (GC-MS). Results: Pretreatment 2HG levels ranged from 10 to 30000 ng/ml and were significantly elevated in IDH-mutant samples (median 3004.1 ng/ml), as compared to the wild-type cohort (median 61.2 ng/ml) (p < 0.0005). 2HG levels did not differ among the specific IDH1 or IDH2 allelic variants. In ROC analysis, a discriminatory level of 700 ng/ml segregated patients with and without IDH mutations with 86.9% sensitivity and 90.7% specificity. On repeat mutational analysis of 13 IDH wild-type samples with 2HG levels >700 ng/ml, IDH mutations were identified in nine samples, most often at low allele burden. IDH mutant patients with 2HG levels ≤ 200 ng/ml at complete remission experienced improved overall survival compared to those with higher 2HG levels (HR 3.5, p = 0.02) (Figure 1). Conclusion: We establish a firm association between IDH mutations and elevated serum 2HG concentration in AML. These data confirm that peripheral blood measurement of an oncometabolite provides useful diagnostic and prognostic information for cancer therapy, and furthermore can inform patient selection of IDH mutant targeted therapies. Disclosures: Levine: Agios Pharmaceuticals: Research Funding. Straley:Agios Pharmaceuticals: Employment. Yen:Agios Pharmaceuticals: Employment. Agresta:Agios Pharmaceuticals: Employment. Carroll:Agios Pharmaceuticals: Research Funding.

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Analysis of ASXL1, IDH1, IDH2, c-CBL, and WT1 Mutations in De Novo Acute Myeloid Leukaemia

Blood ◽

10.1182/blood.v118.21.1450.1450 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1450-1450

Author(s):

Mariam Ibañez ◽

Esperanza Such ◽

Jose Cervera ◽

Irene Luna ◽

Sandra Dolz ◽

...

Keyword(s):

De Novo ◽

Prognostic Impact ◽

Significant Implication ◽

Wild Type ◽

Idh Mutations ◽

Flt3 Mutations ◽

Exon 4 ◽

De Novo Aml ◽

Cebpa Mutations ◽

Acute Myeloid

Abstract Abstract 1450 The clinical relevance and prognostic implications of some recently identified mutations in acute myeloid leukemia (AML) is not yet well established. Among them, we have selected to be analyzed those affecting the following genes: Additional Sex Combs-Like 1 (ASXL1), Isocitrate Dehydrogenase (IDH1 and IDH2), Casitas B-lineage Lymphoma (c-CBL), and Wilms Tumor 1 (WT1). They have been previously reported with a variable incidence: ASXL1 mutations in 10.8% patients with normal karyotype (NK), IDH1 and IDH2 mutations in 8 – 33% of de novo AML, c-CBL mutations in 2% of de novo AML, and WT1 mutations in 5–12% of de novo AML patients. In order to know the incidence and prognostic impact of these mutations and their possible cooperative role in leukemogenesis, we have screened for ASXL1, IDH1, IDH2, c-CBL, WT1, FLT3, NPM1 and CEBPa, mutations in a cohort of de novo AML patients from a single centre. We studied 174 de novo AML patients [98M/76F; median age: 62 yr. (range: 16 – 88); favourable (n= 13), intermediate (n= 86) and high (n= 51) cytogenetic risk classification by the MRC group]. DNA was isolated from bone marrow samples obtained at diagnosis. In order to determine cooperating mutations, we developed a new combination of high-resolution melting (HRM) assays on a LightCycler® 480 and lastly direct sequencing, to detect somatic mutations for ASXL1 (exon 12), IDH1 (exon 4), IDH2 (exon 4), WT1 (exons 7, 8 and 9) and c-CBL (exons 8 and 9). All mutations reported in this study were confirmed al least twice. FLT3 (ITD and D835Y), NPM1 (exon 12) and CEBPa were performed as described previously by standard methods. Sequence analysis was checked by its corresponding GeneBank Accession Number. The number of patients found to carry mutations in our series was: 16 patients with ASXL1 mutations (9.2%), 16 patients with IDH mutations (2.9% had a IDH1R132, 12.6% the SNP rs11554137 and 6.3% IDH2R140), 5 patients with WT1 mutations (2.9%), 37 patients with FLT3 mutations (21.3%), 44 patients with NPM1 mutations (25,3%) and 8 patients with CEBPa mutations (4.6%). No mutations where found in c-CBL. We could not found a pattern of cooperating mutations in the studied group of genes. WT1, FLT3 and NPM1 were associated with leukocyte count >30 × 109/L at diagnosis (80% vs. 31% for WT1, P =0,022; 68% vs. 22% for FLT3, P= 0.001; and 50% vs. 24% for NPM1, P= 0.002; in mutated vs. wild-type patients, respectively). WT1 was also associated with a platelet count > 50 × 109/L at diagnosis (100% vs. 57% in mutated vs. wild-type patients, respectively; P =0,048). Besides, FLT3 and NPM1 mutations were more frequent in the intermediate cytogenetic risk group (82% and 74%; P =0.004 and P =0.047; respectively). ASXL1 and IDH mutations were not correlated with any of the clinical and biological features studied. In univariate analysis, only age and cytogenetics had an impact on overall survival (OS, median of 12mo vs. 3mo, for patients < and ≥65 yr., P <0.001 and 24mo, 11mo and 3mo for favourable, intermediate and high risk, P =0.005). Mutational status of ASXL1, IDH1, IDH2, WT1, FLT3, NPM1 and CEBPa did not impact on outcome in the whole series. However, when the analysis was restricted to patients with intermediate cytogenetic risk, patients with FLT3 mutations had a shorter OS (19mo vs. 8mo, wild-type vs. mutated patients; P =0.047) and those with WT1 mutations showed a trend towards an inferior OS (11mo vs. 1mo, wild-type vs. mutated patients; P = 0.066). In multivariate analysis in patients with intermediate cytogenetic risk, the age [HR (95% CI) = 3.3 (1.9 − 5.9) P <0.001], and FLT3 status [HR (95% CI) = 2.2 (1.2–3.9) P =0.008] retained an independent adverse significance for OS. In terms of relapse free survival any of the variables showed a significant implication. To sum up, the incidence found for the studied genes was lower than the previously reported: ASXL1, 9.2%; IDH1R132, 2.9%; IDH2R140, 6.3%; WT1, 2.9%; and c-CBL, 0%. We were unable to find a pattern of cooperating mutations in the studied group of genes or any impact of these mutations on the outcome. Disclosures: No relevant conflicts of interest to declare.

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Mutant NPM1 is a Reliable marker of Minimal Residual leukemia in patients with Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v120.21.2484.2484 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2484-2484

Author(s):

Preetesh Jain ◽

Hagop M. Kantarjian ◽

Stefan Faderl ◽

Keyur P. Patel ◽

Guillermo Garcia Manero ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

De Novo ◽

Response Rates ◽

Analytical Sensitivity ◽

Newly Diagnosed ◽

Wild Type ◽

Npm1 Mutation ◽

De Novo Aml ◽

Minimal Residual

Abstract Abstract 2484 Background: Mutations in NPM1 (Nucleophosmin-1) have been described in about 35% of adult patients with de novo AML and 45–60 % of AML patients with a diploid karyotype. NPM1 mutations predict for achieving higher complete remission (CR) rates and better outcomes in AML. Few studies have reported on the reliability of mutated NPM1 as a marker for minimal residual disease (MRD) detection in patients with AML. Methods: We conducted a retrospective analysis of patients (n=360) with newly diagnosed AML treated at our institution between 2008 and 2012. The study was approved by the Institutional Review Board. NPM1 mutation status was determined from DNA from unsorted bone marrow (BM) aspirate samples by a PCR-based method at baseline, remission, and relapse. Genomic DNA from bone marrow samples was isolated using the Autopure extractor (QIAGEN/Gentra, Valencia, CA). Mutations in exon 12 of NPM1 were assessed by a DNA-based semi-quantitative polymerase chain reaction capillary electrophoresis (PCR-CE) assay with analytical sensitivity of approximately 2.5%. Results: Data on remission and relapse samples from 360 newly diagnosed and previously untreated patients with AML, with available NPM1 analysis on their BM at the time of initial diagnosis, was collected (see flow chart below). Median age was 60 years (range 21 – 81 years). 262 patients (72%) had de novo AML, and 98 (27%) secondary AML. Cytogenetics was diploid in 137 (38%) patients, t(8;21) in 17 (5%), inversion 16 in 26 (7%), deletion 5 alone in 27 (7.5%), del 7 and 5 in 26 (7%), deletion 7 alone in 21 (5.8%), trisomy 8 in 17 (5%) and miscellaneous in 89 (24.7%) patients, respectively. Overall, 60 (16.6%) patients including 46 of the 137 (33.5%) diploid patients had NPM1 mutation at baseline. Secondary leukemia was more common in the NPM1 wild type (30%) than in the NPM1 mutated (13%) category. When analysed by age, in patients < 60 years (n=175), OS (overall survival), EFS (event free survival) and response rates were significantly superior in NPM1 mutated subgroup (p=0.001, 0.007, 0.02 respectively), while among patients ≥ 60 years (n=185) EFS and response rates were significantly higher in the NPM1 mutated subgroup (p=0.008, 0.03 respectively). Among the patients with diploid cytogenetics who were younger than 60 years (n=60) OS, EFS and CR duration was significantly better in the NPM1 mutated subset (p=0.007, 0.007 and 0.02 respectively), while in those ≥60 years (n=77) there was no statistically significant difference in the outcomes for the NPM1 mutated and wild-type subsets. Among the 60 NPM1 mutated patients 54 (90%) including 41/46 (89%) of those with diploid cytogenetics achieved complete response (CR) or CR without platelet recovery. Thirty nine patients (including 30 with diploid karyotype) had available NPM1 status at the time of CR and all (100%) were negative for NPM1 mutation. Among the patients with mutated NPM1 at baseline who have achieved a NPM1 negative status at CR, 10/39 overall (25%) and 7/30 diploid (23%) patients relapsed. NPM1 status was available for 6 patients overall including 4 with diploid karyotype at the time of relapse. Among them, 5/6 overall (83%) and 3/4 diploid (75%) patients had mutated NPM1, while 1/6 overall (16%) and 1/4 diploid (25%) patients remained NPM1 wild type. This patient relapsed with extramedullary disease (leukemia cutis) without any BM involvement. Among the 300 patients (including 91 with diploid karyotype) with wild type NPM1 at diagnosis, none acquired a mutated NPM1 clone, either at CR or at the time of relapse. Conclusions: These data suggest that mutated NPM1 is a reliable and stable marker for the detection of MRD at the time of CR. Hence, NPM1 mutations can be used to detect MRD and their recurrence may predict pending relapse. Disclosures: Cortes: Celgene: Research Funding. Ravandi:Johnson and Johnson: Honoraria; Celgene: Research Funding.

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PPM1D Mutations Are Rare in De Novo and Therapy-Related Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-118566 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1472-1472

Author(s):

Mutlu Kartal-Kaess ◽

Tilmann Bochtler ◽

Bianca Kraft ◽

Michael Kirsch ◽

Bettina Maier ◽

...

Keyword(s):

Myeloid Leukemia ◽

Research Funding ◽

Mononuclear Cells ◽

De Novo ◽

Mutational Analysis ◽

Cytotoxic Therapy ◽

Myeloid Neoplasms ◽

Cytotoxic Treatment ◽

Equity Ownership ◽

De Novo Aml

Abstract Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in peripheral blood mononuclear cells (PBMC) of otherwise healthy adults that has been associated with increased risk of developing hematological malignancies. Clonal hematopoiesis has been shown to be present in patients with therapy-related myeloid neoplasms (therapy-related acute myeloid leukemia, t-AML) / therapy-related myelodysplastic syndrome, t-MDS) at the time of their primary cancer diagnosis and before exposure to treatment. Such clones expand under selective pressure from cytotoxic treatment for the primary cancer and can subsequently give rise to overt myeloid neoplasms. Somatic mutations in the gene encoding the TP53-inducible protein phosphatase Mg2+/Mn2+ 1D (PPM1D) were initially reported in PBMC of patients with solid tumors (breast, ovary, lung) and lymphoma. They are associated with older age and seem to reflect prior exposure to cytotoxic treatment. Moreover, the mutations, all of which are nonsense or frameshift mutations in exon 6, have been described as one of the most recurrent mutations in CHIP and to be frequent in t-MDS. Methods and results: To resolve this issue and to determine whether clones harboring PPM1D mutations that expand into CHIP after cytotoxic therapy for solid tumors drive leukemogenesis and might be useful as markers to identify patients at risk for t-MDS/t-AML development, we performed PPM1D mutational analysis in 87 patients with de novo AML and in 49 patients with t-AML. As mutations in TP53 as a representative DNA damage response gene are rare in de novo AML, we enriched our de novo AML patient cohort towards poor risk cases with complex karyotypes in order to increase the chance of identifying PPM1D mutations. Patients with core-binding factor AML were excluded from the analysis. Using the published frequency of 15% PPM1D mutations in t-MDS (Lindsley RC et al., N Engl J Med 2017;376(6):536-547) as surrogate for the expected frequency in t-AML, a minimum of 44 t-AML patients was determined to be required to allow for the detection of mutations of PPM1D in t-AML (Chi square with Fisher's exact test for independent groups, α-error 0.05, power 0.8). We performed focused mutational analysis by targeted Sanger sequencing of PPM1D exon 6 on DNA from bone marrow mononuclear cells or PBMC at diagnosis of de novo or t-AML samples taken prior to treatment initiation. Overall, only one patient with de novo AML (1/87, 1.2%) proved mutation positive. He was diagnosed with AML, FAB M4, at the age of 57 years and harbored a complex karyotype with marker chromosomes in the absence of a TP53 mutation. Unexpectedly, none of the 49 patients with t-AML harbored a mutation in PPM1D. Conclusion: In this study, we found that PPM1D mutations, which frequently occur in CHIP especially following prior cytotoxic therapy, are uncommon in AML, whether de novo or after prior cytotoxic therapy. These data are in contrast to previous observations on a high frequency of PPM1D mutations in t-MDS samples relative to primary MDS (15% vs. 3%, Lindsley RC et al., N Engl J Med 2017;376(6):536-547). Our findings suggest that while cytotoxic therapy favors the expansion of PPM1D-mutant CHIP clones, possibly even up to the development of t-MDS, mutations in PPM1D seem to be irrelevant for progression to t-AML. Disclosures Stoelzel: Neovii: Speakers Bureau. Rollig:Bayer: Research Funding; Janssen: Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Ehninger:GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding; Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership.

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The Prognostic Impact of the Diagnostic CD34+/CD38- Cell Burden and Expression of the Stem Cell Marker GPR56 after Stem Cell Transplantation Depends on the AML Origin

Blood ◽

10.1182/blood-2019-127544 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 323-323

Author(s):

Madlen Jentzsch ◽

Marius Bill ◽

Juliane Grimm ◽

Dominic Brauer ◽

Julia Schulz ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Solid Tumors ◽

Cell Transplantation ◽

Research Funding ◽

De Novo ◽

Prognostic Impact ◽

Expression Levels ◽

Rheumatologic Diseases ◽

De Novo Aml

Introduction: Acute myeloid leukemia (AML) developing secondary after other hematologic diseases, or therapy related after cytotoxic treatment for solid tumors or rheumatologic diseases (s/tAML) is clinically, genetically & prognostically distinct from de novo diseases. Data indicate that s/tAML patients (pts) have inferior outcome compared to de novo cases after chemotherapy & therefore often require consolidation therapy using allogeneic stem cell transplantation (HSCT). Leukemic stem cells (LSC) initiate & maintain AML. They are also believed to exist within the CD34+/CD38- &/or high GPR56 expressing bone marrow (BM) population, which have been shown to impact adversely on outcome. The prognostic impact of LSC markers in de novovs s/tAML after HSCT with non-myeloablative conditioning intensity - where the therapeutic approach also relies on immunological graft-versus-leukemia effects - is unknown. Methods: We analyzed 379 AML pts who received an allogeneic peripheral blood HSCT in complete remission (CR, 82%) or CR with incomplete peripheral recovery (CRi, 18%) between 1999 & 2018 after non-myeloablative (3x30 mg/m2 Fludarabine & 2 Gy total body irradiation) conditioning. At diagnosis, cytogenetic & flow cytometric analyses were performed centrally. For pts with pre-treatment BM available the mutation status of CEBPA, NPM1 & presence of FLT3-ITD by fragment analyses as well as expression levels of GPR56 by qPCR were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated (mut) genes in myeloid malignancies on the MiSeq platform (Illumina). Median follow up after HSCT was 3.7 years. Results: 229 pts (60%) had de novo & 150 pts (40%) had AML secondary to myelodysplastic syndrome (MDS, n=82), myeloproliferative neoplasm (MPN, n=22) or MDS/MPN (n=10), or therapy related after Non-Hodgkin lymphoma (n=9), solid tumors (n=25) or rheumatologic diseases (n=2). At diagnosis, s/tAML pts had lower white blood counts (P=.03), lower blasts in BM (P<.001) or blood (P=.007) & a higher BM CD34+/CD38- cell burden (P=.01) & GPR56 expression (P=.04). They also had worse European LeukemiaNet risk (P=.007), were less likely to have a normal karyotype by trend (P=.06), to have a core binding factor AML (P=.02), to be NPM1mut (P=.003), DNMT3Amut (P=.03) & to harbor a FLT3-ITD (P=.002) but more likely to be JAK2mut (P<.001). Comparing pts with s/tAML vsde novo AML, there was no significant different cumulative incidence of relapse (CIR, P=.85) or overall survival (OS, P=.29). Next, we evaluated the prognostic impact of the LSC-associated populations in pts with de novo or s/tAML separately. In pts with de novo AML, we observed a significantly higher CIR & shorter OS for pts harboring a high CD34+/CD38- cell burden (high vs low, 6% cut, P=.006 [Fig. 1A] & P=.003) & a higher CIR but not significantly different OS for pts with a low GPR56 expression (high vs low, median cut, P=.03 [Fig. 1B] & P=.95). Combining both parameters, we observed a stepwise higher CIR & shorter OS for pts with low expression of both variables vs pts with a low CD34+/CD38- cell burden but high GPR56 expression vs pts with a high CD34+/CD38-cell burden (P=.003 [Fig. 1C] & P=.05). In contrast, in pts with s/tAML, there was no prognostic significance of the CD34+/CD38- cell burden (CIR P=.38 [Fig. 1D] & OS P=.95), the GPR56 expression (CIR P=.64 [Fig. 1E] & OS P=.82) & both markers combined (CIR P=.57 [Fig. 1F] & OS P=.98). Also in multivariate analyses, the combination of both markers significantly impacted CIR (Hazard ratio 2.49, P<.001 after adjustment for donor type) & was the only significant factor for OS (Odds Ratio 0.68, P=.04) in de novo AML but not in s/tAML. Conclusion: While there was no significantly different CIR or OS in s/tAML compared to de novo AML pts undergoing non-myeloablative HSCT we observed a significant impact on outcome for the known LSC-associated prognosticators CD34+/CD38- cell burden & GPR56 expression levels at diagnosis only in de novo AML pts. Different underlying disease biology & possibly different LSC-associated populations may be relevant for disease reoccurrence in s/tAML. Figure Disclosures Jentzsch: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Platzbecker:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding.

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Glutaminase Inhibition Selectively Slows the Growth of Primary Acute Myeloid Leukemia (AML) Cells with Isocitrate Dehydrogenase (IDH) Mutations.

Blood ◽

10.1182/blood.v120.21.2624.2624 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2624-2624

Author(s):

Ashkan Emadi ◽

Sung Ah Jun ◽

Takashi Tsukamoto ◽

Amir T Fathi ◽

Mark D. Minden ◽

...

Keyword(s):

Small Molecule ◽

De Novo ◽

Conflicts Of Interest ◽

Myeloproliferative Neoplasms ◽

Growth Curves ◽

Primary Source ◽

Wild Type ◽

Research Groups ◽

Idh Mutations ◽

Significant Difference

Abstract Abstract 2624 Introduction: The incidence of mutations in IDH1 and IDH2 (mIDH) in de novo AML is 10–15%. These mutations are enriched in normal karyotype AML, and their presence carries an unfavorable prognostic factor, according to some studies. Furthermore, mutations in IDH1/2 genes have been identified in approximately 5% of myelodysplastic syndromes and 10% of myeloproliferative neoplasms. Although wild-type IDH in cytosol and mitochondria catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) with the production of NADPH, altered amino acids in mIDH1 and mIDH2 reside in the catalytic pocket and result in a neoenzymatic activity, converting α-KG to 2-hydroxyglutarate with the consumption of NADPH. The primary source for α-KG for these cells is glutamine, which is first converted to glutamate by glutaminase and subsequently to α-KG. Because glutamine is the primary source for α-KG, we hypothesized that cells with mIDH are in essence addicted to glutamine via glutaminase activity, such that depletion of glutamine or interruption of its metabolism would be deleterious to cellular metabolism and survival. The aim of this study was to investigate whether inhibition of glutaminase by a small molecule, BPTES (bis-2-[5-(phenylacetamido)-1,3,4-thiadiazol-2-yl]ethyl sulfide), could selectively kill primary AML cells with mIDH1, but not IDH-wild type AML cells. We and others have previously demonstrated that BPTES inhibits glutaminase effectively. Method: Two independent sets of experiments were performed by two separate research groups. One group was blinded to mutant versus wild type IDH status. The other group was blinded to drug identity including solvent versus BPTES and to various BPTES concentrations. Primary AML cells from patients were cultured in RPMI-1640 medium with 20% fetal bovine serum, 20% 5637 cell-conditioned medium and 1% antibiotics with no drug, DMSO control (0.1% concentration) and 20 or 40 microM BPTES. Cells were counted manually on days 2, 4 and 6. Growth curves were generated for viable cells as assessed by trypan blue exclusion. Experiments were performed in triplicates. Results: Growth curves of primary AML cells (with mutation status indicated) with no drug and with DMSO or BPTES (20 or 40 microM) are shown in Figure 1. Cells #2, #3, #5 and #10 carried IDH1 mutations. Cells #4 and #9 were wild type. On day 4, there was approximately a two-fold decrease in the growth of all IDH-mutant AML cells exposed to 20 microM BPTES compared to DMSO. No significant difference in activity was observed between 20 and 40 microM of BPTES. There was no difference in cell growth between exposure to no drug and to DMSO. The growth of wild type AML cells was not significantly affected by the glutaminase inhibitor. Results were consistent between the two research groups. Conclusions: Although IDH mutations are frequently found in AML, a therapeutic strategy targeted at these mutations has not been reported. To the best of our knowledge, this is the first report of a targeted approach to the treatment of IDH-mutant AML. We found that inhibition of glutaminase by a small molecule, BPTES, preferentially slows the growth of primary AML cells with mutant IDH1 versus those AML cells with wild type IDH. Further investigation in xenograft models and pharmacologic studies are ongoing. Disclosures: No relevant conflicts of interest to declare.

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Efficacy of Single-Agent Decitabine in Relapsed and Primary Refractory (rel/ref) Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v126.23.2518.2518 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2518-2518

Author(s):

Andrew Hantel ◽

Niloufer Khan ◽

Richard A. Larson ◽

Lucy A. Godley ◽

Michael J. Thirman ◽

...

Keyword(s):

Board Of Directors ◽

Genetic Risk ◽

Research Funding ◽

De Novo ◽

Median Number ◽

Advisory Committees ◽

Secondary Aml ◽

Induction Regimen ◽

De Novo Aml ◽

Wbc Count

Abstract Introduction Improving therapy for rel/ref AML remains a challenge. Decitabine, a DNA methyl-transferase inhibitor, initially showed promise in AML as a 5-day, first-line induction regimen and more recently as a 10-day regimen in older and unfit patients (1). However, little is known about the activity of decitabine in the rel/ref patient population despite increased use. Therefore, we sought to analyze the outcomes of these pts treated at our institution. Methods To obtain data regarding decitabine efficacy in rel/ref AML, we performed a retrospective analysis of outcomes following decitabine treatment in 34 adult pts treated at The University of Chicago from January 2009 to June 2014. Permission to access patient charts was granted by the medical centerÕs Institutional Review Board. AML was defined by WHO criteria, genetic risk grouping and complete remission (CR) was according to ELN classification; PR was defined as >50% decrease in bone marrow blasts and normalization of blood counts. Rel/ref AML was defined as either having had a prior CR with recurrence of disease or having received a prior induction regimen (1-2 cycles) without CR. Results Median pt age was 62 yrs (range, 18-81) and 60% were male. Median Charlson comorbidity index (CCI) was 5 (range, 0-8); 29% had ECOG performance status 0-1 and 71% had >2. 21 pts (62%) had de novo AML (7 with myelodysplasia-related changes), 3 (9%) had therapy-related myeloid neoplasm (t-MN), and 10 (29%) had secondary AML after myelodysplastic syndrome. 6% were in the ELN favorable genetic group, 3% intermediate-I, 18% intermediate-II, and 67% adverse; 2 cases were unevaluable. The median number of prior treatment regimens was three. 9% had received prior azacitidine, 85% had received prior HiDAC, and 38% had a prior allogeneic stem cell transplant (SCT). 34 pts received a total of 71 cycles of decitabine, 20 mg/m2 daily, in 5 or 10-day cycles every 28 days. All patients received 10-day courses, 91% had an initial 10-day course, and 74% had only 10-day courses. The median number of cycles per pt was 2; 59% received >1 cycle. 7 (21%) achieved CR and 4 (12%) had a partial response (PR), for an overall response rate (OR) of 33%. Responses occurred in 24% of pts with de novo AML, 66% with t-MN, and 50% with secondary AML. Intermediate and adverse group pts had OR of 14% and 39%, respectively. All pts achieving CR did so after 1 cycle; PR required a median of 3 cycles. Pts who achieved CR or PR had a significantly lower pretreatment WBC count (median, 9.5 vs 49.5 x 103/µL in non-responders; p=0.015) and blast percentage (44 vs 59.4; p=0.035) than those who did not. Pts with secondary AML or t-MN had a higher probability of OR compared to those with de novo AML (54 vs 23%; p=0.042). Median overall survival (OS) of all pts was 256 days; prior SCT was associated with reduced OS (p=0.017). When comparing de novo to secondary AML & t-MN, 1-year OS was not significantly different (Figure 1). Responders had a significantly longer OS (median, 622 days vs 278 days for non-responders; p=0.012). Age, race, CCI, ECOG PS, genetic risk group, prior HiDAC, dysplasia, azacitidine, and number of prior treatments did not impact OR or OS. 16 (47%) pts proceeded to SCT. During treatment, 70% had a grade 3-4 non-hematologic toxicity (based on NCI CTACE v4.0); the most common was fatigue. The median number of hospitalizations for complications per patient was 2 (range, 0-7). Causes of hospitalization were febrile neutropenia (40%), infection (22%), cytopenias (18%), rash (6%), acute kidney injury (6%), and 8% were for other causes. Conclusion Decitabine treatment of 34 adults with rel/ref AML resulted in an OR of 33% (21% CR) and allowed nearly one-half of these pts to proceed to SCT. All pts achieving CR did so after 1 cycle. Responding pts had improved OS over those without response (p=0.012). Interestingly, secondary AML or t-MN were 7.8 times more likely to achieve a response compared to de novo AML (p=0.046); lower WBC count and marrow blast percentage also correlated with higher OR. Further delineation of molecular subsets associated with response to decitabine should be evaluated in a larger prospective trial in this high-risk AML population. Citation 1. Blum KA, et al. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br J of Haem. Jul 2010;150(2):189-195. Figure 1. Figure 1. Disclosures Off Label Use: Decitabine is indicated for treatment of MDS but is often used to treat newly diagnosed or relapsed/refractory AML. In this study we analyzed results of patients with AML who were treated with decitabine in the relapsed/refractory setting.. Thirman:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Gilead: Research Funding; Merck: Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy; Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees.

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Sequential Intensified Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with High-Risk AML in Complete Remission: A Survey from the ALWP of the EBMT

Blood ◽

10.1182/blood.v126.23.3105.3105 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3105-3105

Author(s):

Florent Malard ◽

Myriam Labopin ◽

Gernot Stuhler ◽

Johanna Tischer ◽

Joerg Thomas Bittenbring ◽

...

Keyword(s):

Multivariate Analysis ◽

High Risk ◽

Research Funding ◽

Antithymocyte Globulin ◽

De Novo ◽

Conditioning Regimen ◽

Secondary Aml ◽

Off Label ◽

Advisory Boards ◽

De Novo Aml

Abstract Introduction. Allogeneic hematopoietic cell transplant (HCT) is an established treatment modality that is potentially curative for many patients with acute myeloid leukemia (AML). The development of reduced intensity conditioning (RIC) allows performing HCT in elderly and/or in heavily pretreated patients and in those with comorbidities precluding the use of standard myeloablative conditioning. Post-transplant relapse remains a challenge after RIC, particularly in patients with adverse prognosis factors.The so-called "sequential" transplant approach (e.g. FLAMSA regimen combining both intensive chemotherapy and RIC HCT within the same procedure) initially developed in patients with refractory AML, could be a promising strategy to improve disease control and decrease the risk of relapse in high-risk AML patients in complete remission (CR). Patients and methods. In the current study we analyzed transplantation outcomes in a cohort of 411 adults AML patients in CR at time of transplant, treated between 2002 and 2013. Patients received a "sequential" conditioning regimen based on Fludarabine 30 mg/m2/d, high-dose aracytine 1-2 g/m2/d, amsacrine 100 mg/m2/d for 5 days and after a 3 days rest, total body irradiation (TBI) 4Gy, cyclophosphamide 50-120 mg/kg, and antithymocyte globulin (ATG) for 2 to 3 days (TBI group, n=269 [65%]). In 142 (35%) patients, TBI was substituted by IV Busulfan 3.2 mg/kg/d for 2 days, or orally equivalent dose (Bu group). 323 patients (79%) had de-novo AML and 88 (21%) had a secondary AML (with prior myelodysplastic syndrome). At time of transplant, 300 (73%) patients were in CR1 and 111 (27%) in CR2. Cytogenetic study in de novo AML was favorable in 19 patients (6%), intermediate in 102 (32%) and poor in 41 (13%). Cytogenetic data were missing in 161 (50%). 104 (25%) patients received matched related donors (MRD) and 307 (75%) unrelated donor (URD) HCT. Majority of patients (94%) received mobilized peripheral blood stem cells graft. Results. Median follow-up of surviving patients was 28 months and median age at transplant was 54 years (18-76). ANC>500/μL was achieved at a median of 17 (range, 9-74) days after HCT. Sixteen patients (4%) failed to engraft. Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 22% (95%CI, 18-26%) and 22% (95%CI, 18-27%), respectively. The Kaplan-Meier estimate of overall (OS) and leukemia-free survival (LFS) at 2 years were 59% (95%CI, 54-65%) and 56% (95%CI, 50-61%), respectively. Acute GVHD (grade II-IV) occurred in 109 (28%) patients. The 2-year cumulative incidence of chronic GVHD was 31% (95%CI, 26-36), extensive in 17% (95%CI, 12-21). Two years RI, NRM, LFS and OS in TBI vs. Bu patients were 21.8% vs 21.7% (p=0.69), 29.4% vs 18.3% (p=0.008), 48.8% vs 59.6% (p=0.045) and 51.2% vs 64.0% (p=0.013), respectively. In multivariate analysis adjusted for variable with different distribution between Bu and TBI groups, the type of conditioning (TBI vs Bu) has no impact on RI, NRM, LFS and OS. Age over 55 at transplant was an independent adverse prognostic factor in multivariate analysis for NRM (hazard ratio (HR: 1.61, 95% CI: 1.00-2.61, p=0.05)), LFS (HR: 1.39, 95% CI: 1.00-1.92, p=0.05) and OS (HR: 1.55, 95% CI: 1.11-2.18, p=0.01). Being treated in an experienced center (defined as having including 10 or more transplants in the study) was associated with a significant lower RI (HR: 0.84, 95% CI: 0.75-0.93, p=0.001) and better LFS (HR: 0.91, 95% CI: 0.84-0.98, p=0.01) and OS (HR: 0.91, 95% CI: 0.84-0.98, p=0.02). Finally, transplantation from an URD was associated with a significant increase in NRM (HR: 2.11, 95% CI: 1.14-3.91, p=0.02). Of note, CR1 vs. CR2 and de novo vs. secondary AML had no impact on patients' outcome. Conclusions. These results in a rather large cohort of patients with AML suggest that a FLAMSA "sequential" regimen provided an efficient disease control in high-risk AML patients including in CR2 and secondary AML. Furthermore Busulfan and TBI based FLAMSA "sequential" regimens provide a similar outcome. These results should be confirmed in a multicenter well design randomized study. Disclosures Off Label Use: off-label drug use: antithymocyte globulin (ATG) for allo-SCT conditioning. Tischer:Sanofi-Aventis: Other: advisory board. Schmid:Neovii: Consultancy; Janssen Cilag: Other: Travel grand. Mayer:Janssen: Research Funding. Hallek:Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding.

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KIT D816 Mutated / CBF-Negative Acute Myeloid Leukemia (AML): A New Poor-Risk Subtype Associated with Systemic Mastocytosis (SM-AML)

Blood ◽

10.1182/blood-2018-99-115895 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1535-1535

Author(s):

Mohamad Jawhar ◽

Konstanze Döhner ◽

Sebastian Kreil ◽

Juliana Schwaab ◽

Khalid Shoumariyeh ◽

...

Keyword(s):

Research Funding ◽

De Novo ◽

Systemic Mastocytosis ◽

Response To Treatment ◽

Treatment Modalities ◽

Molecular Characteristics ◽

Molecular Analyses ◽

Poor Risk ◽

Myeloid Neoplasm ◽

De Novo Aml

Abstract Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is the most common subtype of advanced SM (advSM), diagnosed in up to 80% of patients. The AHN is most frequently diagnosed as a myeloid neoplasm, e.g., SM-MDS/MPNu or SM-CMML. Acquired mutations in KIT (usually KIT D816, KIT D816mut) are detectable in >90% of patients. The basis for the SM-AHN phenotype is usually the multi-lineage involvement, e.g. monocytes, eosinophils and other non-mast cell lineages, of KIT mutations. Core binding factor (CBF) positive AML (CBFpos AML) represents a distinct subtype and is identified in 5-8% of all AMLs. KIT mutations, most frequently KITD816mut, are detectable in up to 45% of CBFpos AML patients and are associated with an adverse prognosis. There is, however, only little information on KIT D816mut/CBFneg AML. We therefore evaluated a) clinical and molecular characteristics, b) response to treatment and, c) survival and prognostic factors in 40 KIT D816mut/CBFneg patients with histologically proven SM and associated AML (SM-AML), collected at 4 centers of the European Competence Network on Mastocytosis (ECNM). Molecular analyses (n=32) revealed at least one additional somatic mutation (median, n=3) apart from KIT D816, most frequently SRSF2 (n=12, 38%), RUNX1 (n=11, 34%), TET2 (n=11, 34%), ASXL1 (n=10, 31%), or NPM1 (n=7, 22%). At least one mutation in SRSF2, ASXL1 or, RUNX1 (S/A/Rpos) was identified in 21/32 (66%) patients. At diagnosis of SM-AML 21/40 (52%) patients had an aberrant karyotype. Secondary AML evolved in 29/40 (73%) patients from SM ± associated myeloid neoplasm and longitudinal molecular analyses revealed acquisition of new somatic mutations (TP53, n=2; NPM1, n=1; RUNX1, n=1, ASXL1, n=1; BCOR, n=1; IDH1/2, n=1) and/or karyotype evolution in 15/16 (94%) patients at the time of SM-AML. Thirty-one of 40 (78%) patients were treated with intensive chemotherapy (ICT) with a complete response (CR) rate of 40%. Allogeneic stem cell transplantation (SCT) was performed in 12/40 (30%) patients with durable CR in 6/12 (50%) patients. S/A/Rpos and/or the presence of a poor-risk karyotype were adverse predictive markers for response to treatment. To further investigate whether KITD816mut/CBFneg AMLdefines a distinct AML subtype associated with SM, two independent AML databases (AMLdatabases) were retrospectively screened and 69 KIT D816mut/CBFneg AML patients identified. The comparison between KIT D816mut/CBFneg SM-AML from ECNM (n=40) centers with KIT D816mut/CBFneg AMLdatabases(n=69) revealed remarkable similarities: a) a high KIT D816 variant allele frequency (VAF) (median 34% vs. 29%), b) with the exception of SRSF2 (38 vs. 18%), a highly similar mutation landscape, rather comparable to that of advSM (Jawhar et al., Blood 2017) than to that of de novo AML, c) in contrast to de novo AML, a low frequency of FLT3 mutations (3 vs. 7%), and d) a high frequency of an aberrant karyotype (52 vs. 42%). The median overall survival (OS) of 40 KIT D816mut/CBFneg SM-AML and 17 evaluable KIT D816mut/CBFneg AMLdatabases was 5.4 (95% confidence interval, CI [1.7-9.1]) and 26.4 (95% CI [0-61.0]) (P=0.015) months, respectively (Figure 1). However, if only the patients with ICT ± allogeneic SCT were compared, median OS between the two groupswas not different (16.7 vs. 26.4 months, P=0.4). In multivariate analyses, S/A/Rpos and a poor-risk karyotype remained the only independent poor-risk factors with regard to OS. These results were independent of treatment modalities. We conclude that KIT D816mut/CBFneg AML is a new poor-risk subtype associated with SM (SM-AML). The remarkable clinical, genetic and prognostic similarities between SM-AML and AMLdatabases suggest that a significant proportion of the AMLdatabases patients may in fact have SM-AML. We therefore strongly recommend to determine serum tryptase and KIT D816 mutation status in all AML patients, and to perform bone marrow histology in KIT D816mut patients. These simple diagnostic measures would allow reclassification to SM-AML and inclusion of KIT inhibitors in established treatment modalities of AML. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Döhner:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Jazz: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding. Sperr:Novartis: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria. Valent:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Reiter:Incyte: Consultancy, Honoraria.

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Differential Prognostic Impact of IDH1 and IDH2 Mutations in Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood-2021-150786 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3684-3684

Author(s):

Connor M. Walsh ◽

Anthony Hunter ◽

Terra Lasho ◽

Christy Finke ◽

Rami S. Komrokji ◽

...

Keyword(s):

Board Of Directors ◽

Mayo Clinic ◽

Research Funding ◽

Prognostic Impact ◽

Wild Type ◽

Advisory Committees ◽

Durable Response ◽

Oncology Research ◽

Idh Mutations ◽

Idh1 Mutations

Abstract Introduction: Mutations involving isocitrate dehydrogenase 1/2 (IDH) are known oncogenic drivers in hematological malignancies, conferring neomorphic enzymatic activity to IDH 1/2, resulting in the oncometabolite, 2-hydroxyglutarae (2-HG). 2-HG in turn suppresses TET activity, making IDH and TET2 mutations synthetically lethal and almost mutually exclusive. The frequency of IDH mutations in CMML is <10% and their prognostic impact remains unclear. We carried out this study in a large database of molecularly annotated CMML patients to better define the clinical profile and prognostic impact of these mutations. Methods: After IRB approval, CMML patients from the Mayo Clinic, Minnesota and the Moffitt Cancer Center (MCC), Tampa, Florida, were included in the study. All patients had bone marrow (BM) biopsies with cytogenetics and molecular genetics done either at diagnosis, or at first referral. Clinical and mutational data were abstracted and retrospectively analyzed. Overall survival (OS) was calculated from date of CMML diagnosis to date of death/last follow, while AML-free survival (AML-FS) was calculated from date of CMML diagnosis to date of leukemic transformation (LT). Patients that had undergone allogeneic HCT were excluded from the study (n=3). Statistical analysis was carried out using the Blue Sky software. Results: Six hundred and forty four patients were included in the study (Mayo Clinic-357, MCC- 287), median age 71 years (range, 20-95 years), 67.8% being male. Forty-three (6.7%) patients had IDH mutations, 35 (82%) IDH2 and 8 (18%) IDH1; of which, 34 (97%) involved the IDH2R140 hotspot and 5 (62.5%) involved the IDH1R132 hotspot, respectively. The median variant allele fractions (VAF) for IDH1 mutations was 41% (range, 8-46%) and for IDH2 mutations was 46% (range, 7-70%). There were no significant demographic or clinical differences between IDH mutant and wild type CMML patients, with the exception that IDH mutant CMML patients were less likely to be thrombocytopenic (p=0.006), were less likely to have TET2 co-mutations (14% vs 53.2%; p<0.001) and were more likely to have SRSF2 co-mutations (69.8% VS 40.3%; p<0.001). Importantly there were no differences in proliferative or dysplastic subtypes (p=0.3), cytogenetic (p=0.12) and molecular risk stratifications (p=045). There were also no significant demographic or clinical differences between IDH1 vs IDH2 mutant CMML patients. Six (14%) IDH mutant CMML patients had TET2 co-mutations; 5 (83%) with IDH2R140Q (median VAF-28%;all male) and 1 (17%) with IDH1R132H (VAF-44%;female) (Figure 1). Five (11%) IDH2 mutant patients were treated with enasidenib (IDH2 inhibitor), none with a durable response, while none of the IDH1 mutant patients received targeted therapy. At last follow up (median 18 months), 337 (52%) deaths and 119 (18.5%) LT have been documented, with IDH mutant patients having a higher LT rate (30.2% vs 17.6%, p=0.04) compared to wildtype patients. The median OS of the entire cohort was 35 months, with no difference in OS between IDH mutant and wild type patients (34.5 vs 35 months, p=0.12), with IDH1 mutant patients having a shorter OS in comparison to IDH2 mutant patients (31 vs 37 months; p=0.005- Figure 1). IDH mutant CMML patients also had a shorter AML-FS in comparison to wild type patients (36.6 vs 210 months, p=0.005), with there being no differential impact on AML-FS of IDH1 vs IDH2 mutations (p=0.26, Figure 1). Conclusions: IDH mutations are infrequent in CMML (7%), with IDH2 mutations being more common than IDH1 mutations (80 vs 20%). IDH mutations co-occur very infrequently with TET2 mutations (14%), with IDH mutant patients being less likely to have thrombocytopenia and more likely to have SRSF2 co-mutations. IDH mutations negatively impacting AML-FS without a significant impact on OS. Prospective clinical trials testing the safety and efficacy of IDH1/2 inhibitors in CMML are much needed. Figure 1 Figure 1. Disclosures Komrokji: AbbVie: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Acceleron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Padron: BMS: Research Funding; Stemline: Honoraria; Taiho: Honoraria; Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria. Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding.

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Prognostic Impact of MYC Oncoprotein Expression on Survival Outcome in Secondary AML Patients

Blood ◽

10.1182/blood-2018-99-120048 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2756-2756

Author(s):

Seongseok Yun ◽

Rohit Sharma ◽

David A Sallman ◽

Nicole D. Vincelette ◽

Kendra L. Sweet ◽

...

Keyword(s):

Multivariate Analysis ◽

Research Funding ◽

Tp53 Mutation ◽

Somatic Mutations ◽

De Novo ◽

Chromosomal Abnormalities ◽

Survival Outcomes ◽

Prognostic Impact ◽

Poor Prognostic Factor ◽

De Novo Aml

Abstract INTRODUCTION: Treatment outcomes of secondary Acute Myeloid Leukemia (sAML) including AML with myelodysplasia related changes (AML-MRC) and therapy related AML (tAML) are dismal compared to de novo AML patients, where long term disease free survival (DFS) remains less than 40%. Studies in pediatric AML identified frequent MYC somatic mutation and gene amplification, and although MYC somatic mutations are rare in adult AML, a recent study showed de novo AML patients expressing high levels of the MYC oncoprotein have inferior survival outcomes versus low levels of MYC. Compared to other AML subtypes, AML-MRC patients were shown to have dynamic range of MYC protein expression, yet the clinical significance of MYC levels in these patients group is unknown. Here we report the prognostic impact of MYC protein levels on survival outcomes in AML-MRC patients. METHODS: Using Total Cancer Care (TCC) Moffitt Cancer Center (MCC) databases, we retrospectively identified histologically confirmed AML-MRC patients from 2011 to 2018. MYC protein expression was assessed by immunohistochemistry (IHC) staining. TP53 mutation was tested by 54 myeloid targeted gene sequencing. We used 5% as cut-off (calculated as MYC positive cells out of total counted blasts in the selected area with sheets of blasts) as previously reported (Ohanian et al. 2018). Clinical variables and disease-related prognostic factors including age, gender, cytogenetics and somatic mutations were characterized at the time of AML-MRC diagnosis and were annotated using descriptive statistics. The overall survival (OS) were estimated with the Kaplan-Meier method and compared using the log-rank test. All statistical analyses were performed using SPSS v24.0 and GraphPad Prism 7. RESULTS: A total of 132 AML-MRC patients were included in this study. The median age at AML-MRC diagnosis was 67 (22-86) years and 64% of patients were male (n=84). A total of 49% (n=65) patients had chromosome 17p deletion [del(17p)] based on cytogenetic analyses or/and fluorescence in situ hybridization (FISH) assays. A total of 42% (n=55) patients had TP53 mutation and 29% (n=38) patients had both del(17p) and TP53 mutation. Additional chromosomal abnormalities including deletion 5q, trisomy 8, deletion 7q, deletion 20q, and complex karyotypes were observed in 28% (n=37), 17% (n=23), 20% (n=27), 7% (n=9), and 31% (n=41) of patients, respectively. A total of 55% (n=73) of patients were treated with intensive chemotherapy, 18% (n=24) were treated with hypomethylating agents and 20% (n=27) patients underwent allogeneic stem cell transplant. A total of 39% (n=51) patients had high MYC expression and 61% (n=81) patients had low MYC expression. Notably, the median OS was significantly longer in low MYC patients compared to high MYC patients (median OS 33.1 vs. 15.2 months, p=0.0222). Further, when considering only TP53 wild type patients without del(17p), low MYC patients had even longer median OS (median OS 58.6 vs. 17.7 months, p=0.0224). In AML-MRC patients with either TP53 mutation and/or del(17p), the median OS was not statistically different between low and high MYC groups (median OS 21.0 vs. 15.1 months, p=0.3101). Finally, multivariate analysis including TP53 mutation status, del(17p), transplantation status, gender, and age, revealed that high MYC expression is a poor prognostic factor (HR 2.08, 95%CI=1.136-3.807, p=0.018). CONCLUSIONS: AML-MRC patients with high MYC expression have inferior OS outcome compared to low MYC patients. Further, multivariate analysis established that high MYC level is a poor prognostic factor in AML-MRC patients. These findings warrant further study of the prognostic impact of MYC expression in addition to MYC gene amplification or/and somatic mutations in AML patients, with larger numbers of patients having other somatic mutations or chromosomal abnormalities that have adverse outcomes. Figure. Figure. Disclosures Sallman: Celgene: Research Funding, Speakers Bureau. Sweet:BMS: Honoraria; Jazz: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; Astellas: Consultancy; Agios: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; Phizer: Consultancy. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. List:Celgene: Research Funding.

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