Clinical characteristics and outcomes in patients with acute myeloid leukemia with concurrent FLT3 ‐ITD and IDH mutations

Cancer ◽  
2020 ◽  
Author(s):  
Mahran Shoukier ◽  
Tapan Kadia ◽  
Marina Konopleva ◽  
Ahmad S. Alotaibi ◽  
Mansour Alfayez ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Characteristics ◽  
Idh Mutations ◽  
Acute Myeloid

scholarly journals Isocitrate dehydrogenase inhibitors in acute myeloid leukemia

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Xiaoyan Liu ◽  
Yuping Gong
Keyword(s):  
Acute Myeloid Leukemia ◽  
Isocitrate Dehydrogenase ◽  
Myeloid Leukemia ◽  
Acquired Resistance ◽  
Tca Cycle ◽  
Idh Mutation ◽  
Hematopoietic Stem ◽  
Idh Mutations ◽  
Key Enzyme ◽  
Acute Myeloid

Abstract Isocitrate dehydrogenase (IDH) is a key enzyme involved in the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle. IDH mutation produces a neomorphic enzyme, which can lead to the abnormal accumulation of R-2-HG and promotes leukemogenesis. IDH mutation occurs in 20% of acute myeloid leukemia (AML) patients, mainly including IDH1 R132, IDH2 R140, and IDH2 R172. Different mutant isoforms have different prognostic values. In recent years, IDH inhibitors have shown good clinical response in AML patients. Hence, enasidenib and ivosidenib, the IDH2 and IDH1 inhibitors developed by Agios Pharmaceuticals, have been approved by the Food and Drug Administration on 1 August 2017 and 20 July 2018 for the treatment of adult relapsed or refractory (R/R) AML with IDH2 and IDH1 mutations, respectively. IDH inhibitor monotherapy for R/R AML is efficacious and safe; however, there are problems, such as primary or acquired resistance. Clinical trials of IDH inhibitors combined with hypomethylating agents or standard chemotherapy for the treatment of R/R AML or newly diagnosed AML, as well as in post hematopoietic stem cell transplantation as maintenance therapy, are ongoing. This article summarizes the use of IDH inhibitors in AML with IDH mutations.

Clinical Characteristics and Prognostic Implications of NPM1 Mutations in Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2368-2368
Author(s):  
Tatsuya Suzuki ◽  
Hitoshi Kiyoi ◽  
Kazutaka Ozeki ◽  
Akihiro Tomita ◽  
Ritsuro Suzuki ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Characteristics ◽  
Sequential Analysis ◽  
Normal Karyotype ◽  
Npm1 Mutation ◽  
Distinct Subgroup ◽  
Paired Samples ◽  
Number Of Patients ◽  
Acute Myeloid

Abstract Nucleophosmin (NPM) is a nucleolar protein with multi-functions including centromere duplication, nuclear-cytoplasmic shuttling, ribosomal biogenesis, p53 stability. NPM1 mutations were found in a large number of patients with acute myeloid leukemia (AML) especially with normal karyotype. The mutations lead to the aberrant subcellular localization of NPM protein. However, their impacts on clinical outcome remain controversial. We screened the mutations of NPM1 in 257 AML patients and analyzed the clinical significance. NPM1 mutations were found in 64 of 257 patients (24.9%). Seven types of mutations, including four novel mutations, were identified. NPM1 mutations were associated with normal karyotype, FLT3 mutations (both FLT3-ITD and D835 mutation) but not with other gene alterations such as N-RAS, p53 mutations and partial tandem duplication of the MLL gene. In 190 patients except the M3 subgroup, who were treated according to the protocol of Japan Adult Leukemia Study Group, the multivariate analysis revealed that NPM1 mutation was a favorable factor for achieving complete remission, but significantly associated with relapse. A sequential analysis, using paired samples obtained at diagnosis and relapse in 39 patients, revealed that NPM1 mutations were lost at relapse in 2 of the seventeen patients who had NPM1 mutations at diagnosis and none of the patients, who did not have NPM1 mutations at diagnosis, gained NPM1 mutations at relapse. Our results suggest that NPM-mutated AML should be a distinct subgroup with specific clinical characteristics and outcome. Loss of NPM mutations at relapse implies that NPM mutation is not necessarily a primary genetic alteration and that these leukemic clones could be sensitive to chemotherapy.

Clinical Characteristics of JAK2 V617F Mutation Positive Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4508-4508
Author(s):  
Sarolta Nahajevszky ◽  
Hajnalka Andrikovics ◽  
Zoltan Matrai ◽  
Nora Lovas ◽  
Sandor Lueff ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Characteristics ◽  
De Novo ◽  
Age Of Onset ◽  
Jak2 V617f ◽  
Blastic Transformation ◽  
V617f Mutation ◽  
Acute Myeloid ◽  
Time Point

Abstract Chronic myeloproliferative diseases (CMPD) are clonal disorders of pluripotent hematopoietic stem cells. Acquired JAK2 V617F point mutation has recently been identified as disease causing activating genetic abnormality in classic BCR-ABL negative CMPD (80% of polycythemia vera, 35% of essential thrombocythemia and 50% of chronic idiopathic myelofibrosis cases). JAK2 V617F is rare in other myeloid stem cell disorders like acute myeloid leukemia, chronic myelomonocyter leukemia or myelodysplasia with reported frequency of 3–8%. Between January 2001 and December 2005 155 consecutive adult patients [87 females and 68 males, median age of onset was 49±14 (range 18–83) years] were diagnosed with AML in our institute. Peripheral blood or bone marrow samples drawn at the time point of diagnosis were analyzed for the presence of JAK2 V617F by allele-specific PCR. JAK2 V617F mutation was present in 5 patients (3 males and 2 females; 3.2%). 3 of the 5 patients had prior history of CMPD, while 2 patients were diagnosed with de novo AML. The clinical characteristics and laboratory features of JAK2 V617F positive patients are shown in Table 1. FLT3 internal tandem duplication, FLT3 tyrosine kinase domain mutations, AML1-ETO, CBFB-MYH, PML-RARA rearrangements or nucleophosmin mutations were not present at the time point of AML diagnosis. In the case of patient 1, thrombocytosis was present prior the diagnosis of AML, and bone marrow biopsy revealed grade 3 fibrosis at diagnosis of AML, suggesting the presence of an atypical CMPD with the coexistence of del(5q) MDS. Patient 2 had no remarkable disease in his previous medical history. Induction therapy resulted in complete hematological and cytogenetic remission with persistent JAK2 V617F positivity. 10 month later clinical features of CMPD (elevated white blood cell count, left shifted peripheral blood smear, hepatosplenomegaly) appeared. In conclusion, these two cases suggest that acute myeloid leukemia with JAK-2 V617F mutation in fact corresponds to the blastic transformation of a clinically atipical chronic myeloproliferative disorders. Clinical characteristics and laboratory features of JAK2 V617F positive patients Case Sex AML subtype Age of onset (years) FAB subtype Cytogenetic abnormality Therapy Overall Survival (months) 1 F de novo 52 M1 del(5q) DNR+ara-C, HDara-C 23 2 M de novo 65 M4 t(13;17) DNR+ara-C, HDara-C 12 3 F CMPD blastic transformation 65 M4 trisomy (1q) Supportive 18 4 M CMPD blastic transformation 70 M4 not available Supportive 3 5 M CMPD blastic transformation 71 M4 not available Supportive 6

Lack of Association of Mutations in IDH1, IDH2, DNMT3A with Outcome in Older Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents (± Histone Deacetylase Inhibitors).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2483-2483
Author(s):  
Farhad Ravandi ◽  
Keyur P. Patel ◽  
Rajyalakshmi Luthra ◽  
Sherry A. Pierce ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Histone Deacetylase ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hypomethylating Agents ◽  
Idh Mutations ◽  
Acute Myeloid

Abstract Abstract 2483 Background: Mutations of several genes believed to be important in the methylation apparatus of the cell have been recently described in patients with acute myeloid leukemia (AML) but their presence has not been correlated with a worse or better outcome using hypomethylating agents. Methods: We evaluated the association of mutations in IDH1, IDH2, DNMT3A, and EZH2 with the outcome [complete response (CR) rate, event free survival (EFS) and overall survival (OS)] among patients older than 60 with AML (≥ 20% blasts) treated with hypomethylating agents as their first line of treatment. TET2 mutations were not evaluated due to lack of available material. Results: Among the 68 patients (median age 72 years; range, 60 – 83) with available data, 11 patients (16%) had IDH1 or IDH2 mutations (mutually exclusive) and 10 patients (15%) had DNMT3A mutations with 5 patients (7%) having both IDH and DNMT3A mutations. Cytogenetics was diploid in 19 (28%), abnormal chromosome 5/7 and/or complex in 27 (40%), trisomy 8 in 5 (7%), miscellaneous in 14 (21%), and insufficient in 3 (4%). Presence of IDH mutations was associated with a diploid karyotype and the presence of NPM1 mutations (p=.03 and p=.02, respectively) but not with FLT3- ITD or RAS mutations (present in 7 and 4 patients, respectively). DNMT3A mutations were not associated with any specific karyotype or with the presence of NPM1, FLT3-ITD, or RAS mutations. None of the 68 patients had EZH2 mutations. All patients were treated with hypomethylating agents [decitabine in 39 (57%) and 5-azacytidine in 29 (43%)] with 42 patients (62%) receiving concomitant histone deacetylase inhibitor therapy (SAHA or valproic acid). Overall, 17 patients (25%) achieved CR; the presence of IDH or DNMT3A mutations or both was not associated with achievement of CR. With a median duration of follow-up of 60 months, the median EFS is 3.3 months (range, 0.25 – 3.75 months) and the median overall survival is 6 months (range, 0.25 – 90.5 months). Presence of IDH mutations was not associated with an impact on EFS (p=.29) or OS (p=.14). Similarly, DNMT3A mutations were not associated with an effect on EFS (p=.21) or OS (p=.58). The presence of both IDH and DNMT3A mutations was also not associated with a better or worse response, EFS, or OS as compared with patients with neither mutation. Conclusion: We were not able to detect an association between presence of IDH1/2 and DNMT3A mutations and outcome in this elderly population of patients with AML treated with epigenetic modulators. Disclosures: Ravandi: Johnson and Johnson: Honoraria; Celgene: Research Funding. Off Label Use: Use of decitabine, 5-azacytidine, SAHA, and valproic acid in the treatment of older patients with AML. Garcia-Manero:Celgene: Research Funding. Cortes:Celgene: Research Funding; Eisai: Research Funding.

A Novel Path for ATRA Differentiation Therapy in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3727-3727
Author(s):  
Jean-Emmanuel Sarry ◽  
Helena Boutzen ◽  
Christian Récher
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Negative Regulator ◽  
Granulocytic Differentiation ◽  
Induced Differentiation ◽  
Idh1 R132h ◽  
Recurrent Mutations ◽  
Idh Mutations ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is characterized by accumulation of malignant blasts with impaired differentiation programs due to recurrent mutations, among which IDH mutations occur in 15% of AML patients. These mutations lead to a block in erythroid commitment while they may also bias hematopoietic differentiation to myeloid lineage. Interestingly, Lyn tyrosine kinase is required for erythroid differentiation and we have observed a reduction of Lyn expression in the presence of IDH1-R132H mutation. It is also a negative regulator of ATRA-induced granulocytic differentiation. Accordingly, we hypothesized that IDH mutations may sensitize AML cells to ATRA-induced differentiation. Here, we report that clinically achievable doses of ATRA are sufficient to trigger differentiation specifically on AML cell lines, primary patient samples and xenograft mice models carrying IDH1 mutation as observed by an increase in CD11b expression, granulocytic enzyme activity and morphologic changes in May-Grunwald-Giemsa staining. We also showed that ATRA-induced terminal granulocytic differentiation increases apoptosis while decreases proliferation and colony formation specifically in IDH1 mutant cells. Moreover, inhibition of IDH1-R132H activity reduced ATRA-sensitivity while increasing expression of IDH mutation correlated with highest ATRA sensitivity. Furthermore, treatment with a cell-permeable form of the oncometabolite specifically produced by the mutant (eg. 2-HydroxyGlutarate) sensitized AML cells to ATRA-induced differentiation. Finally, because ATRA-induced differentiation triggers a transient increase of Lyn activation, its association with Lyn inhibitors synergistically increased ATRA-induced differentiation of IDH mutant blasts. In summary, our results showed that IDH mutations by producing 2-HG sensitized leukemic blasts to ATRA and that this synergizes with Lyn inhibition. Since 2HG concentration reaches millimolar in AML patient serum and is 100-fold higher in IDH mutated patients than in non-mutated ones, we would predict a strong efficacy and specificity of ATRA. Furthermore, as IDH mutations are systematically conserved at relapse, this therapeutic strategy might be promising to achieve a long-term remission specifically for this AML patient subgroup. Disclosures No relevant conflicts of interest to declare.

Type and location of isocitrate dehydrogenase mutations influence clinical characteristics and disease outcome of acute myeloid leukemia

2012 ◽  
Vol 54 (5) ◽  
pp. 1028-1035 ◽  
Author(s):  
Magdalena Koszarska ◽  
Andras Bors ◽  
Angela Feczko ◽  
Nora Meggyesi ◽  
Arpad Batai ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Isocitrate Dehydrogenase ◽  
Myeloid Leukemia ◽  
Clinical Characteristics ◽  
Disease Outcome ◽  
Acute Myeloid

Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value

Blood ◽  
2010 ◽  
Vol 116 (12) ◽  
pp. 2122-2126 ◽  
Author(s):  
Saman Abbas ◽  
Sanne Lugthart ◽  
François G. Kavelaars ◽  
Anita Schelen ◽  
Jasper E. Koenders ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Single Case ◽  
Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Isocitrate Dehydrogenase 1 ◽  
Idh Mutations ◽  
Idh1 And Idh2 Mutations ◽  
Acute Myeloid

Abstract Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) were recently demonstrated in acute myeloid leukemia (AML), but their prevalence and prognostic impact remain to be explored in large extensively characterized AML series, and also in various other hematologic malignancies. Here, we demonstrate in 893 newly diagnosed cases of AML mutations in the IDH1 (6%) and IDH2 (11%) genes. Moreover, we identified IDH mutations in 2 JAK2 V617F myeloproliferative neoplasias (n = 96), a single case of acute lymphoblastic leukemia (n = 96), and none in chronic myeloid leukemias (n = 81). In AML, IDH1 and IDH2 mutations are more common among AML with normal karyotype and NPM1mutant genotypes. IDH1 mutation status is an unfavorable prognostic factor as regards survival in a composite genotypic subset lacking FLT3ITD and NPM1mutant. Thus, IDH1 and IDH2 mutations are common genetic aberrations in AML, and IDH1 mutations may carry prognostic value in distinct subtypes of AML.

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