Prognostic relevance of combined IDH1 and NPM1 mutations in the intermediate cytogenetic de novo acute myeloid leukemia

2021 ◽  
Vol 67 (3) ◽  
pp. 92-98
Author(s):  
Amal Ezzat Abd El-Lateef ◽  
Manar M. Ismail ◽  
Mohammed Almohammadi ◽  
Amr M. Gawaly
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Melting Curve ◽  
Idh1 Mutation ◽  
Prognostic Indicators ◽  
Melting Curve Analysis ◽  
P Value ◽  
Newly Diagnosed ◽  
Mutant Idh1 ◽  
Acute Myeloid

Despite the great advance in treatment, cytogenetically normal Acute myeloid leukemia (CN-AML) is still a challenging entity. The discovery of IDH1 mutation in AML together with the frequent co-mutations; NPM1 and FLT3-ITD throughs a new insight into the pathogenesis and outcome of CN-AML. Recently, there has been an increasing number of recurring mutations in other genes for which the forecasting effect is still required. Despite the large number of risk variables established, there are relatively few prognostic indicators that can help in treatment decisions in AML patients. This study aimed at recording the frequency of IDH1 and NPM1 mutations in newly diagnosed AML and, dual clinicopathological significance. IDH1 and NPM1 mutations were analyzed using High-Resolution Melting curve analysis PCR in 78 newly diagnosed AML patients; 30 pediatric and 48 adult AML patients. IDH1 mutation was detected in 6 out of the 48 adult AML cases (12.5%) and all of them had intermediate cytogenetic prognostic stratification. 5/6 mutant IDH1 patients showed NPM1 co-mutation (P-value= 0.008). Mutant IDH1 patients showed significant resistance to induction therapy (P-value <0.001) and even those who achieved complete remission were relapsed later. Within the intermediate cytogenetic group, the IDH1 mutated patients had short overall survival (HR 12.9, 95% CI (3.1- 53.45) and event-free survival (HR 15.7, 95% CI (2.99-82.72) and P-value <0.001). IDH1 mutation is closely linked to the intermediate cytogenetic stratified group and in particular old age patients and has a great impact on their survival.

Detection of the JAK2V617F Mutation in Myeloproliferative Disorders by Melting Curve Analysis Using the LightCycler System

2006 ◽  
Vol 130 (7) ◽  
pp. 997-1003
Author(s):  
Randall J. Olsen ◽  
Zhouwen Tang ◽  
Daniel H. Farkas ◽  
David W. Bernard ◽  
Youli Zu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Clinical Laboratory ◽  
Melting Curve ◽  
Myeloproliferative Disorder ◽  
Curve Analysis ◽  
Melting Curve Analysis ◽  
Wild Type ◽  
Acute Myeloid

Abstract Context.—A specific mutation, JAK2V617F, was recently recognized as having diagnostic value for myeloproliferative disorders. No practical assay is currently available for routine use in a clinical laboratory. Objective.—We report the development of a real-time polymerase chain reaction melting curve analysis assay that is appropriate for molecular diagnostics testing. Design.—Specific primers and fluorescence resonance energy transfer probes were designed, and patients with a previously diagnosed myeloproliferative disorder, de novo acute myeloid leukemia, or reactive condition were selected. The DNA was extracted from fresh and archived peripheral blood and bone marrow specimens, and real-time polymerase chain reaction melting curve analysis was performed on the LightCycler platform (Roche Applied Science, Indianapolis, Ind). Results.—The JAK2 region was successfully amplified, and wild-type amplicons were reproducibly discriminated from JAK2V617F amplicons. Titration studies using homozygous wild-type and mutant cell lines showed the relative areas under a melting curve were proportional to allele proportion, and the assay reliably detected one mutant in 20 total cells. JAK2V617F was identified in patients previously diagnosed with a myeloproliferative disorder or acute myeloid leukemia transformed from myeloproliferative disorder, whereas a wild-type genotype was identified in patients with reactive conditions or de novo acute myeloid leukemia. Conclusions.—These findings demonstrate the suitability of this assay for identifying JAK2V617F in a clinical laboratory setting. Furthermore, the semiquantitative detection of JAK2V617F in archived specimens provides a new tool for studying the prognostic significance of this mutation.

scholarly journals Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia

Blood ◽  
2020 ◽  
Vol 135 (7) ◽  
pp. 463-471 ◽  
Author(s):  
Gail J. Roboz ◽  
Courtney D. DiNardo ◽  
Eytan M. Stein ◽  
Stéphane de Botton ◽  
Alice S. Mims ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Idh1 Mutation ◽  
Newly Diagnosed ◽  
Isocitrate Dehydrogenase 1 ◽  
Hematologic Disorder ◽  
Transfusion Independence ◽  
Acute Myeloid

Abstract Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.

scholarly journals Assessment of Minimal Residual Disease in Acute Myeloid Leukemia patient in Adult Egyptian Acute myeloid Leukemia Patients

QJM ◽  
2020 ◽  
Vol 113 (Supplement_1) ◽  
Author(s):  
M M Moussa ◽  
E A Abdelhady ◽  
N H Abdallah ◽  
I J Mahmoud
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Statistical Significance ◽  
University Hospital ◽  
P Value ◽  
Newly Diagnosed ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background The term minimal residual disease (MRD) is used to describe residual disease after suboptimal induction chemotherapy, but at the same time refers to the lowest levels of disease potentially compatible with cure or to molecularly defined relapse after long term remission. This study assesses the minimal residual disease in relation to the outcome in acute myeloid leukemia patients after 6 months of treatment of chemotherapy. Aim of the work The aim of this study is assessment of measurable minimal residual disease after treatment to identify acute myeloid leukemia patients who are at high risk of poor outcome. Patients and methods Minimal Residual Disease was measured using Flow cytometry in 30 newly diagnosed a 30 newly diagnosed acute myeloid leukemia (AML) patients. The patients were recruited from clinical hematology department at Ain shams university hospital over the period from May 2017 to November 2018. Results A total number of 30 acute myeloid leukemia patients were recruited from Ain Shams University hospital, hematology and Oncology Unit outpatient clinic, with age ranging from 18-60 years old (median age 40 years), 14 of them were males representing 46.6% of the total number and 16 were females representing 53.3% of the total number. There was no statistical significance between the age of the studied group and the MRD with P-value 0.147, the sex of the patients doesn’t contribute to the risk stratification with a P-value of 0.200. The number of cases with negative MRD after induction was 13 representing 43.3% of the total number, and was 12 patients after 6 months representing 70.5% of the remitted patients, considering that the cut out value of MRD is 0.1. There was a significant relationship between TLC and MRD, the higher the TLC the more positive the MRD. Positive MRD is associated with higher mortality rates, exhibiting a statistical significance with P-value of 0.005. Conclusion We concluded that assessment of minimal residual disease in AML is of great value in determination of prognosis of the disease and its outcome and it is of great value to determine the levels of minimal residual disease (MRD) during the course of therapy and to stratify patient to identify high risk patient and to plan the therapeutic program accordingly.

scholarly journals PS1023 MUTANT IDH1 INHIBITOR IVOSIDENIB (AG-120) IN COMBINATION WITH AZACITIDINE FOR NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 460-461 ◽  
Author(s):  
C.D. DiNardo ◽  
A.S. Stein ◽  
E.M. Stein ◽  
A.T. Fathi ◽  
O. Frankfurt ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Newly Diagnosed ◽  
Mutant Idh1 ◽  
Acute Myeloid

Mutant IDH1 Inhibitor Ivosidenib (IVO; AG-120) in Combination with Azacitidine (AZA) for Newly Diagnosed Acute Myeloid Leukemia (ND AML)

2019 ◽  
Vol 19 ◽  
pp. S217-S218
Author(s):  
Courtney D. DiNardo ◽  
Anthony S. Stein ◽  
Eytan M. Stein ◽  
Amir T. Fathi ◽  
Olga Frankfurt ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Newly Diagnosed ◽  
Mutant Idh1 ◽  
Acute Myeloid

A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older

Blood ◽  
2009 ◽  
Vol 114 (6) ◽  
pp. 1166-1173 ◽  
Author(s):  
Jean-Luc Harousseau ◽  
Giovanni Martinelli ◽  
Wieslaw W. Jedrzejczak ◽  
Joseph M. Brandwein ◽  
Dominique Bordessoule ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Supportive Care ◽  
Myeloid Leukemia ◽  
Best Supportive Care ◽  
Rank Test ◽  
P Value ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Acute Myeloid

AbstractThis phase 3, multicenter, open-label study evaluated the efficacy and safety of tipifarnib compared with best supportive care (BSC), including hydroxyurea, as first-line therapy in elderly patients (≥70 years) with newly diagnosed, de novo, or secondary acute myeloid leukemia. A total of 457 patients were enrolled with 24% 80 years of age or older. Tipifarnib 600 mg orally twice a day was administered for the first 21 consecutive days, in 28-day cycles. The primary endpoint was overall survival. The median survival was 107 days for the tipifarnib arm and 109 days for the BSC arm. The hazard ratio (tipifarnib vs BSC) for overall survival was 1.02 (P value by stratified log-rank test, .843). The complete response rate for tipifarnib in this study (8%) was lower than that observed previously, but with a similar median duration of 8 months. The most frequent grade 3 or 4 adverse events were cytopenias in both arms, slightly more infections (39% vs 33%), and febrile neutropenia (16% vs 10%) seen in the tipifarnib arm. The results of this randomized study showed that tipifarnib treatment did not result in an increased survival compared with BSC, including hydroxyurea. This trial was registered at www.clinicaltrials.gov as #NCT00093990.

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