scholarly journals Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia

2020 ◽  
Vol 21 (22) ◽  
pp. 8505
Author(s):  
Carmelo Gurnari ◽  
Simona Pagliuca ◽  
Valeria Visconte
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Cellular Differentiation ◽  
Therapeutic Response ◽  
Chemotherapeutic Agents ◽  
Therapeutic Resistance ◽  
Hypomethylating Agents ◽  
Induction Failure ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by abnormal proliferation, lack of cellular differentiation, and infiltration of bone marrow, peripheral blood, or other organs. Induction failure and in general resistance to chemotherapeutic agents represent a hindrance for improving survival outcomes in AML. Here, we review the latest insights in AML biology concerning refractoriness to therapies with a specific focus on cytarabine and daunorubicin which still represent milestones agents for inducing therapeutic response and disease eradication. However, failure to achieve complete remission in AML is still high especially in elderly patients (40–60% in patients >65 years old). Several lines of basic and clinical research have been employed to improve the achievement of complete remission. These lines of research include molecular targeted therapy and more recently immunotherapy. In terms of molecular targeted therapies, specific attention is given to DNMT3A and TP53 mutant AML by reviewing the mechanisms underlying epigenetic therapies’ (e.g., hypomethylating agents) resistance and providing critical points and hints for possible future therapies overcoming AML refractoriness.

scholarly journals Long-term survival after intensive chemotherapy or hypomethylating agents in AML patients aged 70 years and older: a large patient data set study from European registries

Leukemia ◽  
2021 ◽  
Author(s):  
Christian Récher ◽  
Christoph Röllig ◽  
Emilie Bérard ◽  
Sarah Bertoli ◽  
Pierre-Yves Dumas ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Intensive Chemotherapy ◽  
Hypomethylating Agents ◽  
Term Survival ◽  
Acute Myeloid

AbstractThe outcome of acute myeloid leukemia patients aged 70 years or older is poor. Defining the best treatment option remains controversial especially when choosing between intensive chemotherapy and hypomethylating agents. We set up a multicentric European database collecting data of 3 700 newly diagnosed acute myeloid leukemia patients ≥70 years. The primary objective was to compare overall survival in patients selected for intensive chemotherapy (n = 1199) or hypomethylating agents (n = 1073). With a median follow-up of 49.5 months, the median overall survival was 10.9 (95% CI: 9.7–11.6) and 9.2 months (95% CI: 8.3–10.2) with chemotherapy and hypomethylating agents, respectively. Complete remission or complete remission with incomplete hematologic recovery was 56.1% and 19.7% with chemotherapy and hypomethylating agents, respectively (P < 0.0001). Treatment effect on overall survival was time-dependent. The Royston and Parmar model showed that patients treated with hypomethylating agents had a significantly lower risk of death before 1.5 months of follow-up; no significant difference between 1.5 and 4.0 months, whereas patients treated with intensive chemotherapy had a significantly better overall survival from four months after start of therapy. This study shows that intensive chemotherapy remains a valuable option associated with a better long-term survival in older AML patients.

Evolution of FLT3 Internal Tandem Duplication at the Diagnosis, Relapse, Remission or Induction Failure during the Treatment in Acute Myeloblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4485-4485
Author(s):  
Soo-Mee Bang ◽  
Jeong Yeal Ahn ◽  
Jiyoon Park ◽  
Se Hoon Park ◽  
Eun Mi Nam ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Remission Rate ◽  
Prognostic Significance ◽  
Chemotherapeutic Agents ◽  
Internal Tandem Duplication ◽  
Induction Failure ◽  
Flt3 Internal Tandem Duplication ◽  
Acute Myeloid

Abstract The FLT3 is class III fms-like tyrosine kinase. FLT3 mutations are one of the most frequent genetic changes at diagnosis and have been reported to be of prognostic significance in acute myeloid leukemia. FLT3 internal tandem duplication of the juxtamembrane domain (FLT3 ITD) was analyzed by PCR of genomic DNA at diagnosis or during the follow-up in patients with acute myeloid leukemia (AML). Total 223 patients were diagnosed as AML from Mar. 1996 till Aug. 2005. Their median age was 34 years-old (range: 0–86). The number of male or female patients was 116 or 107. Their FAB classifications were M0/1/2/3/4/5/6/7/RAEB/biphenotypic in 6/23/85/20/32/21/13/16/2/5 patients, respectively. Cytogenetic data at diagnosis were available in 182 patients; good/ intermediate/poor risk in 51/107/24 patients, respectively. Among the 190 patients receiving induction therapy, 147 patients achieved hematologic remission with a remission rate of 77%. Median event-free (EFS) and overall survival were 9 (95% confidence interval: 8–12) months and 14 (95% CI: 11–14) months, respectively. The incidence of FLT3 ITD at diagnosis was 13% (29/223). FLT3 ITD was more prevalent in M0~4 subtypes and older age. Among non-M3 population (N=203), patients with FLT3 ITD had a significantly short EFS when compared with those without ITD (p=0.0454). Among the 52 relapsed patients, 9 patients had a FLT3 ITD at diagnosis. Six patients showed reappearing of ITD and 3 patients remained negative at relapse. One patient acquired new ITD at relapse among 43 relapsed patients who had not baseline ITD. Tested 100 samples of 92 patients at remission were all negative for FLT3 ITD. Among the 28 patients at induction failure, one patient showed persistent ITD, one another re-appeared ITD after relapse, and the other one newly-developed ITD. Two others showed disappearance of ITD despite of persistent disease. Leukemic clones with FLT3 ITD may be susceptible to conventional chemotherapeutic agents and have no value for minimal residual disease. Therefore, effective induction and consolidation therapy could convert the poor prognosis of AML with FLT3 ITD.

scholarly journals Analysis of FLT3-ITD and FLT3-ASP835 Mutations in De Novo Acute Myeloid Leukemia: Evaluation of Prevalence, Distribution Pattern and Correlation with FAB Subtype, and Cytogenetics from a Tertiary Referral Hospital in India

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5172-5172
Author(s):  
Shruti Mishra ◽  
Kishore Kumar
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Cytogenetic Analysis ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Clinical Parameters ◽  
Duration Of Symptoms ◽  
Flt3 Mutations ◽  
Induction Failure ◽  
Acute Myeloid

Introduction: After introduction of Midostaurin, the importance of FLT3 mutation analysis in AML is irreplaceable. In this study we tried to find the incidence of this mutation in Indian Population. Aims and Objective: -To evaluate clinical parameters like age, sex, clinical presentation and duration of symptoms in atleast 60 de novo AML patients. -Perform bone marrow examination, FAB subtyping and cytogenetic analysis in these cases. -To estimate the prevalence of FLT3-ITD and FLT3-Asp835 mutations by DNA-PCR in these cases. -To compare the FLT3-ITD and FLT3-Asp835 mutations status with clinical parameters and cytogenetics data. Methods: We Included: -All cases of primary de novo Acute Myeloid Leukemia cases, who have not received any kind of chemotherapy for the same. -Cases in whom adequate representative sample was available for cytogenetic analysis and PCR studies. We excluded: -All secondary Acute myeloid leukemia cases. -Children less than 2 years of age. -Patients who have received any chemotherapy before. We did cytogenetics, Flowcytometry and RT-PCR based detection of FLT-3 as per standard protocol. Results and Discussion: In the time period between January 2015 to September 2016, a total of 68 Acute Myeloid Leukemia (AML) patients were admitted to our Institute and included in the study. In the current study, the following observations were noted: -Around 30% of patients referred to us with a provisional diagnosis of AML are not affording any further workup or treatment. -The median age of occurrence of AML is much lower than in western countries. -De novo cases are much more frequent. -More than 80% of our patients presented with some form of bleeding with infections of variable severity in nearly 90% of patients. -According to FAB classification AML-M2 was the most prevalent subtype in our study. -Nearly 67% of our patients belong to Normal Karyotype followed by inv (16) and t(8:21) in around 10% of cases each. -FLT3-ITD was present in 24% of cases and FLT3-Asp835 mutations were present in 6% of cases in concordance with reported literature. -NPM 1 mutations were present in 24% of cases. -NPM 1 overlapped with FLT3-ITD in 8% of the cases with one case showing overlap of NPM 1 AND FLT3-Asp835 mutation. -At presentation FLT3-ITD positive patients reveal significantly high total count, low hemoglobin, low platelets and high Serum LDH values. -All t(8:21) positive were negative for FLT3 mutations in this study. -FLT3-ITD positivity correlated significantly with dim or no expression of immaturity markers namely CD34 and HLA-DR in Immunophenotyping. -In our study 65.7% of patients achieved complete remission following standard induction -Primary resistant disease was noted in 8% of cases (20% induction failure cases following one cycle of induction). -2% of patients succumbed to induction related mortality with neutropenic sepsis being the major contributor. -Induction failure significantly correlated with FLT-ITD positivity but no significant differences were noted in induction death. -A 42% relapse rate is noted in our patients with >70% of them occurring within a year of therapy completion. -4 % of our treated patients are alive during evaluation with median complete remission duration of 11 months. -Most patients who had a relapse did not undergo further therapy and were referred back to their primary physicians for supportive care only. Since a meaningful survival analysis was not possible with most of these patients being lost to follow up, the overall survival data has not been reported. -Only two patients underwent Allogeneic transplant and were alive during data analysis. -Midostaurin was not available during study period and 30% of patients were put on Sorafenib. Conclusion: In conclusion the prevalence of FLT3 mutations in our population is similar to reported literature. Since patients who harbour FLT3/ITD have dismal outcome with standard therapy and considering the fact in India most patients are unable to afford treatment, patients should be encouraged to be a part of a clinical trial wherever possible. Although the complete response rates in our study are comparable to published literature, even patients who did not have any mutations had a poorer disease free survival compared to patients reported previously who were treated on a similar protocol without stem cell transplantation. Hence there is a need to study the biology of these patients looking at a wider range of genes which can have an impact on the outcomes. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Outcomes of Adults With Relapsed/Refractory Acute Myeloid Leukemia Treated With Venetoclax Plus Hypomethylating Agents at a Comprehensive Cancer Center

2021 ◽  
Vol 11 ◽  
Author(s):  
Matthew E. Tenold ◽  
Benjamin N. Moskoff ◽  
David J. Benjamin ◽  
Rasmus T. Hoeg ◽  
Aaron S. Rosenberg ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Comprehensive Cancer Center ◽  
Cell Transplant ◽  
Hypomethylating Agents ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid ◽  
Refractory Aml

Relapsed/refractory acute myeloid leukemia (AML) is a devastating disease with a poor prognosis and represents a major unmet medical need. We report on a real-world academic center experience of treating 25 patients with relapsed/refractory AML using venetoclax in combination with decitabine or azacitidine, which is not otherwise widely evaluated in the current literature. Our patients come from a large, socioeconomically and geographically diverse area including the majority of Northern California. Most had ELN Adverse Risk (52%) or Intermediate Risk (44%) AML, and most had an ECOG Performance Status of 1 (64%). Over half (52%) had prior hypomethylating agent exposure, and 40% had Secondary AML. We observed an overall response rate of 52%, with eight patients (32%) achieving composite complete remission. Median overall survival was 5.5 months, and for patients achieving composite complete remission this was 21.6 months. One-year estimated overall survival was 38%. Three patients were able to proceed directly to stem cell transplant for consolidation, and all three were alive at last follow-up, ranging 13.8–24.0 months. We found venetoclax in combination with hypomethylating agents to be well tolerated and potentially efficacious in securing long-term remissions for patients with relapsed/refractory AML.

scholarly journals NPM1 mutation is not associated with prolonged complete remission in acute myeloid leukemia patients treated with hypomethylating agents

Haematologica ◽  
2018 ◽  
Vol 103 (10) ◽  
pp. e455-e457 ◽  
Author(s):  
Pedro Henrique Prata ◽  
Cécile Bally ◽  
Thomas Prebet ◽  
Christian Recher ◽  
Geoffroy Venton ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Hypomethylating Agents ◽  
Npm1 Mutation ◽  
Acute Myeloid

Complete remission induced by G-CSF in a patient with acute myeloid leukemia with t(8;21)(q22;q22)

2003 ◽  
Vol 4 (3) ◽  
pp. 218-221 ◽  
Author(s):  
Felicetto Ferrara ◽  
Ettore Mariano Schiavone ◽  
Salvatore Palmieri ◽  
Giuseppina Mele ◽  
Barbara Pocali ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Acute Myeloid

scholarly journals Hypomethylating Agents in Combination with Venetoclax As a Bridge to Allogeneic Transplant in Acute Myeloid Leukemia

2021 ◽  
Vol 27 (3) ◽  
pp. S150
Author(s):  
Vanessa E Kennedy ◽  
Gavin Hui ◽  
Daria Gaut ◽  
Varun Mittal ◽  
Caspian Oliai ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hypomethylating Agents ◽  
Allogeneic Transplant ◽  
Acute Myeloid

Associations between complete remission and 2- to 3-year survival following 7 + 3 induction for acute myeloid leukemia

2021 ◽  
pp. 1-6
Author(s):  
Megan Othus ◽  
Guillermo Garcia-Manero ◽  
John Godwin ◽  
James Weick ◽  
Derek Stirewalt ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Acute Myeloid

scholarly journals NUP-98 Rearrangements Led to the Identification of Candidate Biomarkers for Primary Induction Failure in Pediatric Acute Myeloid Leukemia

2021 ◽  
Vol 22 (9) ◽  
pp. 4575
Author(s):  
Vincenza Barresi ◽  
Virginia Di Bella ◽  
Nellina Andriano ◽  
Anna Provvidenza Privitera ◽  
Paola Bonaccorso ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutational Analysis ◽  
Integrated Analysis ◽  
Induction Phase ◽  
Pediatric Acute Myeloid Leukemia ◽  
Expression Arrays ◽  
Primary Induction ◽  
Induction Failure ◽  
Acute Myeloid

Conventional chemotherapy for acute myeloid leukemia regimens generally encompass an intensive induction phase, in order to achieve a morphological remission in terms of bone marrow blasts (<5%). The majority of cases are classified as Primary Induction Response (PIR); unfortunately, 15% of children do not achieve remission and are defined Primary Induction Failure (PIF). This study aims to characterize the gene expression profile of PIF in children with Acute Myeloid Leukemia (AML), in order to detect molecular pathways dysfunctions and identify potential biomarkers. Given that NUP98-rearrangements are enriched in PIF-AML patients, we investigated the association of NUP98-driven genes in primary chemoresistance. Therefore, 85 expression arrays, deposited on GEO database, and 358 RNAseq AML samples, from TARGET program, were analyzed for “Differentially Expressed Genes” (DEGs) between NUP98+ and NUP98-, identifying 110 highly confident NUP98/PIF-associated DEGs. We confirmed, by qRT-PCR, the overexpression of nine DEGs, selected on the bases of the diagnostic accuracy, in a local cohort of PIF patients: SPINK2, TMA7, SPCS2, CDCP1, CAPZA1, FGFR1OP2, MAN1A2, NT5C3A and SRP54. In conclusion, the integrated analysis of NUP98 mutational analysis and transcriptome profiles allowed the identification of novel putative biomarkers for the prediction of PIF in AML.

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