scholarly journals Mechanisms of Resistence of New Target Drugs in Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Debora Capelli ◽  
Francesco Saraceni ◽  
Diego Menotti ◽  
Alessandro Fiorentini ◽  
Attilio Olivieri
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
New Drugs ◽  
Tumor Escape ◽  
Leukemic Stem Cell ◽  
Secondary Aml ◽  
High Incidence ◽  
Acute Myeloid

New drugs targeting single mutations have been recently approved for Acute Myeloid Leukemia (AML) treatment, but allogeneic transplant still remains the only curative option in intermediate and unfavorable risk settings, because of the high incidence of relapse. Molecular analysis repertoire permits the identification of the target mutations and drives the choice of target drugs, but the etherogeneity of the disease reduces the curative potential of these agents. Primary and secondary AML resistance to new target agents is actually an intriguing issue and some of these mechanisms have already been explored and identified. Changes in mutations, release of microenvironment factors competing for the same therapeutic target or promoting the survival of blasts or of the leukemic stem cell, the upregulation of the target-downstream pathways and of proteins inhibiting the apoptosis, the inhibition of the cytochrome drug metabolism by other concomitant treatments are some of the recognized patterns of tumor escape. The knowledge of these topics might implement the model of the ‘AML umbrella trial’ study through the combinations or sequences of new target drugs, preemptively targeting known mechanisms of resistance, with the aim to improve the potential curative rates, expecially in elderly patients not eligible to transplant.

scholarly journals Leukemic Stem Cell Phenotype Is Associated with Mutational Profile in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3852-3852
Author(s):  
Ja Min Byun ◽  
Dong-Yeop Shin ◽  
Youngil Koh ◽  
Sung-Soo Yoon ◽  
Junshik Hong ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Genomic Dna ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Leukemic Stem Cell ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Acute Myeloid

Background: Understanding leukemic stem cell (LSC) is important for acute myeloid leukemia (AML) treatment. As such, understanding the relationship between LSC and genetically defined sub-clones can, in turn, help to understand the heterogeneity of AML. However, to date, there are only a few reports specifically focusing on this topic. To this end, we conducted this study to (1) examine the phenotypic diversity of AML-LSC, (2) explore the association between AML-LSC phenotypes and gene mutations, and (3) investigate the prognostic implications of AML-LSCs. Methods: Mononuclear cells (MNCs) were isolated from the patient's bone marrow aspirates by ficoll gradient centrifugation and cryopreserved in serum-free medium. Stored cells were thawed to Iscove's Modified Dulbecco's Medium (IMDM) and washed with fluorescence-activated cell sorting (FACS) buffer [1% FBS, Dulbecco's Phosphate-Buffered Saline (DPBS)]. Cells were stained with following anti-human monoclonal antibodies: CD45-APC/cy7, CD34-APC, CD38-BV421, CD90-PE, CD123-PE/Cy7, CD45RA-PerCP/Cy5.5. Analyses were performed on a FACSCanto II (HTS) (BD Bioscience) and FlowJo V 10.0 (BD Bioscience) program. For sequencing, the DNA capture probes for 76 target genes were designed using the Agilent SureDesign web-based application. The target regions included protein coding exons with 10 bp intron flanking regions and hot spot regions of the 20 genes involved in recurrent translocations. DNA was extracted on a Chemagic 360 instrument (Perkin Elmer, Baesweiler, Germany). The genomic DNA was sheared using Covaris S220 focused‐ultrasonicator (Covaris, Woburn, MA). We used 50ng of total input genomic DNA. A library preparation was performed according to Agilent's SureSelectQXT Target Enrichment protocol. Paired-end 150-bp sequencing was using NextSeq 550 Dx platform (Illumina, San Diego, CA). Targeted sequencing raw data was obtained in FASTQ format. Results: In secondary AML patients, MPP-like LSC was significantly higher than de-novo AML (p=0.0037), and was higher in MPN-AML than in MDS-AML (p=0.0485). There was no correlation between age and LSC phenotype, though CD34+CD38- subpopulation was enriched in younger patients (<65 yrs). Mutations of KRAS and NRAS were frequently observed in MPP-like LSC dominant patients (3/14 and 4/14), TP53 and ASXL1 mutations in LMPP-like LSC dominant patients (4/12 and 4/12) , and CEBPA, DNMT3A and IDH1 (6/12, 4/12, and 3/12) mutations in GMP-like LSC dominant patients. Furthermore, as shown in Figure, KRAS mutation was significantly associated with the percentage of MPP-like LSC phenotype (p=0.0540), and TP53 mutation with the percentage of LMPP-like LSC phenotype (p=0.0276). When the patients were separated according to the combined risk including next generation sequencing data, the poorer the prognosis, the higher the LMPP-like LSC expression (p=0.0052). The importance of our study lies in that we showed for a given AML patients there is a dominant LSC phenotype and LSCs are associated with clinical outcomes, supporting the significance of cancer stem cell model for human AML. First of all, based on detailed characterization of the surface immunophenotype of AML LSCs we found that AML show evidence of a hierarchical cellular organization. We also recognized that the composition of LSC phenotypes is associated with AML phenotypes. For example, secondary AML patients showed higher fraction of MPP-like LSCs compared to de novo AML patients. In this regard, the higher expression of MPP-like LSCs could explain the poor response to standard treatments traditionally associated with secondary AML. Furthermore, the higher expression of MPP-like LSCs in post-MPN AML compared to post-MDS AML could explain the dismal prognosis associated with post-MPN AML, despite the relative indolent clinical course in their chronic phase and the presence of druggable target. Conclusion: In conclusion, our findings provide better insights into the characteristics and clinical implications of LSC. Although in a small scale, we provide evidence that specific LSC phenotypes are associated with certain mutations thus should be in the AML risk stratification process. Figure Disclosures Yoon: Janssen: Consultancy; Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Yuhan Pharma: Research Funding; MSD: Consultancy; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

scholarly journals Target Therapy in Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Vasko Graklanov
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Acute Leukemia ◽  
Mechanism Of Action ◽  
Myeloid Leukemia ◽  
Target Therapy ◽  
New Drugs ◽  
Cytotoxic Treatment ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is the most common form of acute leukemia in elderly patients. Over the past four decades the basic therapeutic armamentarium was the standard cytotoxic treatment. The new insights in understanding the pathogenesis of AML was the momentum that revolutionized the treatment landscape in AML. The last five years unprecedented growth has been seen in the number of target therapy drugs for the treatment of AML. These new drugs did not just have a clinical benefit as single agents but also have improved AML patient outcomes if combined with conventional cytotoxic therapy. Here, we review recent advances in target-based therapy for patients with AML focusing on their mechanism of action and the results from already published clinical trials.

scholarly journals Low-intensity regimens versus standard-intensity induction strategies in acute myeloid leukemia

2020 ◽  
Vol 11 ◽  
pp. 204062072091301 ◽  
Author(s):  
Norbert Vey
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Treatment Options ◽  
Assessment Tools ◽  
New Drugs ◽  
Prognostic Scores ◽  
Hypomethylating Agents ◽  
Low Intensity ◽  
Acute Myeloid

Treatment options for elderly patients with acute myeloid leukemia (AML) remain limited. In this age group, AML is frequently associated with poor-risk features, while patients’ present comorbidities and reduced functional reserves. As such, intensive chemotherapy (ICT) is frequently too toxic or ineffective in elderly patients and is restricted to a select minority, though it is standard therapy for the youngest and fittest patients or for those belonging to either the favorable or intermediate-risk groups. The use of hypomethylating agents represent an effective alternative for patients who are unfit for ICT, yet the results remain unsatisfactory. In recent years, prognostic scores were developed that include geriatric assessment tools and improved risk-stratification. In addition, several effective new drugs have emerged. The combination of these drugs with hypomethylating agents or low-dose cytarabine has produced encouraging preliminary results that may change standard practices and offer an alternative to the dilemma of ICT versus low-intensity therapies.

Acute myeloid leukemia transformed to a targetable disease

2020 ◽  
Vol 16 (14) ◽  
pp. 961-972
Author(s):  
Khalil Saleh ◽  
Nadine Khalifeh-Saleh ◽  
Hampig Raphael Kourie
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Traditional Treatment ◽  
Heterogeneous Neoplasm ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the monoclonal proliferation of immature progenitors. It is the most common acute leukemia in adults and its incidence increases with age. The standard traditional treatment in fit patients was the ‘3 + 7’ regimen and cytarabine consolidation followed or not with allogeneic stem cell transplantation. Recently, several targeted therapies such as gemtuzumab ozogamicin targeting the CD33+ AML, midostaurin, gilteritinib and crenolanib inhibiting FLT3-positive AML and ivosidenib and enasidenib blocking IDH-mutated AML have been approved. These new drugs led to the change of the landscape of the treatment of AML and transforming this disease to a targetable one. We aimed in this paper to review the implications of each new target, the mechanisms of action of these new drugs and we discuss all the studies leading to the approval of these new drugs in their indications according to each target.

scholarly journals Leukemic Stem Cell Frequency: A Strong Biomarker for Clinical Outcome in Acute Myeloid Leukemia

PLoS ONE ◽  
2014 ◽  
Vol 9 (9) ◽  
pp. e107587 ◽  
Author(s):  
Monique Terwijn ◽  
Wendelien Zeijlemaker ◽  
Angèle Kelder ◽  
Arjo P. Rutten ◽  
Alexander N. Snel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Leukemic Stem Cell ◽  
Cell Frequency ◽  
Acute Myeloid

Co-Existence of LMPP-Like and GMP-Like Leukemia Stem Cells In Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 91-91
Author(s):  
Nicolas Goardon ◽  
Emmanuele Marchi ◽  
Lynn Quek ◽  
Anna Schuh ◽  
Petter Woll ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Leukemic Stem Cell ◽  
Self Renewal ◽  
Two Populations ◽  
Acute Myeloid

Abstract Abstract 91 In normal and leukemic hemopoiesis, stem cells differentiate through intermediate progenitors into terminal cells. In human Acute Myeloid Leukemia (AML), there is uncertainty about: (i) whether there is more than one leukemic stem cell (LSC) population in any one individual patient; (ii) how homogeneous AML LSCs populations are at a molecular and cellular level and (iii) the relationship between AML LSCs and normal stem/progenitor populations. Answers to these questions will clarify the molecular pathways important in the stepwise transformation of normal HSCs/progenitors. We have studied 82 primary human CD34+ AML samples (spanning a range of FAB subtypes, cytogenetic categories and FLT3 and NPM1 mutation states) and 8 age-matched control marrow samples. In ∼80% of AML cases, two expanded populations with hemopoietic progenitor immunophenotype coexist in most patients. One population is CD34+CD38-CD90-CD45RA+ (CD38-CD45RA+) and the other CD34+CD38+CD110-CD45RA+ (GMP-like). Both populations from 7/8 patients have leukemic stem cell (LSC) activity in primary and secondary xenograft assays with no LSC activity in CD34- compartment. The two CD34+ LSC populations are hierarchically ordered, with CD38-CD45RA+ LSC giving rise to CD38+CD45RA+ LSC in vivo and in vitro. Limit dilution analysis shows that CD38-CD45RA+LSCs are more potent by 8–10 fold. From 18 patients, we isolated both CD38-CD45RA+ and GMP-like LSC populations. Global mRNA expression profiles of FACS-sorted CD38-CD45RA+ and GMP-like populations from the same patient allowed comparison of the two populations within each patient (negating the effect of genetic/epigenetic changes between patients). Using a paired t-test, 748 genes were differentially expressed between CD38-CD45RA+ and GMP-like LSCs and separated the two populations in most patients in 3D PCA. This was confirmed by independent quantitative measures of difference in gene expression using a non-parametric rank product analysis with a false discovery rate of 0.01. Thus, the two AML LSC populations are molecularly distinct. We then compared LSC profiles with those from 4 different adult marrow normal stem/progenitor cells to identify the normal stem/progenitor cell populations which the two AML LSC populations are most similar to at a molecular level. We first obtained a 2626 gene set by ANOVA, that maximally distinguished normal stem and progenitor populations. Next, the expression profiles of 22 CD38-CD45RA+ and 21 GMP-like AML LSC populations were distributed by 3D PCA using this ANOVA gene set. This showed that AML LSCs were most closely related to their normal counterpart progenitor population and not normal HSC. This data was confirmed quantitatively by a classifier analysis and hierarchical clustering. Taken together, the two LSC populations are hierarchically ordered, molecularly distinct and their gene expression profiles do not map most closely to normal HSCs but rather to their counterpart normal progenitor populations. Finally, as global expression profiles of CD38-CD45RA+ AML LSC resemble normal CD38-CD45RA+ cells, we defined the functional potential of these normal cells. This had not been previously determined. Using colony and limiting dilution liquid culture assays, we showed that single normal CD38-CD45RA+ cells have granulocyte and macrophage (GM), lymphoid (T and B cell) but not megakaryocyte-erythroid (MK-E) potential. Furthermore, gene expression studies on 10 cells showed that CD38-CD45RA+ cells express lymphoid and GM but not Mk-E genes. Taken together, normal CD38-CD45RA+ cells are most similar to mouse lymphoid primed multi-potential progenitor cells (LMPP) cells and distinct from the recently identified human Macrophage Lymphoid progenitor (MLP) population. In summary, for the first time, we show the co-existence of LMPP-like and GMP-like LSCs in CD34+ AML. Thus, CD34+ AML is a progenitor disease where LSCs have acquired abnormal self-renewal potential (Figure 1). Going forward, this work provides a platform for determining pathological LSCs self-renewal and tracking LSCs post treatment, both of which will impact on leukemia biology and therapy. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation for Secondary Acute Myeloid Leukemia- a Report from the Acute Leukemia Working Party of the EBMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 63-63
Author(s):  
Bipin N. Savani ◽  
Myriam Labopin ◽  
Ariane Boumendil ◽  
Gerhard Ehninger ◽  
Arnold Ganser ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Working Party ◽  
Registry Study ◽  
Hematopoietic Stem ◽  
Secondary Aml ◽  
Relapse Risk ◽  
Secondary Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Secondary acute myeloid leukemia (sAML) is a very heterogeneous group of disease derived from myelodysplasia, chronic myeloproliferative disorders or after exposure to chemotherapy and or radiation therapy (therapy related AML) or due to exposure to environmental carcinogens. sAML has traditionally been considered a devastating disease with inferior outcomes compared to de novo AML, affecting a vulnerable population of heavily pretreated, especially older patients. Allogeneic hematopoietic stem cell transplantation (HCT) is the only potential curative therapy and usually considered in patients with low comorbidities and transplant related risk score. However, relapse is the most frequent cause of failure after HCT, occurring in more than 50% of the patients. No systematic large analysis of HCT for sAML is available to study the risk factors and outcome. Therefore, the EBMT Acute Leukemia Working Party has performed a retrospective registry study on patients with sAML (n=4256) undergoing HCT. Patients who underwent HLA-identical sibling (n=2290) or unrelated donor (n=1966) peripheral blood (n=3781) or bone marrow transplantation (n=475) from 2000 to 2013 are included in the study. All unrelated donors were Human Leucocyte Antigens (HLA)-matched (10/10) (n=1532) or one locus mismatched (9/10) (n=434). 1901 (45%) patients received ablative (MAC) and 2355 (55%) reduced-intensity conditioning (RIC) regimen. Median age at transplant was 56 years, IQR 48-63 (MAC 51, IQR 42-58; RIC 60, IQR 54-64). Median time from diagnosis of sAML to HCT was 6.2 months, IQR 4.1-12.0 (MAC 5.6, IQR 3.8-9.7; RIC 7.0, IQR 4.4-14.12; p<0.0001). At time of transplant, 2313 (54%) patients were in CR1, 278 (7%) in ≥CR2 and active diseases in 1665 (39%) patients. 158 (4%) patients had prior autologous HCT (MAC 58 [3%], RIC 100 [4%], p=0.049). Median follow-up of surviving patients was 26 months (IQR 7 -56). Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 33% (95% CI, 32-35%) and 25% (95% CI, 24-27%), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia-free survival (LFS) at 2 years were 46% (95% CI, 44-48%) and 41% (95% CI, 39-43%), respectively. Acute GVHD (grade II-IV) occurred in 1043 (26%) patients. The 2-year cumulative incidence of chronic GVHD was 54% (95% CI, 51-56). Two year OS, LFS, RI and NRM of MAC and RIC groups were 48% (95% CI, 46-50) vs. 44% (95% CI, 42-47), p=0.06, 44% (95% CI, 41-46) vs. 39% (95% CI, 37-41), p=0.003, 30% (95% CI, 28-32) vs. 36% (95% CI, 34-38), p<0.0001, 26% (95% CI, 24-28) vs. 25% (95% CI, 24-27), p=0.273, respectively. Two year OS of patients in CR1, ≥CR2 and active disease before HCT was 54% (95% CI, 52-56), 45% (95% CI, 39-52) and 35% (95% CI, 33-38), respectively (p<0.0001). In multivariate analysis adjusted for variable with different distribution between groups, the type of conditioning (RIC vs. MAC) had no impact on OS and LFS, however RIC group had higher RI (HR, 1.3, 95% CI 1.12-1.44, p=0.0001) and lower NRM (HR 0.8, 95% CI 0.72-0.96, p=0.01). Older age at HCT was an independent adverse prognostic factor for OS, LFS and NRM. Time from diagnosis to HCT had no impact on transplant outcome. Patients receiving PB grafts had superior OS (HR 0.84, 95% CI 0.73-0.97, p=0.01), LFS (HR 0.85, 95% CI 0.74-0.97, p=0.02) and lower RI (HR 0.83, 95% CI 0.70-0.99, p=0.049) compared with BM. Patients in remission and receiving HCT from HLA-identical siblings were independently associated better outcome. In summary, our registry study in the largest cohort of patients studied so far receiving HCT for secondary AML, demonstrated that about 45% of patients with secondary AML can attain long term survival after HCT. Patients receiving ablative regimens were associated with lower relapse risk and patients in remission had superior survival. Patients receiving PB grafts were associated potent graft-versus leukemia effects with decreased relapse risk and improved survival. Post- transplant pre-emptive therapy to decrease relapse risk might improve outcome further in these high risk populations. Disclosures Niederwieser: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Glass:Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Schmid:Janssen Cilag: Other: Travel grand; Neovii: Consultancy.

Sign in / Sign up

Export Citation Format

Share Document