scholarly journals Clinical Characteristics and Outcomes of Patients Diagnosed with Acute Myeloid Leukemia with Expression of CD71

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4449-4449
Author(s):  
Daniel Rivera ◽  
Yesid Alvarado ◽  
Guillermo Garcia-Manero ◽  
Gautham Borthakur ◽  
Hagop Kantarjian ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Hematologic Malignancy ◽  
Intensive Chemotherapy ◽  
Low Intensity ◽  
Frontline Treatment ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction Acute myeloid leukemia (AML) is a clonal hematologic malignancy characterized by the proliferation and accumulation of blasts in the bone marrow (BM) which results in hematopoietic failure. Transferrin receptor (CD71) plays an important role by up-taking iron into the cell, and its expression is regulated by cellular iron levels. Recently, CD71 has emerged as a sensitive and specific marker of cell proliferation in solid tumors. The clinical significance of CD71 expression in AML remains unclear. Current efforts are also exploring its potential as a therapeutic target in AML. We aimed to describe the clinical characteristics and outcomes of patients diagnosed with de novo AML who expressed CD71. Methods We conducted a retrospective analysis of 453 patients with newly diagnosed AML that came to our institution from December 2019 to June 2021 in whom CD71 antibody was available at diagnosis. CD71 expression was assessed by flow cytometry immunophenotypic studies performed using bone marrow aspirate specimens at presentation. For each analysis, a minimum of 200,000 events was acquired on FACSCanto II instruments (8-color and 10-color, BD Biosciences). The CD45 dim-blast region including monocytes based on CD45 / side scatter was analyzed. The antibody panel included 5 tubes; CD71 antibody was included in tube 3, which contains the following antigen combination: CD41/CD71/CD56/CD34/CD64/HLA-DR/CD14/CD45. The neoplasm was CD71-positive if at least 20% of blasts demonstrated CD71 expression. Additionally, frontline treatment was categorized into intensive chemotherapy (HiDAC based), and Low-Intensity regimen (double nucleoside analog or hypomethylating agent-based therapies). Outcomes in terms of survival and treatment response were analyzed and reported by age, ELN risk groups (Favorable, Intermediate, and Adverse), and the presence of somatic mutations. Results Baseline characteristics are detailed in table 1. We identified 359 (79%) patients diagnosed with AML in whom CD71 was expressed. Our study focused on 184 (41%) patients diagnosed with previously untreated de novo AML, the median age was 63 years (IQR 50-73). Fifty-seven percent of patients were male. Median hemoglobin and platelet counts were 8.2 g/dL and 40 x10 9/L, respectively. The Median BM blast percentage was 54%, among these patients, there was a higher representation of patients with adverse risk features when compared with the intermediate and favorable group (50%, 34%, and 16% respectively). The molecular landscape of our population showed higher representation of RAS (25%), DMNT3A (23%), TP53 (21%), WT1 (21%), NPM1 (20%), FLT3-ITD (16%), and IDH2 (15%), figure 1. Frontline treatment information was available on 108 patients, of these, 43% were treated with intensive chemotherapy, while 57% of patients were treated with a low-intensity regimen. In terms of outcomes, with a median follow-up time of 6 months, the median overall survival of the whole patient cohort was 9 months (95% CI: 4.3-13.6). Patients aged more than 60 years showed inferior OS compared to younger patients (6 vs. 14 months; p=0.059), respectively, figure 2. Among patients with adverse risk features, the median OS was 5 months (95% CI: 3-6.9, p=0.068) versus those with intermediate (12 months) and favorable risk features (16 months), figure 3. Next, among the somatic mutations with higher representation with known prognostic impact, patients with TP53 mutated showed a significantly inferior OS compared to those with wild type (median 4 vs. 12 months, p=0.006) respectively, figure 4. Patients treated with intensive chemotherapy showed a trend to higher ORR versus low-intensity regimen (89% vs. 74% respectively, p=0.051). Similarly, CR/CRi rates were higher among those treated with intensive chemotherapy compared to those with a low-intensity regimen (85% vs. 70% respectively, p=0.106), figure 5. Conclusion Acute myeloid leukemia is an aggressive hematologic malignancy with a heterogeneous nature. CD71 expression appears to be a common event and was identified in up to 40% of de novo AML cases in our institution. Its expression appears to be associated with cytopenias in addition to the presence of molecular abnormalities commonly associated with an adverse prognosis. Its clinical significance, applicability as a diagnostic marker, and potential as a therapeutic target in AML need to be fully elucidated. Figure 1 Figure 1. Disclosures Alvarado: Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; Sun Pharma: Consultancy, Research Funding. Kantarjian: Immunogen: Research Funding; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; Jazz: Research Funding; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria; Aptitude Health: Honoraria; Novartis: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; BMS: Research Funding; Ascentage: Research Funding; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria.

Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy

2020 ◽  
Vol 38 (30) ◽  
pp. 3506-3517 ◽  
Author(s):  
Chong Chyn Chua ◽  
Andrew W. Roberts ◽  
John Reynolds ◽  
Chun Yew Fong ◽  
Stephen B. Ting ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
Acute Myeloid

PURPOSE The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. PATIENTS AND METHODS Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days −6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m2 on days 1-5 and idarubicin 12 mg/m2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days −6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2. RESULTS Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML. CONCLUSION Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).

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.

Analysis Of Micro-RNA-142 Mutations In a Cohort Of 944 Patients With MDS and AML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2804-2804
Author(s):  
Felicitas Thol ◽  
Aylin Kirchner ◽  
Rabia Shahswar ◽  
Sofia Kade ◽  
Christian Koenecke ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Gene Mutations ◽  
Seed Region ◽  
Target Specificity ◽  
Related Gene ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background MicroRNAs are short (20-40 nucleotides) non-coding RNA molecules that are responsible for the post-transcriptional regulation of gene expression. Aberrant expression of MicroRNAs has been associated with various malignancies. Specifically, downregulation of MicroRNA-142 (miR-142) has been shown to occur in acute myeloid leukemia (AML). Interestingly, also gene mutations in miR-142 have been recently described in de novo AML. So far, little is known about mutations in miR-142 in myeloid malignancies. The aim of this study was to analyze mutations in the miR-142 in a large cohort of 944 patients with AML and myelodysplastic syndrome (MDS). Patients and Methods The patient group consisted of 425 de novo AML patients (excluding AML M3) who entered the multicenter treatment trials AML SHG 0199 or AML SHG 0295, 326 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for secondary acute myeloid leukemia after a prior diagnosis of MDS (sAML) (n=170) or primary MDS (n=156), and 193 primary MDS patients not undergoing intensive therapy or allogeneic HSCT. The genomic region of the miR-142 gene, containing miR-142-5p and miR-142-3p, was sequenced by Sanger sequencing. Patient samples were also assessed for other frequently mutated genes in AML and MDS. Results and Discussion We identified five patients with mutations in miR-142. All mutations were heterozygous point mutations affecting the seed region of miR-142-3p, thereby potentially changing the target specificity of miR-142. Mutations in miR-142 occurred in male and female patients. Of the five patients with mutations in miR-142, only one patient carried the diagnosis of de novo AML (0.2% in de novo AML), while two patients were diagnosed with sAML (1.2% in sAML) and two patients had MDS (0.56% in MDS, corresponding to 0.77% in MDS/AML from MDS). Apart from one patient who underwent allogeneic transplantation for sAML, all other patients with follow-up died of the disease in less than a year. 3 patients had normal cytogenetics, while one patient had a complex karyotype and one patient had a trisomy 8 with translocation t(1;4). No mutated patient showed aberrations typically associated with de novo AML (RUNX1/RUNX1T1, CBFB/MYH11, FLT3-ITD, NPM1 mutations or CEBPA mutations). However, myelodysplasia-related gene mutations such as mutations in the splicing genes or chromatin remodelling genes were found in two patients (one patient with mutated ASXL1 and SRSF2, one patient with mutated U2AF1). Furthermore, one patient had a concomitant mutation in NRAS and IDH1. Thus, the associated mutational profile suggests that miR-142 mutations play a role in the pathogenesis of MDS rather than de novo AML. Conclusion MicroRNA-142 is recurrently but infrequently mutated in MDS and secondary AML evolving from MDS, and some mutations co-occur with MDS-related gene aberrations. As miR-142 mutations affect the seed region of the miRNA the target specificity is likely changed, and the miRNA may lose its tumor suppressor function, which has been implicated from functional studies. Disclosures: Platzbecker: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

scholarly journals Efficacy, Toxicity and Cost of Venetoclax-Based Combinations for the Treatment of Acute Myeloid Leukemia: Real-World Evidence from a Canadian Academic Center

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1253-1253
Author(s):  
Philippe Bouchard ◽  
Annie Brisebois-Boyer ◽  
Anne Beaudry ◽  
Jean-Francois Berthiaume ◽  
Nadia M. Bambace ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Response Rate ◽  
De Novo ◽  
Response Rates ◽  
First Line ◽  
De Novo Aml ◽  
Dose Reductions ◽  
Acute Myeloid

Abstract Introduction: Venetoclax (ven) in combination with azacitidine (aza) or low-dose cytarabine (LDAC) has demonstrated efficacy for the first-line treatment of acute myeloid leukemia (AML) patients who are deemed unfit for intensive induction chemotherapy. The efficacy of ven-based treatment for relapsed or refractory (r/r) AML has not been prospectively evaluated. We have used off-label ven-based combinations to treat r/r AML patients and de novo AML in otherwise fit patients to avoid prolonged hospitalization. The objective of this study was to review the efficacy, toxicity and medication costs associated with ven-based treatments for AML in a Canadian university hospital. Methods: After local IRB approval, we conducted a retrospective chart review of all patients who received ven-based treatments, outside of a clinical trial, for AML at Hopital Maisonneuve-Rosemont. Supportive care included tumor lysis syndrome (TLS) prophylaxis, antiviral, antifungal and antibacterial prophylaxis. Results: 40 patients received 41 ven-based treatments between November 2017 and July 2021. Most patients had r/r AML (n=25, including 17 in first relapse after allogeneic hematopoietic cell transplantation), while 16 patients had de novo AML (10 deemed fit for intensive chemotherapy). Median age was 62 years old. Median duration of ven-based treatment was 4 cycles and median follow-up was 140 days after ven initiation. Ven-aza was used for 33 patients. ven-LDAC was used for the first 7 patients. One patient received ven-gilteritinib. Posaconazole was the main antifungal agent used, with ven dose reduced to 70 mg daily (25 patients). The complete remission (CR) and CR with incomplete hematological recovery (CRi) rate was 46%, higher for de novo vs r/r AML (56% vs 40%). Most patients achieved blast clearance with treatment: CR+CRi+morphologic leukemia-free state (MLFS) rate 63% (75% de novo and 56% r/r). Median overall survival was 258 days (376 days for ven-aza treated patients). All 8 patients (de novo n=5, r/r n=3) with NPM1 or IDH1/2 mutations achieved blast clearance (CR+CRi 87%), while 22 patients with adverse-risk AML as defined by 2017 ELN risk stratification had a lower yet respectable response rate (CR+CRi 36%). Ven-LDAC had no activity in advanced disease, with no response for 6 r/r patients who all had adverse-risk AML, and is no longer used in our institution. The majority of patients were able to receive treatment on an outpatient basis after a brief hospital stay during ven ramp-up. Five patients remained hospitalized for the entire first cycle. Four patients died from infectious causes during the first cycle (2 unfit patients with first line ven-aza, 2 r/r patients with ven-LDAC). Two cases of suspected TLS requiring treatment delays occurred, with no clinical TLS. Venetoclax dose reductions for hematological toxicity were frequently required (51% for all patients, 73% of patients that achieved a response to ven). The average medication cost per cycle of ven-aza was 4 394 $ CAN and was 6 765 $ CAN per cycle for ven-LDAC. Conclusion: In this retrospective real-life review, ven-based treatment produced response rates in line with published prospective evidence among de novo AML patients, and a very clinically meaningful response rate for r/r AML, where therapeutic options are limited and outcomes with conventional chemotherapy dismal. The presence of NPM1 or IDH1/2 mutations was predictive of high response rates. Dose reductions were often required for cytopenias but non-hematological toxicities were limited. Although associated with significant cost, ven-aza represents a safe and effective treatment option for r/r AML which can successfully be delivered in an ambulatory setting. Figure 1 Figure 1. Disclosures Bouchard: Otsuka: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy. Bambace: AbbVie: Consultancy; Excelthera: Research Funding; Kiadis: Research Funding. Bernard: Kiadis: Research Funding; Excelthera: Research Funding; BMS: Consultancy; Taiho: Consultancy. Hebert: BMS-Celgene: Research Funding. Bergeron: Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Servier: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy. OffLabel Disclosure: Venetoclax to treat relapsed or refractory acute myeloid leukemia

Association of TET2 Alterations with NPM1 Mutations and Prognostic Value in De Novo Acute Myeloid Leukemia (AML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 163-163 ◽  
Author(s):  
Olivier Nibourel ◽  
Olivier Kosmider ◽  
Meyling Cheok ◽  
Nicolas Boissel ◽  
Aline Renneville ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Prognostic Value ◽  
De Novo ◽  
Missense Mutations ◽  
Npm1 Mutation ◽  
Tet2 Mutation ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 163 In acute myeloid leukemia (AML), both cytogenetic and molecular abnormalities are strongly associated with prognosis. In particular, in cytogenetically normal AML (CN-AML), FLT3-ITD (internal tandem duplication) carries adverse prognostic factor whereas NPM1 or CEBPA mutations are associated with favorable outcome. Recently, mutations of the ten eleven translocation 2 gene (TET2) have been reported myeloid neoplasms. We evaluated the frequency and prognostic value of TET2 alterations, in a cohort of 111 de novo AML patients. We studied 111 patients aged between 15 years and 69 years with previously untreated de novo AML who had reached complete remission (CR) using intensive chemotherapy. 28 of them also received an allogenic bone marrow transplantation in first CR. Analysis of TET2 sequence variation was performed by direct sequencing of PCR products from 111 genomic DNA samples obtained at diagnosis. Frameshift and nonsense variations were all scored as mutation whereas missense mutations were retained when observed at diagnostic but absent in the CR paired sample obtained. Previously identified single nucleotide polymorphisms (SNP) were not considered. TET2 anomalies were numbered according to Genebank reference FM992369. Paired diagnosis and CR genomic DNAs were analyzed using Affymetrix Genome-Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA). Data were analyzed using Gene Chip Genotyping Console 3.0.2 and Partek Genomics Suite (www.partek.com/). Comparisons were made by Fisher's exact test for binary variables and the Mann-Whitney‘s test for continuous variables. Disease Free Survival (DFS) and overall survival (OS) were calculated according to the Kaplan-Meier method. Comparisons regarding DFS and OS were performed with the log-rank test. 24 acquired TET2 mutations were observed in 19 of the 111 (17%) de novo AML patients, suggesting the alteration of the two TET2 alleles in 5 patients. They included 21 different events: 6 frameshift, 7 non-sense and 11 missense mutations. Four of the missense mutations were located in conserved regions and 7 outside. All of them were detected in the diagnostic sample but were absent in the paired remission sample. Except for two missense mutations (S282F, T492S) both detected in two patients, no recurrent TET2 mutation was observed. Acquired mutations were spread over all exons. No case of uniparental disomy (UPD) was observed and only one patient presented a small deletion of 60Kb in the TET2 gene locus without TET2 mutation. No significant difference was observed between patients with or without TET2 alterations for gender, age, hemoglobin level, platelet count, FAB subtypes distribution and cytogenetics according to MRC classification, but there was a trend for higher WBC count in patients with TET2 alteration. No significant association was observed between TET2 mutations and FLT3 or CEBPA alterations. However, TET2 alterations were significantly associated with NPM1 mutations (p=0.032). In the entire patient cohort, no difference in DFS or OS was seen between patients with and without TET2 alteration. However, a significantly worse DFS was observed for patients presenting TET2 mutations within the subgroup of patients with NPM1 mutations (3y-DFS: 0% vs 66.4%, 95% CI [45.6–87.2], p=0.008) Considering both the favorable prognosis of NPM1 mutations without FLT3-ITD in CN-AML and the absence of clear association between FLT3-ITD and TET2 alterations in this study, prognostic value of the genotype characterized by NPM1 mutation without FLT3-ITD or TET2 alteration (NPM1+FLT3-ITD-TET2-) was compared to other patients within CN-AML group (N=54). NPM1+FLT3-ITD-TET2- patients showed a significantly better DFS and OS compared to other patients in CN-AML group (3y-DFS: 82.1%, 95% CI [59.1–100] vs 37.3%, 95% CI [20.2–54.3], p=0.01; 3y-OS: 80.8%, 95% CI [56.1–100] vs 42.3%, 95% CI [23.3–61.3], p=0.04). In conclusion, we observed point mutations of TET2 in 17% of patients, whereas TET2 deletion or UPD are very rare. In our study, TET2 mutations were clearly associated with NPM1 mutations and carried a negative prognostic impact in this subgroup. Screening for TET2 mutations may improve the characterization of CN-AML and help to identify within the low-risk subgroup with NPM1 mutation and without FLT3-ITD, patients at high risk of relapse. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

scholarly journals Trials and Tribulations in the Frontline Treatment of Older Adults with Acute Myeloid Leukemia

Hemato ◽  
2021 ◽  
Vol 2 (3) ◽  
pp. 515-544
Author(s):  
Adam S. Zayac ◽  
John L. Reagan
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Adult ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Intensive Chemotherapy ◽  
Growth And Survival ◽  
Frontline Treatment ◽  
Life Threatening ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous aggressive hematologic malignancy derived from malignant clones that promote their own growth and survival at the expense of normal hematopoiesis resulting in life-threatening bleeding and infections. Traditional initial AML therapy has been centered on a backbone of intensive chemotherapy often composed of an anthracycline and cytarabine. This strategy has proven most effective in patients less than 60 years of age due to both patient-related tolerability factors as well as changes in AML biology centered on chemotherapy refractory mutational profiles that are seen with advancing age. Recent improvements in frontline AML therapy have been seen in patients 60 years of age and over, a population most typically referred to as “older” adult AML. Herein, we describe the characteristics of “older” adult AML, review the differences in outcomes amongst those 60–75 and those over 75 years of age, and cite challenges in delivering frontline therapies within this group based not only on therapeutic toxicity but also on the patient’s overall level of “fitness” and inherent biology. We also discuss the role of targeted therapies that inhibit specific mutations and have the potential to deliver improved efficacy with less side effects while also recognizing that some selected older AML patients still benefit from intensive induction therapy.

Antileukemic activity of rapamycin in acute myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2527-2534 ◽  
Author(s):  
Christian Récher ◽  
Odile Beyne-Rauzy ◽  
Cécile Demur ◽  
Gaëtan Chicanne ◽  
Cédric Dos Santos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Mammalian Target Of Rapamycin ◽  
Cell Types ◽  
Mtor Inhibition ◽  
Growth And Survival ◽  
Clinical Responses ◽  
De Novo Aml ◽  
Acute Myeloid

AbstractThe mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.

scholarly journals Mini- Vs. Regular-Dose CLAG-M (Cladribine, Cytarabine, G-CSF, and Mitoxantrone) in Medically Less Fit Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) and Other High-Grade Myeloid Neoplasms

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1364-1364 ◽  
Author(s):  
Anna B. Halpern ◽  
Megan Othus ◽  
Kelda Gardner ◽  
Genevieve Alcorn ◽  
Mary-Elizabeth M. Percival ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Intensive Therapy ◽  
Treatment Intensity ◽  
High Grade ◽  
Intensive Chemotherapy ◽  
Myeloid Neoplasms ◽  
Acute Myeloid

Background: Optimal treatment for medically less fit adults with acute myeloid leukemia (AML) remains uncertain. Retrospective data suggest intensive therapy may lead to better outcomes in these patients. However, these findings must be interpreted cautiously because of the possibility of selection bias and other confounders. Ideally, the optimal treatment intensity is defined via randomized trial but whether patients and their physicians are amenable to such a study is unknown. We therefore designed a trial (NCT03012672) to 1) evaluate the feasibility of randomization between intensive and non-intensive therapy in this population and 2) examine the impact of treatment intensity on response rate and survival. We used CLAG-M as high-dose cytarabine-based intensive induction therapy. Rather than selecting different classes of drugs in the 2 treatment arms- which may have different modes of action and therefore confound the question of treatment intensity - we used reduced-dose ("mini") CLAG-M as the non-intensive comparator. Methods: Adults ≥18 years were eligible if they had untreated AML or high-grade myeloid neoplasms (≥10% blasts in blood or marrow) and were medically less fit as defined by having a "treatment related mortality" (TRM) score of ≥13.1, corresponding to a &gt;10-15% 28-day mortality with intensive chemotherapy. Left ventricular ejection fraction ≤45% was the only organ function exclusion. Patient-physician pairs were first asked if they were amenable to randomized treatment allocation. If so, they were randomized 1:1 to mini- vs. regular-dose CLAG-M. If not, in order to evaluate our secondary endpoints, the patient or physician could choose the treatment arm and still enroll on study. Patients and physicians then completed surveys elucidating their decision-making processes. Up to 2 induction courses were given with mini- vs. regular-dose CLAG-M: cladribine 2 or 5 mg/m2/day (days 1-5), cytarabine 100 or 2,000 mg/m2/day (days 1-5), G-CSF 300 or 480µcg/day for weight &lt;/≥76kg in both arms (days 0-5), and mitoxantrone 6 or 18 mg/m2/day (days 1-3). CLAG at identical doses was used for post-remission therapy for up to 4 (regular-dose CLAG) or 12 (mini-CLAG) cycles. The primary endpoint was feasibility of randomization, defined as ≥26/50 of patient-physician pairs agreeing to randomization. Secondary outcomes included rate of complete remission (CR) negative for measurable ("minimal") residual disease (MRD), rate of CR plus CR with incomplete hematologic recovery (CR+CRi), and overall survival (OS). Results: This trial enrolled 33 patients. Only 3 (9%) patient/physician pairs agreed to randomization and thus randomization was deemed infeasible (primary endpoint). Eighteen pairs chose mini-CLAG-M and 12 regular-dose CLAG-M for a total of 19 subjects in the lower dose and 14 subjects in the higher dose arms. The decision favoring lower dose treatment was made largely by the physician in 5/18 (28%) cases, the patient in 11/18 (61%) cases and both in 2/18 (11%). The decision favoring the higher dose arm was made by the patient in most cases 9/12 (75%), both physician and patient in 2/12 (16%) and the physician in only 1/12 (8%) cases. Despite the limitations of lack of randomization, patients' baseline characteristics were well balanced with regard to age, performance status, TRM score, lab values and cytogenetic/mutational risk categories (Table 1). One patient was not yet evaluable for response or TRM at data cutoff. Rates of MRDneg CR were comparable: 6/19 (32%) in the lower and 3/14 (21%) in the higher dose groups (p=0.70). CR+CRi rates were also similar in both arms (43% vs. 56% in lower vs. higher dose arms; p=0.47). Three (16%) patients experienced early death in the lower dose arm vs. 1 (7%) in the higher dose arm (p=0.43). With a median follow up of 4.2 months, there was no survival difference between the two groups (median OS of 6.1 months in the lower vs. 4.7 months in the higher dose arm; p=0.81; Figure 1). Conclusions: Randomization of medically unfit patients to lower- vs. higher-intensity therapy was not feasible, and physicians rarely chose higher intensity therapy in this patient group. Acknowledging the limitation of short follow-up time and small sample size, our trial did not identify significant differences in outcomes between intensive and non-intensive chemotherapy. Analysis of differences in QOL and healthcare resource utilization between groups is ongoing. Disclosures Halpern: Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Othus:Celgene: Other: Data Safety and Monitoring Committee. Gardner:Abbvie: Speakers Bureau. Percival:Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding. Scott:Incyte: Consultancy; Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy. Walter:BioLineRx: Consultancy; Astellas: Consultancy; Argenx BVBA: Consultancy; BiVictriX: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Cladribine is FDA-approved for Hairy Cell Leukemia. Here we describe its use for AML, where is is also widely used with prior publications supporting its use

scholarly journals The Novel Dihydroorotate Dehydrogenase (DHODH) Inhibitor PTC299 Inhibit De Novo Pyrimidine Synthesis with Broad Anti-Leukemic Activity Against Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Sujan Piya ◽  
Marla Weetall ◽  
Josephine Sheedy ◽  
Balmiki Ray ◽  
Huaxian Ma ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Dihydroorotate Dehydrogenase ◽  
Nucleotide Synthesis ◽  
Inhibition Of Proliferation ◽  
Acute Myeloid

Introduction: Acute myeloid leukemia (AML) is characterized by both aberrant proliferation and differentiation arrest at hematopoietic progenitor stages 1,2. AML relies upon de novo nucleotide synthesis to meet a dynamic metabolic landscape and to provide a sufficient supply of nucleotides and other macromolecules 3,4. Hence, we hypothesized that inhibition of de novo nucleotide synthesis would lead to depletion of the nucleotide pool and pyrimidine starvation in leukemic cells compared to their non-malignant counterparts and impact proliferative and differentiation inhibition pathways. PTC299 is an inhibitor of dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme for de novo pyrimidine nucleotide synthesis that is currently in a clinical trial for the treatment of AML. Aim: We investigated the pre-clinical activity of PTC299 against AML in primary AML blasts and cytarabine-resistant cell lines. To confirm that PTC299 effects are due to inhibition of de novo pyrimidine nucleotide synthesis for leukemic growth, we specifically tested the impact of uridine and orotate rescue. In addition, a comprehensive analysis of alteration of metabolic signaling in PI3K/AKT pathways, apoptotic signatures and DNA damage responses were analyzed by Mass cytometry based proteomic analysis (CyTOF) and immunoblotting. The potential clinical relevance of DHODH inhibition was confirmed in an AML-PDX model. Results: The IC50s for all tested cell lines (at 3 day) and primary blasts (at 5-7 day) were in a very low nanomolar range: OCI-AML3 -4.43 nM, HL60 -59.7 nM and primary samples -18-90 nM. Treatment of AML in cytarabine-resistant cells demonstrated that PTC299 induced apoptosis, differentiation, and reduced proliferation with corresponding increase in Annexin V and CD14 positive cells (Fig.1). PTC299-induced apoptosis and inhibition of proliferation was rescued by uridine and orotate. To gain more mechanistic insights, we used an immunoblotting and mass cytometry (CyTOF) based approach to analyze changes in apoptotic and cell signaling proteins in OCI-AML3 cells. Apoptotic pathways were induced (cleaved PARP, cleaved Caspase-3) and DNA damage responses (TP53, γH2AX) and the PI3/AKT pathway were downregulated in response to PTC299. In isogenic cell lines, p53-wildtype cells were sustained and an increased DNA damage response with corresponding increase in apoptosis in comparison to p53-deficient cells was shown. (Fig.2) In a PDX mouse model of human AML, PTC299 treatment improved survival compared to mice treated with vehicle (median survival 40 days vs. 30 days, P=0.0002) (Fig.3). This corresponded with a reduction in the bone marrow burden of leukemia with increased expression of differentiation markers in mice treated with PTC299 (Fig.3). Conclusion: PTC299 is a novel dihydroorotate dehydrogenase (DHODH) inhibitor that triggers differentiation, apoptosis and/or inhibition of proliferation in AML and is being tested in a clinical trials for the treatment of acute myeloid malignancies. Reference: 1. Thomas D, Majeti R. Biology and relevance of human acute myeloid leukemia stem cells. Blood 2017; 129(12): 1577-1585. e-pub ahead of print 2017/02/06; doi: 10.1182/blood-2016-10-696054 2. Quek L, Otto GW, Garnett C, Lhermitte L, Karamitros D, Stoilova B et al. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. The Journal of experimental medicine 2016; 213(8): 1513-1535. e-pub ahead of print 2016/07/06; doi: 10.1084/jem.20151775 3. Villa E, Ali ES, Sahu U, Ben-Sahra I. Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides. Cancers (Basel) 2019; 11(5). e-pub ahead of print 2019/05/22; doi: 10.3390/cancers11050688 4. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv 2016; 2(5): e1600200. e-pub ahead of print 2016/07/08; doi: 10.1126/sciadv.1600200 Disclosures Weetall: PTC Therapeutic: Current Employment. Sheedy:PTC therapeutics: Current Employment. Ray:PTC Therapeutics Inc.: Current Employment. Konopleva:Genentech: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Ablynx: Research Funding; Ascentage: Research Funding; Agios: Research Funding; Kisoji: Consultancy; Eli Lilly: Research Funding; AstraZeneca: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AbbVie: Consultancy, Research Funding; Calithera: Research Funding; Cellectis: Research Funding; Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Sanofi: Research Funding. Andreeff:Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Borthakur:BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; Oncoceutics: Research Funding.

scholarly journals Outcome of Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia before Second-Generation FLT3 Tyrosine Kinase Inhibitors: A Toulouse–Bordeaux DATAML Registry Study

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 773 ◽  
Author(s):  
Sarah Bertoli ◽  
Pierre-Yves Dumas ◽  
Emilie Bérard ◽  
Laetitia Largeaud ◽  
Audrey Bidet ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Intensive Chemotherapy ◽  
Line Treatment ◽  
First Line ◽  
Low Intensity ◽  
First Line Treatment ◽  
Acute Myeloid

A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) improved with gilteritinib, a single-agent second-generation FLT3 tyrosine kinase inhibitor (TKI), compared with standard of care. In this trial, the response rate with standard therapy was particularly low. We retrospectively assessed the characteristics and outcome of patients with R/R FLT3-mutated AML included in the Toulouse–Bordeaux DATAML registry. Among 347 patients who received FLT3 TKI-free intensive chemotherapy as first-line treatment, 174 patients were refractory (n = 48, 27.6%) or relapsed (n = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy (n = 99, 56.9%), azacitidine or low-dose cytarabine (n = 9, 5.1%), other low-intensity treatments (n = 17, 9.8%), immediate allogeneic stem cell transplantation (n = 4, 2.3%) or best supportive care only (n = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, n = 32, 28.1%; relapsed, n = 82, 71.9%), the rate of CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) after high- or low-intensity salvage treatment was 50.0%, with a bridge to transplant in 34.2% (n = 39) of cases. The median overall survival (OS) was 8.2 months (interquartile range, 3.0–32); 1-, 3- and 5-year OS rates were 36.0% (95%CI: 27–45), 24.7% (95%CI: 1–33) and 19.7% (95%CI: 1–28), respectively. In this real-word study, although response rate appeared higher than the controlled arm of the ADMIRAL trial, the outcome of patients with R/R FLT3-mutated AML remains very poor with standard salvage therapy.

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