Mutations In the DNA Methyltransferase Gene DNMT3A Are Highly Recurrent In Patients with Intermediate Risk Acute Myeloid Leukemia, and Predict Poor Outcomes

Abstract Abstract 99 Whole genome sequencing with next generation technologies represents a new, unbiased approach for discovering somatic variations in cancer genomes. Our group recently reported the DNA sequence and analysis of the genomes of two patients with normal karyotype acute myeloid leukemia (AML). Improvements in next generation sequencing technologies (principally, paired-end sequencing) led us to reevaluate the first case (Ley et al, Nature 456:66–72, 2008) with deeper sequence coverage. We discovered a novel frameshift mutation in DNMT3A, one of the three genes in humans (DNMT1, DNMT3A, and DNMT3B) that encodes a DNA methyltransferase that catalyzes the addition of methyl groups to cytosine within CpG dinucleotides. We then sequenced all the coding exons of this gene in 280 additional de novo cases of AML to define recurring mutations. 62/281 de novo AML cases (22%) had mutations with translational effects in the DNMT3A gene. 18 different missense mutations were identified, the most common of which was at amino acid R882 (37 cases). Frameshifts (n=6), nonsense mutations (n=6), splice site mutations (n=3), and a 1.5 Mbp deletion that included the DNMT3A gene were also identified. DNMT3A mutations were highly enriched in cases with intermediate risk cytogenetics (56/166=33.7%; p<0.0001) and were not found in any cases with favorable cytogenetics (0/79; p<0.0001). Genomic 5-methylcytosine content, the general pattern of CpG island methylation, and gene expression patterns were essentially unaltered in genomes with DNMT3A mutations. The median overall survival of all AML patients with DNMT3A mutations was strikingly reduced, regardless of whether the mutation was at R882 or any other site (12.3 vs. 41.1 months, p<0.0001, Figure A). Patients with a FLT3 ITD mutation and no DNMT3A mutation (n=39) had a median survival of 33.5 months, but patients with a FLT3 ITD mutation and any DNMT3A mutation (n=18) had a median survival of 7.7 months (p=0.003, Figure B). Finally, DNMT3A mutation status independently predicted poor outcomes in a Cox Proportional Hazards analysis. In sum, DNMT3A mutations are highly recurrent in de novo AML cases with intermediate risk cytogenetics, and are independently associated with poor survival. These mutations may be valuable for identifying patients who need early intensification of therapy (allogeneic stem cell transplantation and/or innovative early phase clinical trials in first remission or consolidation). Disclosures: Westervelt: Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau. DiPersio:Genzyme: Honoraria.

Download Full-text

Prognostic Impact of the Interaction between DNMT3A mutation and Internal Tandem Duplication of the FLT3 Gene (FLT3-ITD) in Patients with De Novo Mutated NPM1 (NPM1mut) acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-115337 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1492-1492

Author(s):

Guadalupe Oñate ◽

Ana Garrido ◽

Jordi Esteve ◽

Rosa Coll ◽

Montserrat Arnan Sangerman ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

De Novo ◽

Prognostic Impact ◽

Intermediate Risk ◽

Mutational Status ◽

De Novo Aml ◽

Acute Myeloid

Abstract Introduction The association of NPM1mut and FLT3-ITD in de novo acute myeloid leukemia (AML) with intermediate-risk cytogenetics has different prognostic impact depending on the FLT3 allelic burden. Previous studies published by our cooperative group showed that patients with de novo AML of intermediate-risk cytogenetics with NPM1mut and FLT3-ITD low ratio (<0.5, FLT3low) at diagnosis presented an overall survival and relapse rate similar to those with NPM1mut and FLT3wt. Therefore, in the CETLAM-2012 protocol, patients with FLT3low NPM1mut AML are not considered for allogenic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1). Recent studies suggest that the co-occurrence of DNMT3A mutation in FLT3-ITD NPM1mut AML patients confers a worse prognosis regardless of FLT3-ITD ratio. We analysed our data to determine whether these findings were confirmed in our cohort, specifically in the low FLT3-ITD ratio patients, since this could have therapeutic implications. Methods and patients A total of 163 patients with de novo AML, intermediate-risk cytogenetics and NPM1mut were analysed (median age 53 years (18-72); male:female 72:91 (0.79)). Eighty patients (49%) harboured an FLT3-ITD, with a high allelic ratio in 42 of 76 patients with available ITD/wt ratio (55%). They were included in the AML-2003 (n=49) and AML-2012 (n=114) CETLAM protocols. Proportion of patients undergoing alloHSCT in CR1 is detailed in table 1. Bone marrow samples from diagnosis were studied for DNMT3A mutations as previously described. The definition of complete remission (CR), overall survival (OS), leukemia-free survival (LFS) and risk of relapse (RR) followed recommended ELN criteria. The Kaplan-Meier method was used to estimate the distribution of LFS and OS, for RR cumulative incidence was used. Results Out of the 163 patients with AML of intermediate risk cytogenetics and NPM1mut, 78 presented DNMT3A mutations (48%). Of these, 62 (79%) presented mutations in codon R882 or corresponded to DNA insertions/deletions while 16 (21%) harboured missense mutations. Presence of DNMT3A mutation did not associate with FLT3-ITD (ITD/85 DNMT3Awt vs ITD/78 DNMT3Amut, p=0.394). In the entire cohort, 5-year OS, LFS and RR were 58±4.5%, 59±4.6% and 27±13.9%. FLT3-ITD ratio confirmed its prognostic impact when analysing FLT3wt (n=83) vs FLT3low (n=34) vs FLT3high (n=42) patients (5-year OS of 68±6% vs 62±8.7% vs 37±8.6%; p=0.002; and 5-year RR of 18±9.4% vs 27±16.1% vs 41±23.2%; p=0.023). On the contrary, DNMT3Amut did not exert any effect on overall outcome (5-yr OS DNMT3Awt vs DNMT3Amut 61±6.2% vs 55±6.2%; p=0.234) When DNTM3A mutational status was considered, the impact of FLT3-ITD on outcome was mitigated in wild-type DNMT3A population. Thus, we found that DNMT3Awt patients presented no statistical differences in OS according to FLT3 mutational status or ratio: FLT3wt (n=46) vs FLT3-ITD (n=39) was 67±8.5% vs 57±8.2%; p=0.122, whereas FLT3wt (n=46) vs FLT3low (n=18) vs. FLT3high (n=19) was 67±8.5% vs. 66±11.5% vs 46±11.8%; p=0.088 (image 1A).This was also seen in relation to LFS and RR according to FLT3 ratio: 5-yr LFS of FLT3wt vs FLT3low vs FLT3high was 72±7.9% vs 61±12.6% vs 51±13.4%; p=0.244 and 5-year RR of the same groups: 19±8.8% vs 26±12.5% vs 27±21.9%; p=0.724 (image 2A). In the DNMT3Amut group, patients with FLT3-ITD (n=41) presented shorter OS than those with FLT3wt (n=37) with an OS of 37±10.7% vs 69±7.8%; p=0.028. When FLT3 ratio was considered, FLT3wt (n=37) vs FLT3low (n=16) vs FLT3high (n=23) showed an OS of 69±7.8% vs. 58±13.2% vs 27±13.1%; p=0.038 (image 1B). Similar results were seen in LFS according to FLT3 ratio (FLT3wt (n=29) vs FLT3low (n=16) vs FLT3high (n=20) 71±8.6% vs 53±12.9% vs 18±13.8%; p=0.012). Finally, we observed significant differences in the 5-year RR when considering DNMT3Amut patients in relation to FLT3 ratio (FLT3wt vs FLT3low vs FLT3high 18±10.6% vs 27±20% vs 54±28.8%; p=0.021)(image 2B). Conclusions In this study, patients with NPM1mut and FLT3-ITDlow presented a similar outcome to patients with NPM1mut and FLT3wt regardless of DNMT3A mutational status. These results support the modification of alloHCST policy in CR1 in CETLAM-2012, which do not consider alloHSCT for patients with FLT3low. On the other hand, concurrence of DNMT3A mutation may have an added negative effect in patients with NPM1mut and FLT3-ITDhigh, which should be further confirmed in larger studies. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Prospective Multicenter Study for Patients with Therapy - Related Acute Myeloid Leukemia (AML) Using Intensive Induction and Postremission Therapy.

Blood ◽

10.1182/blood.v108.11.2001.2001 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2001-2001

Author(s):

Bernhard Josef Wormann ◽

Claudia Schoch ◽

Albrecht Reichle ◽

Peter Staib ◽

Wolf-Dieter Ludwig ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Survival Rate ◽

Autoimmune Disease ◽

Median Survival ◽

Myeloid Leukemia ◽

De Novo ◽

Postremission Therapy ◽

De Novo Aml ◽

Acute Myeloid

Abstract Therapy - related acute myeloid leukemia (t-AML) is one of the most severe long - term complications of successful cancer treatment using chemo- and/or radiotherapy. Its frequency is increasing, also in patients with autoimmune disease after cytostatic therapy. Cytogenetic and molecular biological analysis have identified several subgroups, however large prospective trials on optimal treatment are lacking. In 1999 the German AMLCG started a prospective multicenter randomized trial including patients with t-AML. Patients received induction treatment, randomized to either TAD (standard dose thioguanine, araC, daunorubicin) followed by HAM (HAM, high-dose araC 1 or 3 g/m2x6/mitoxantrone 10mg/m2x3), or to induction by two courses of HAM. Above the age of 60 years, the second induction course was given only to patients with 5 % or more residual bone marrow blasts. Postremission therapy was randomized to either TAD followed by three year maintenance, or to autologous stem cell transplantation. Patients under the age of 60 years with a suitable donor received an allogeneic stem cell transplantation. 137 patients were included. The most frequent primary diagnoses were breast cancer (n = 43), Non Hodgkin’s lymphoma (n = 18), Hodgkin’s lymphoma (n = 9), autoimmune disease (n = 9), multiple myeloma (n = 5), germ cell tumor (n = 5) and ovarian cancer (n = 5). The median age was 57 years (23 – 77). 64 of 119 currently evaluable patients achieved CR (53,8 %), 34 (29 %) had persistent leukaemia, 20 (17,1 %) were classified as early death without evidence of disease. The CR rate was significantly lower than in 1532 patients with de novo AML (65,6 %), but higher than in patients with AML after MDS (46,8 %). Cytogenetic analysis was routinely performed in all patients with t-AML. 21 (17,7 %) had a favourable karyotype, 47 (39,5 %) an unfavourable karyotype, 51 (42,9 %) were classified as intermediate. Patients with favourable karyotype had a median survival of 25 months and an estimated survival rate at 5 yrs of 47,4 %. Median survival was 3 months for patients with unfavourable karyotype with an estimated survival rate of 12,5 %, while the intermediate group had a median survival of 19 months and an estimated survival rate of 24,2 %. This is one of the largest prospective studies on the therapy of patients with t-AML. The CR rate of all patients was inferior to patients with de novo AML. However, this difference was mainly due to the high number of patients with unfavourable karyotype. Within cytogenetically defined subgroups, the prognosis of t-AML patients does not differ significantly from patients with de novo AML.

Download Full-text

Importance of DNMT3A Gene mutations detection in Prognostic Analyses of Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.5321.5321 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5321-5321

Author(s):

Ekaterina Petrova ◽

Irina Martynkevich ◽

Lyubov Polushkina ◽

Lyudmila Martynenko ◽

Marina Ivanova ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Molecular Markers ◽

Myeloid Leukemia ◽

De Novo ◽

Common Mutation ◽

Intermediate Risk ◽

Wild Type ◽

Laboratory Parameters ◽

De Novo Aml ◽

Acute Myeloid

Abstract Objectives and background: Normal karyotype (NK) in AML patients accounts for nearly 45% of all cases and were assigned into intermediate risk group. The identification of new molecular markers in this group is the focus of most of researches. The application of the next-generation sequence techniques led to detect molecular markers with valuable prognostic significance. F.e., identification of DNMT3A mutations has gained the tremendous attention in recent times, because of its essential role in cell development, high frequency in AML patients and association of poor clinical outcome. Objects: to analyse character and frequency of DNMT3A mutations in AML patients; to study their associations with clinical and laboratory parameters and other molecular markers; to investigate their prognostic value. Methods: The screening of DNMT3A mutations was performed by the high-resolution melting curve analysis. Mutations in FLT3, CKIT and NPM1 were analysed by polymerase chain reaction and in NRAS by sequencing. Standard GTG-method was used for patients karyotyping. The investigation group included 98 AML patients. Missense mutations of DNMT3A exon 23 (R882) were identified in 16 (16,3%) de novo AML patients. The most common mutation in DNMT3A was R882H (n=9;56.3%), followed by R882C (n=6;37.5%), and R882S (n=1;6.2%). All but one patients (with mutation R882S) were heterozygous and retained a wild-type allele. Patients with isolated DNMT3A mutations were seen in 3 cases; 3 pts with R882C had also mutations in NRAS; 3 pts had DNMT3Amut/FLT3-ITDmut; 1 pt - DNMT3Amut/FLT3-ITDmut/ FLT3-TKDmut; 4 pts - DNMT3Amut/FLT3-ITDmut/ NPM1mut and 3 pts - DNMT3Amut/ NPM1mut. Results: Patients who harbored a mutation in DNMT3A had higher white blood cells count (p=0.039) at diagnosis and more frequently belonged to FAB group M4 (p=0.033), as compared with DNMT3A wild-type. Of the 16 patients who had AML with DNMT3A mutation, 13 (26.5%) had tumors with normal cytogenetic profiles (of a total of 49 cytogenetically normal samples) (p=0.006). There was no statistical correlation with other parameters, including sex, age, hemoglobin, and platelet count between patients with and without DNMT3A mutations (p>0.05). DNTM3A mutations were significantly more prevalent in NPM1 positive cases when compared to NPM1 wild type cases (p=0.000). DNTM3A mutations were also more dominant in FLT3-ITD positive pts than wild type (p=0.000). In contrast, DNMT3A mutations were not observed in cases with CKIT mutations indicating that these mutations can be mutually exclusive in nature. There was a statistical significance between overall survival (OS) of NK-AML pts with DNMT3A mutations and DNMT3Awt (p=0.032). Figure 1 Figure 1. Conclusions: AML with DNMT3A mutations represent the group, homogeneous on a number of clinical and laboratory parameters. DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile. FLT3-ITD and NPM1 mutations appear as a major significant coexisting genetic mutations in DNMT3Amut pts. The presence of DNMT3A mutations can be considered as independent adverse prognostic factor for OS, suggesting that testing of DNMT3A mutations can help further improve risk stratification in NK-AML. References: Ley T.J., Ding L., Walter M.J., McLellan M.D. et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010;363:2424-2433. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Risk-Stratified Therapy and the Intensive Use of Cytarabine Improves the Outcome in Childhood Acute Myeloid Leukemia: The AML99 Trial From the Japanese Childhood AML Cooperative Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.7948 ◽

2009 ◽

Vol 27 (24) ◽

pp. 4007-4013 ◽

Cited By ~ 151

Author(s):

Ichiro Tsukimoto ◽

Akio Tawa ◽

Keizo Horibe ◽

Ken Tabuchi ◽

Hisato Kigasawa ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Death Rate ◽

Myeloid Leukemia ◽

De Novo ◽

Risk Group ◽

Intermediate Risk ◽

Free Survival ◽

De Novo Aml ◽

Acute Myeloid

Purpose To improve the prognosis in children with newly diagnosed acute myeloid leukemia (AML) by introducing a dose-dense intensive chemotherapy regimen and an appropriate risk stratification system. Patients and Methods Two hundred forty children with de novo AML were treated with continuous cytarabine-based induction therapy and stratified to three risk groups based on the initial treatment response, age, and WBC at diagnosis and cytogenetics. All of the patients were treated with intensive consolidation chemotherapy including three or four courses of high-dose cytarabine. Allogeneic hematopoietic stem-cell transplantation (HSCT) was indicated for only the intermediate-risk patients with matched related donors and for all the high-risk subsets. Results Two hundred twenty-seven children (94.6%) achieved a complete remission (CR). Four children demonstrated induction death. The median follow-up of the live patients was 55 months (range, 37 to 73 months). The 5-year overall survival of all 240 children was 75.6% (95% CI, 70.3% to 81.4%) and event-free survival was 61.6% (95% CI, 55.8% to 68.1%). The 5-year disease-free survival in each risk group were 71.3% (95% CI, 63.4% to 80.2%) in the low-risk group (n = 112), 59.8% (95% CI, 50.6% to 70.7%) in the intermediate-risk group (n = 92), and 56.5% (95% CI, 39.5% to 80.9%) in the high-risk group (n = 23). Eight children died during the first CR, including four after HSCT. Conclusion A high survival rate, 75.6% at 5 years, was achieved for childhood with de novo AML in the AML99 trial. The treatment strategy was well tolerated with only 1.7% induction death rate and 3.5% remission death rate. Low-risk children were successfully treated with chemotherapy alone.

Download Full-text

Therapy-related acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases

Blood ◽

10.1182/blood.v65.6.1364.bloodjournal6561364 ◽

1985 ◽

Vol 65 (6) ◽

pp. 1364-1372 ◽

Cited By ~ 213

Author(s):

SD Michels ◽

RW McKenna ◽

DC Arthur ◽

RD Brunning

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Median Survival ◽

Myeloid Leukemia ◽

De Novo ◽

Poor Response ◽

Significant Difference ◽

Multiple Cell ◽

De Novo Aml ◽

Acute Myeloid

Abstract This study consists of 65 patients (pts) who developed a myelodysplastic syndrome (MDS) (39 pts) or acute myeloid leukemia (AML) (26 pts) following chemotherapy and/or radiotherapy; the interval from the onset of therapy to bone marrow abnormality ranged from 11 to 192 months (median, 58). Thirty-three patients had been previously treated for lymphoproliferative diseases, 29 for carcinoma, and three for a nonneoplastic disorder. Approximately 30% of the cases presenting in the MDS phase evolved to AML in one to 12 months (median, 3.5). The AML in 49% of the cases was not readily classified according to French- American-British (FAB) criteria; the primary difficulty in classification related to the involvement of multiple cell lines. Among the cases that could be classified, all FAB types were represented except for M1; M2 was the most frequent type. Clonal chromosome abnormalities were found in marrow specimens from 22 of 24 (92%) patients studied with G banding; 11 had abnormalities of chromosomes 5 and/or 7. The median survival for all patients was four months with no significant difference between those treated and not treated with antileukemic therapy. The median survival was three months for the patients presenting with AML, six months for the patients with AML following an MDS, and four months for the patients with an MDS that did not evolve to AML. The findings in the present study suggest that there are three stages of therapy-related panmyelosis: (1) pancytopenia with associated myelodysplastic changes, (2) a frank MDS, and (3) overt AML. Many patients will present in the stage of overt AML that differs from de novo AML primarily by the high incidence of trilineage involvement, difficulty in classification, frequent cytogenetic abnormalities, and poor response to antileukemic therapy. The myelodysplastic phase, with or without evolution to acute leukemia, is a highly lethal disease with a median survival comparable to that of the patients who present with AML.

Download Full-text

The Prognostic Impact Of Complex Gene Mutation In The Intermediate Risk Karyotype Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v122.21.1418.1418 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1418-1418

Author(s):

Satoshi Wakita ◽

Hiroki Yamaguchi ◽

Takeshi Ryotokuji ◽

Tuneaki Hirakawa ◽

Ikuko Omori ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Gene Mutation ◽

Myeloid Leukemia ◽

De Novo ◽

Gene Mutations ◽

Nippon Medical School ◽

Prognostic Impact ◽

Intermediate Risk ◽

De Novo Aml ◽

Acute Myeloid

Abstract Background Many gene mutations were detected and overlapped in de novo acute myeloid leukemia (AML), but the prognosis of complex gene mutation remains to be unclear. In this study, we analyzed the prognostic impact of complex gene mutation in de novo AML patients with the intermediate risk karyotype. Methods We analyzed 143 samples from de novo AML patients with the intermediate risk karyotype diagnosed at Nippon Medical School Hospital from 2000 to 2012. Bone marrow or peripheral blood samples containing 20% or more blast cells were used for analyses. Mutation analyses were performed using PCR method for FLT3-ITD, FLT3-TKD and MLL-PTD, and direct sequence for NPM1, C/EBPα, DNMT3a, IDH1/2, TET2 and N/K-RAS. Results The NPM1 (39.9%), DNMT3a (26.6%), FLT3-ITD (24.5%), IDH1/2 (18.9%), TET2 (17.5%), C/EBPα (14.7%), N/K-RAS (14.0%) and MLL-PTD (6.3%) mutations were detected in our cohort, respectively. When we performed prognostic analyses for mutations of these genes, DNMT3 mutation and FLT3-ITD were isolated as a poor prognostic factor in overall survival (OS) , respectively (DNMT3a mutation positive: n=39, 3yOS 17.9%. negative: n=104, 3yOS 33.2%. p=.0056) (FLT3-ITD positive: n=35, 3yOS 12.2%. negative: n=108, 3yOS 35.0%. p=.0077). Moreover, in the FLT3-ITD positive cases, OS of patients with DNMT3a R882 mutation was significantly shorter than those without R882 mutation (R882 positive: n=20, 3yOS: 0%. negative: n=15, 3yOS 25.0%. p<.0256). Interestingly, High rate of patients with FLT3-ITD (91.4%), NPM1 (89.5%), DNMT3a (92.1%), TET2 (84.0%), and IDH1/2 (88.9%) mutations were detected other overlapped mutations, respectively. The frequency of the overlapped mutations in patients with DNMT3a mutation, especially with mutations on R882, was significantly higher than those in patients without them (DNMT3a: p=.0001, R882: p<.0001). For total cohort, the rates of and OS and relapse free survival (RFS) in patients with three or more overlapping mutations (complex gene mutation: CGM) were significantly lower than those in patients without them (CGM+: n=36, 3yOS 5.6%. CGM-: n=107, 3yOS 37.7%. p<.0001) (CGM+: n=12, 3yRFS: 8.3%. CGM-: n=57, 3yRFS: 36.0%. p=.0013). Moreover, among the patients without FLT3-ITD, the rates of RFS and OS at 3 years in patients with complex gene mutation were significantly lower than those in patients without them (CGM+: n=11, 3yOS 5.6%. CGM-: n=96, 3yOS 37.7%. p<.0408) (CGM+: n=4, 3yRFS: 8.3%. CGM-: n=51, 3yRFS: 36.0%. p=.0179). Conclusions Our study revealed that the gene mutations appeared to be overlapped, and the complex gene mutation significantly affected the prognosis of de novo AML with the intermediate risk karyotype. Intriguingly the DNMT3a mutation may contribute to an occurrence of complex gene mutation by giving genetic instability to AML cells. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Antileukemic activity of rapamycin in acute myeloid leukemia

Blood ◽

10.1182/blood-2004-06-2494 ◽

2005 ◽

Vol 105 (6) ◽

pp. 2527-2534 ◽

Cited By ~ 207

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.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.20.00572 ◽

2020 ◽

Vol 38 (30) ◽

pp. 3506-3517 ◽

Cited By ~ 4

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).

Download Full-text

Expression of c-mpl mRNA, the receptor for thrombopoietin, in acute myeloid leukemia blasts identifies a group of patients with poor response to intensive chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.6.2262 ◽

1997 ◽

Vol 15 (6) ◽

pp. 2262-2268 ◽

Cited By ~ 31

Author(s):

M Wetzler ◽

M R Baer ◽

S H Bernstein ◽

L Blumenson ◽

C Stewart ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Prognostic Factor ◽

Myeloid Leukemia ◽

De Novo ◽

Prognostic Significance ◽

Poor Response ◽

Significant Difference ◽

De Novo Aml ◽

Cd34 Expression ◽

Acute Myeloid

PURPOSE c-mpl, the human homolog of v-mpl, is the receptor for thrombopoietin. Given that c-mpl expression carries an adverse prognosis in myelodysplastic syndrome and given the prognostic significance of expression of other growth factor receptors in other diseases, we attempted to determine whether c-mp/mRNA expression is a prognostic factor in acute myeloid leukemia (AML). PATIENTS AND METHODS We analyzed bone marrow samples from 45 newly diagnosed AML patients by reverse-transcription polymerase chain reaction. RESULTS Samples from 27 patients (60%) expressed c-mpl mRNA (c-mpl+); their clinical and laboratory features were compared with those of the 18 patients without detectable levels of c-mpl(c-mpl-). No significant differences in age, sex, leukocyte count, French-American-British subtype, or karyotype group were found. c-mpl+ patients more commonly had secondary AML (41% v 11%; P = .046) and more commonly expressed CD34 (67% v 12%; P = .0004). There was no significant difference in complete remission (CR) rate. However, c-mpl+ patients had shorter CR durations (P = .008; median, 6.0 v > 17.0 months). This was true when only de novo AML patients were considered and when controlling for age, cytogenetics, or CD34 expression. There was a trend toward shorter survival in c-mpl+ patients (P = .058; median, 7.8 v 9.0 months). CONCLUSION These data suggest that c-mpl expression is an adverse prognostic factor for treatment outcome in adult AML that must be considered in the analysis of clinical studies using thrombopoietin in AML.

Download Full-text