scholarly journals 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 ◽  
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.

High Expression Levels of Iaps Predict Poor Overall Survival in Childhood De Novo Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4396-4396
Author(s):  
Ingo Tamm ◽  
Stephan Richter ◽  
Doreen Oltersdorf ◽  
Ursula Creutzig ◽  
Jochen Harbott ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
High Expression ◽  
Prognostic Impact ◽  
Poor Overall Survival ◽  
Expression Levels ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Apoptosis-related proteins are important molecules for predicting chemotherapy response and prognosis in adult acute myeloid leukemia (AML). However, data on the expression and prognostic impact of these molecules in childhood AML are rare. Using flow cytometry and western blot analysis, we therefore investigated 45 leukemic cell samples of children with de novo AML enrolled and treated within the German AML-BFM93 study for the expression of apoptosis-regulating proteins (CD95, Bcl-2, Bax, Bcl-xL, Procaspase-3, XIAP, cIAP-1, Survivin). XIAP (p&lt;0.002) but no other apoptosis regulators showed maturation-dependent expression differences as determined by FAB morphology with the highest expression levels observed within the immature M0/1 subtypes. XIAP (p&lt;0.01) and Bcl-xL (p&lt;0.01) expression was lower in patients with favorable than intermediate/poor cytogenetics. After a mean follow-up of 34 months, a shorter overall survival was associated with high expression levels of XIAP {30 (n=10) vs. 41 months (n=34); p&lt;0.05} and Survivin {27 (n=10) vs. 41 months (n=34); p&lt;0.05}. We conclude that apoptosis-related molecules are associated with maturation stage, cytogenetic risk groups and therapy outcome in childhood de novo AML. The observed association of XIAP with immature FAB types, intermediate/poor cytogenetics and poor overall survival should be confirmed within prospective pediatric AML trials.

Decitabine and Sorafenib Therapy in Patients with FLT3-ITD Mutant Acute Myeloid Leukemia Is Associated with High Response Rates—a Single Institute Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5284-5284 ◽  
Author(s):  
Monica Reddy Muppidi ◽  
Elizabeth A. Griffiths ◽  
James E. Thompson ◽  
Laurie A Ford ◽  
Craig W Freyer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Case Series ◽  
De Novo Aml ◽  
Dna Hypomethylating Agent ◽  
Acute Myeloid

Abstract Introduction: Patients with acute myeloid leukemia (AML) characterized by FMS-like tyrosine kinase-3 (FLT-3) internal tandem duplication (ITD) mutations have poor outcomes, especially in the relapsed setting. Although small molecule inhibitors of FLT-3 have been explored for these patients, many inhibitors have demonstrated limited single-agent efficacy with short response durations. Sorafenib, a multi-kinase inhibitor with activity against FLT-3, has previously been evaluated alone and in combination with induction chemotherapy or azacytidine in AML patients. Here we describe our experience with the combination of the DNA hypomethylating agent, decitabine (D), and sorafenib (S) for the treatment of FLT-3 ITD mutant AML. Methods: We retrospectively reviewed records of patients with FLT-3 ITD mutant AML who were treated off protocol with decitabine and sorafenib from 2011-present. Descriptive statistics, treatment response, and overall survival were recorded. Results: A total of six patients were identified. Mean age was 56 (range 34-70) years. Two-thirds (4/6) were female. All patients were confirmed to have recurrence of de novo AML characterized by FLT-3 ITD mutations prior to therapy. Patients received at least 1-2 cycles of concurrent decitabine 20 mg/m2 for 10 days and sorafenib 200-400 mg twice a day for 28 days. Five patients had relapsed/refractory AML (RR-AML) following 1-3 prior therapies. One patient had de novo AML in complete remission with incomplete count recovery (CRi) and received DS as consolidation. The overall response rate was 83%. Eighty percent (4/5) of patients with RR-AML attained CRi. One patient receiving DS consolidation attained complete remission (CR). Two patients received subsequent allogeneic stem cell transplantation with one individual still alive after 348 days. FLT3 ITD allelic ratio (available on 3 patients) decreased after DS therapy and correlated with CRi. Median overall survival was 111 days (range 59-348) from the initiation of DS to death from any cause or last known follow-up. Two patients developed treatment-related neutropenic fever/sepsis and elevated liver enzymes, respectively, which did not require dose adjustment. One patient developed heart failure of uncertain etiology. Conclusions: In this single institute case series, we demonstrated that the combination of decitabine (10 days) and sorafenib was well tolerated, resulted in high CR/CRi rates (80%), and prolonged overall survival in patients with heavily pretreated relapsed/refractory FLT-3 ITD mutant AML. Further investigation of this regimen in clinical trials is warranted. Table 1: Case series Patient Age(years) Sex No. of Prior therapies PriorAlloSCT * Blasts Prior to DS (%) No. of DSCycles Responseto therapy Overall survival (Days) 1 54 Female 3 N BM 70% 1 CRi 141 2 70 Female 1 N PB 53% 2 CRi 82 3 64 Male 1 N BM 68% 2 CRi 62 4 60 Male 1 N BM 2% 1 CR 198 5 34 Female 3 Y PB 48% 1 NR 348 6 58 Female 3 Y NA 2 CRi 59 Figure 1 Figure 1. *Allogeneic stem cell transplantation Disclosures Off Label Use: We are going to discuss the use of decitabine and sorafenib combination in relapsed/refractory FLT3 mutant AML. Decitabine is a DNA hypomethylating agent and sorafenib is a multikinase inhibitor, both of which have been evaluated individually in AML patients..

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

Blood ◽  
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.

The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2137-2145 ◽  
Author(s):  
Sabine Kayser ◽  
Konstanze Döhner ◽  
Jürgen Krauter ◽  
Claus-Henning Köhne ◽  
Heinz A. Horst ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Negative Impact ◽  
Primary Malignancy ◽  
De Novo Aml ◽  
The Impact ◽  
Acute Myeloid

Abstract To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

Acute Myeloid Leukemia with Coexpression of Lymphoid-Associated Antigens: Clinicobiological Associations and Prognostic Implications,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3596-3596
Author(s):  
Georgia Voutiadou ◽  
Konstantina Kotta ◽  
Barbara Tachynopoulou ◽  
Apostolia Papalexandri ◽  
Chryssanthi Vadikolia ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Prognostic Impact ◽  
Prognostic Implications ◽  
Cytogenetic Profile ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 3596 Immune phenotyping plays a critical role in the diagnosis and classification of acute leukemia. Several studies have reported a variable proportion of patients with acute myeloid leukemia (AML) expressing lymphoid-associated antigens (LAA). The exact frequency and true clinical significance of this phenomenon remains undefined due to inconsistencies between series, likely related to methodological aspects or potential case selection biases. We retrospectively evaluated the expression of LAA in blast cells from 278 consecutive and unselected patients with AML diagnosed in our Department between 2002 and 2010. The patient cohort included 168 males and 110 females with a median age of 61 years (range, 10–88); 146/278 cases were above the age of 60. Within this cohort, 190 cases (68%) had de novo AML, whereas the remaining 88 cases (32%) concerned secondary AML (sAML) to either MDS (n=80) or other non-hematologic malignancies (n=8). Patients were treated uniformly according to age with Aracytin/Idarubicin induction regimens (“3+7” or “2+5” for ages \q60 or ≥60, respectively). The immunophenotype was determined by flow cytometric analysis of (mainly) bone marrow aspirate and/or peripheral blood samples utilizing a primary CD45/side scatter (SSC) gating procedure with antibodies against CD7, CD13, CD19, CD33, CD4, CD10, CD34, CD117, CD64, HLA-DR, CD20, CD2, CD15, CD56, CD14, CD8, MPO, CD3, CD79a, CD22, TdT and lysozyme; a cut-off value for positivity of 20% was adopted. Overall, we identified 153/278 cases (55%) expressing at least one LAA. The most commonly expressed LAAs were CD4 (outside AML with monocytic differentiation), CD56, CD7, CD2, CD10 and CD79a (in 39%, 33%, 29%, 14%, 10% and 8% of LAA+ AML cases, respectively); interestingly, all CD79a-positive cases co-expressed at least one more LAA. A significant association was identified between LAA expression and cytogenetic profile: in particular, at least one LAA was detected in 37/50 cases (74%) with adverse cytogenetics (SWOG unfavorable and/or monosomal karyotype), compared to 24/41 (58%) cytogenetically favorable cases and 68/134 (51%) cytogenetically intermediate risk cases (p=0.01). No other statistically significant associations were found for LAA expression (positive vs. negative) in respect to age and complete remission (CR) rate. Furthermore, the frequency of LAA-positive cases was identical (55%) in both de novo AML (105/190 cases) and sAML (48/88 cases). Monoparametric statistical analysis was also performed individually for each of the six more frequent LAAs. Significant associations (p<0.05) were identified between: (i) CD7 expression and adverse cytogenetics; (ii) CD10 expression and adverse cytogenetics as well as failure to achieve CR, at both cohort level as well as patients \q60 years with de novo AML; and (iii) CD2 expression and shorter overall and disease-free survival (DFS and OS, respectively). Cox-multivariate analysis identified CD2 expression in addition to advanced age, sAML and adverse cytogenetic profile as negative prognostic indicators (p=0.05) for both DFS and OS. In conclusion, expression of LAAs is frequent in AML, among both de novo AML and sAML cases, and significantly associated with adverse cytogenetics. Although the negative prognostic impact of CD2 expression is noteworthy, however, the precise prognostic implications of the expression of individual LAAs are hard to define on single institution retrospective series and will require evaluation in large prospective and well-controlled studies. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 99-99
Author(s):  
Timothy J Ley ◽  
Li Ding ◽  
Matthew J. Walter ◽  
Michael D. McLellan ◽  
Tamara Lamprecht ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Intermediate Risk ◽  
Next Generation ◽  
De Novo Aml ◽  
Poor Outcomes ◽  
Acute Myeloid

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.

Clinical Implications of Reticulin Fibrosis of Bone Marrow in De Novo Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2585-2585
Author(s):  
Tzung-Chih Tang ◽  
Hung Chang ◽  
Chien-Feng Sun ◽  
Lee-Yung Shih ◽  
Po Dunn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Recovery Duration ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 2585 Background: Microenvironment of bone marrow (BM) plays an important role to support proliferation, renewal and differentiation of hematopoietic stem cells. Whether the stroma of BM affects leukemic cells with the same manner, or impacts on the prognosis in leukemia patients, has not been fully investigated. Previous studies have described that increased reticulin content in the BM is associated with poor outcome in patients with acute lymphoblastic leukemia, chronic myeloid leukemia and primary myelofibrosis, but there is no cohort study to determine the clinical correlation between degree of reticulin fibrosis of BM and acute myeloid leukemia (AML). To investigate prognostic impact of reticulin fibrosis on de novo AML, 881 patients diagnosed between Jun 1999 to Dec 2011 in Chang Gung Memorial Hospital and treated with anthracycline-containing induction chemotherapy were retrospectively reviewed. Patients and methods: According to the grading of reticulin content in the bone marrow, we categorized the 881 patients into four groups: A. BM easily aspirated without biopsy, n = 698; B. Reticulin grade 0, n = 99; C. Reticulin grade 1–2, n = 51; D. Reticulin grade 3–4, n = 33. The induction failure (IF) rate after treatment with induction chemotherapy, the recovery duration of absolute neutrophil count (ANC) greater than 0.5 × 109/L in patients who achieved the first complete remission, the overall survival (OS) and relapse-free survival (RFS) in four groups were analyzed. Based on the cytogenetic or molecular features, 648 of the patients were stratified into unfavorable, intermediate and favorable risk groups, and the clinical significance of reticulin fibrosis of BM were also examined for various risk groups. Results: Of the 881 patients, the patients in group D had a statistically higher IF rate (P = 0.0108) and longer ANC recovery duration (P = 0.0008). But the OS and RFS between four groups were not significantly different (P = 0.5146 and 0.3853, respectively). After risk stratified by cytogenetic and molecular analysis, increased reticulin content of BM (group C or D) had an adverse impact on OS in the intermediate and favorable risk groups (P = 0.006 and 0.0215, respectively). Conclusion: Reticulin content of BM influences the IF rate and myeloid recovery for the patients of de novo AML, and affects OS in patients with intermediate or favorable risk factors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals De Novo and Secondary Acute Myeloid Leukemia, Real World Data on Outcomes from the French Nord-Pas-De-Calais Picardie Acute Myeloid Leukemia Observatory

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4013-4013 ◽  
Author(s):  
Loïc Renaud ◽  
Olivier Nibourel ◽  
Celine Berthon ◽  
Christophe Roumier ◽  
Céline Rodriguez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Supportive Care ◽  
Real World ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Secondary Aml ◽  
Secondary Acute Myeloid Leukemia ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background. Population-based registries may provide data complementary to that from clinical intervention studies. Registries with high coverage of the target population reduce the impact of selection on outcome and the subsequent problem with extrapolating data to nonstudied populations like secondary Acute Myeloid Leukemia (AML). Actually, secondary AML are frequently excluded from clinical trials so the registries constitute the only way to fine data for establishing recommendations for the management of these patients in the real world. Method. The French Nord-pas-de-calais Picardie AML observatory containing 1 582 AML patients diagnosed between 2000 and 2015. We compared 974 primary AML to 514 Secondary AML include AML arising from a pre-existing myelodysplastic (n=211), myeloproliferative (n=88) or myelodysplastic/myeloproliferative (n=57) disease and therapy related AML (t-AML) (n=158). Results. Median survival and 5 years overall survival were respectively 420 days [95%IC: 349-491] and 32% for patients with de novo AML; 157 days [95%IC: 118-196] and 7% for patients with secondary AML. 1101 patients were classified according to the MRC as favorable, intermediate and unfavorable, respectively 18(5.2%), 178(51.9%) and 147(42.9%) patients with secondary AML including 100(29.2%) complexes karyotypes and 117(15.4%), 468(61.7%) and 173(22.8%) patients with de novo AML including 121 (15.9%) complexes karyotypes. 987 patients were classified according to the ELN as favorable, intermediate-1, intermediate-2 and unfavorable for respectively 35(11.7%), 53(17.7%), 67(22.%) and 144(48.2%) patients with secondary AML and 219(31.8%), 167(24.%), 136(19.8%) and 166(24.1%) patients with de novo AML. The age at diagnosis was significantly different (p < 10-3) with a median of 72.6 years for secondary AML and 63.2 for de novo AML. 206 (40.4%) patients with secondary AML received demethylating agents versus 184 (19%) for de novo AML and 152(29%) received high dose chemotherapy (HDC) versus 619 (63.9%) patients with de novo AML. Best supportive care was the only treatment for 170 (17.5%) de novo AML and 164 (31.9%) secondary AML patients. For patients over than 60 years old, median survival and 5 years overall survival were respectively 182 days [95%IC: 136.5-127.4] and 12.9% for 559 patients with de novo AML; 128 days [95%IC: 95.0-161.0] and <4% for 413 patients with secondary AML. Conclusion. The poor prognosis of secondary and t- AML is confirmed by this registry study. Possible explanations for this worse outcome could be older age at diagnosis and increased frequency of complex karyotypes which lead to less intensive therapy or supportive care only. In this specific population, the choice of demethylating agent therapy was frequently made because of the weak efficacy of HDC and increased frequency of side effects in this vulnerable group. Disclosures No relevant conflicts of interest to declare.

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