Incidence and Outcomes of a Rare Translocation t(3,5) in Patients (pts) with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1456-1456
Author(s):  
Mona Lisa Alattar ◽  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Tapan M. Kadia ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Median Number ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Nras Mutation ◽  
Agent Based ◽  
Molecular Abnormalities ◽  
Novel Treatment

Abstract Abstract 1456 Background: Cytogenetic analysis of large pt cohorts allows us to evaluate the prognostic impact of rare and unique translocations. Little is known about the clinical outcomes of pts with t(3,5), which generally results in fusion of NPM and MLF1 in pts with MDS and AML. Methods: We retrospectively reviewed the charts of 8,215 pts with a diagnosis of MDS or AML evaluated at our institution from 1985–2011. Results: A total of 17 pts with a t(3,5) either at diagnosis or post-treatment were identified (10 pts, as the sole cytogenetic abnormality, and 7 pts, as part of other/complex karyotype). Among evaluable cases (15/17), frequently occurring breakpoints included q25;q34 (n=4), p21;q15 (n=2), and p21;q13 (n=2).10 pts had MDS with IPSS of Int-1(n=5) and Int-2(n=5), and 7 pts had AML. Four pts had therapy-related MDS (3 pts with prior lymphoma, 1 pt small cell lung cancer) and one pt with MDS had PNH. Median age was 56 years (range, 20–78) at diagnosis. Four pts (24%) had a FLT3-ITD mutation (3 with AML and 1 with MDS), 1 of these FLT3-mutated pts had additional mutations in c-KIT and NRAS mutation, 9 pts were tested and negative for molecular abnormalities, and 4 pts did not have molecular analysis available. Therapies were diverse, with two most common: cytarabine-based regimens (n=6) and hypomethylating agent-based therapy (n=6). Overall, median number of therapies for all pts was 1 (range, 0–5), including 2 pts treated with upfront stem cell transplant (SCT) and 1 pt treated with only growth factors/supportive care. Six pts (35%) (MDS 3 pts, AML 3 pts) underwent SCT during their course of therapy (including 1 cord blood, 1 SCT with NK cells, and 4 allogeneic MUD SCT). Overall median survival for pts with MDS was 8.1 months (range, 1–57) and for pts with AML, 21 months (range, 2–53). CR was achieved overall in 12 pts (71%) with median CR duration of 3.2 months (range, 1–60 months). Three (18%) pts were refractory to all chemotherapy and one pt died during induction chemotherapy (infection and diffuse alveolar hemorrhage). One pt never received treatment. Conclusions: Survival is particularly poor among patients with MDS and t(3;5) while those with AML have survival comparable to normal karyotype (NK) AML. Further investigation with novel treatment approaches is warranted in this subpopulation of MDS/AML pts. Disclosures: No relevant conflicts of interest to declare.

Biological and Clinical Features of Patients with Acute Myeloid Leukemia Bearing Trisomy 21

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1488-1488
Author(s):  
Paolo Strati ◽  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Farhad Ravandi ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Features ◽  
Trisomy 21 ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Induction Treatment ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Increased Risk ◽  
Acute Myeloid

Abstract Abstract 1488 Background: Individuals with congenital Trisomy 21 (+21) (Down syndrome) have an increased risk of developing acute myeloid leukemia (AML). As +21 in AML frequently occurs in association with other karyotypic abnormalities, its prognostic impact remains poorly defined. Thus +21 has been empirically categorized as an intermediate risk cytogenetic aberration. This study focuses on the biological and clinical features of +21 AML. Methods: We analyzed the records of all AML patients treated at MD Anderson Cancer Center (MDACC) between January 1995 and December 2011. Only patients presenting to MDACC at the time of diagnosis with no prior therapy were included. Four cytogenetic groups were defined: +21 alone, +21 plus favorable cytogenetics, +21 plus intermediate cytogenetics and +21 plus unfavorable cytogenetics (Grimwade D et al, Blood 2010). Progression free survival (PFS) was defined as time from diagnosis to relapse or last follow up. Survival curves were calculated using Kaplan-Meier estimates and were compared using the log-rank test. Results: A total of 90 patients harboring +21 aberrations at diagnosis were identified. Median age was 59 years (range, 18–88) and 58% were male. At diagnosis, median white cell count was 4.6 (0.6–190) × 109/L, hemoglobin 8.6 (3.3–13.4)g/dL, platelets 53 (4–395) × 109/L, peripheral blasts 17% (0–96), and bone marrow blasts 48% (0–97). FAB classification: M0–2 64%, M3 1%, M4–5 20%, M6 10%, M7 4%. Cytogenetic subgroups included: +21 alone: 12%, +21 with favorable: 8%, +21 with intermediate: 8%, and +21 with unfavorable: 72%. Molecular mutations: FLT3 4/49 (2 ITD, 2 D835) (8%), NRAS 4/53 (7%), NPM1 1/25 (4%), CEBPA 2/13 (15%) and CKIT 0/26 (0%). Induction regimens included: Idarubicin+AraC-based (IA) 36%, fludarabine-based (FLU) 24%, clofarabine-based (CLO) 11%, topotecan-based (CAT) 10%, hypomethylating-based (HMT) 11%, and miscellaneous (MISC) 8%. Overall Response Rate (ORR) was 54%. Clofarabine-based induction showed the highest frequency of complete remission (CR) (70%) and HMT the lowest frequency of CR (56%) (Table 1). Median time to CR (TTCR) from initiation of therapy for those patients achieving CR was 5 (3–19) weeks. Patients with +21 alone or treated with HMT had a significantly longer TTCR (p=0.038 and 0.006; respectively). Median PFS was 11 (2–130) months and median CR duration was 5 (1–100) months. PFS was significantly higher in patients with +21 alone (101 months) as compared to the intermediate and unfavorable group (11 and 2 months, respectively) (p=0.006). CR duration did not differ significantly among the 4 cytogenetic groups. Both PFS and CR duration did not differ significantly by induction regimen. Median Overall Survival (OS) for the entire group was 9 (0–130) months. Median OS for stem cell transplant (SCT) recipients (14 months) was significantly higher than those who did not undergo SCT (8 months) (p=0.003). Patients with +21 alone had better OS (32 months) than those in the intermediate and unfavorable groups (5 months and 2 months; respectively) (p <0.01). On multivariate COX regression, +21 alone group maintained an improved OS as compared to the intermediate and unfavorable groups (covariates were WBC, peripheral blasts, previous hematological malignancies, performance status, age and induction treatment)(p<0.001). Conclusions: Patients with AML harboring +21 aberrations have unique biological and clinical features. When present as a sole aberration it is associated with significantly improved PFS and OS. Thus +21 alone may be a favorable prognostic factor in AML. Disclosures: No relevant conflicts of interest to declare.

Nucleophosmin Gene Mutations Identify a Favorable Risk Group in Childhood Acute Myeloid Leukemia with a Normal Karyotype.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 366-366
Author(s):  
Iris H. Hollink ◽  
Christian M. Zwaan ◽  
Marry M. van den Heuvel-Eibrink ◽  
Martin Zimmerman ◽  
Susan Arentsen-Peters ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Type A ◽  
Prognostic Impact ◽  
Wild Type ◽  
Molecular Abnormalities ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Exon 12 gene mutations in nucleophosmin (NPM1) were recently discovered in approximately 30% of adult acute myeloid leukemia (AML) samples, and cluster in the normal karyotype subgroup (NK-AML). NPM1-mutated adult NK-AML has a favorable outcome (pOS in the 40-50% range), but in case a FLT3 internal tandem duplication (FLT3/ITD) is also present outcome is worse with 25–30% pOS. In pediatric AML, NPM1 mutations are less frequent (6–8%; Cazzaniga, Blood 2005 & Brown, Blood 2007). No studies have specifically addressed pediatric NK-AML, a subgroup lacking favorable prognostic cytogenetic aberrations and therefore mostly stratified in the intermediate risk arm of pediatric AML treatment protocols. We screened 292 newly diagnosed AML samples, and detected NPM1 mutations in 25 cases (8.6%). We also screened 46 initial diagnosis-relapse pairs, and no clonal instability was observed, which suggests that NPM1 mutations may be used for minimal residual disease detection. In contrast to adults, where type A mutations (TCTG-insertion) are most frequent (80%), in our cohort type B (CATG-insertion) mutations were found in 39% and type A in 23%. In the NK-AML cohort (n=98), 20% was NPM1-mutated, which was age dependent: &lt;3 years, 0%; 3–10 years, 19%; &gt;10 years, 29% (p=0.04). None of the 10 FAB M5 cases was NPM1 mutated (p=0.09). NPM1 mutations had an independent favorable prognostic impact on outcome in patients with NK-AML (5-year pEFS 77% vs. 41% for wild type patients; p=0.003), irrespective of FLT3 mutational status. In fact, NPM1-mutated patients with a FLT3/ITD did better than patients without an ITD, although this was not statistically significant (5-year pEFS 90% vs. 63%, respectively; p=0.48). In NK-AML without NPM1 mutations, patients with FLT3/ITD positive AML did significantly worse than wild type FLT3 AML patients (5-year pEFS 18% vs. 52%, p=0.002). The differential prognostic impact of FLT3/ITD between the NPM1-mutated vs. the wild type patients was not caused by differences in the FLT3/ITD allelic ratio or ITD length, nor was there a relationship with the type of NPM1 mutations. Multivariate analysis, including age, white blood cell count, NPM1 and FLT3 status and stem cell transplantation as time-dependent co-variable, showed that only NPM1 mutations had independent prognostic significance for pEFS (RR 0.34, p=0.02). We conclude that the incidence of NPM1 mutations increases with age, and that NPM1 mutations define a subgroup with favorable prognosis in pediatric NK-AML. Our data suggest that these molecular abnormalities allow stratification of children with NK-AML. However, different from adult NK-AML, we observed that all children with NPM1 mutations did well, irrespective of FLT3 status. Therefore, treatment in the ‘good risk’ arm should be considered for children with NPM1-mutated NK-AML.

scholarly journals FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Naval Daver ◽  
Sangeetha Venugopal ◽  
Farhad Ravandi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Prognostic Significance ◽  
Treatment Algorithm ◽  
Molecular Testing ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

FLT3 mutations have no prognostic impact in elderly patients with acute myeloid leukemia and normal karyotype

2009 ◽  
Vol 84 (8) ◽  
pp. 532-534 ◽  
Author(s):  
Felicetto Ferrara ◽  
Clelia Criscuolo ◽  
Cira Riccardi ◽  
Tiziana Izzo ◽  
Mariangela Pedata ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Flt3 Mutations ◽  
Acute Myeloid

The Detection of Multilineage Dysplasia (MLD) Has No Influence on Prognosis in NPM1 Mutated Acute Myeloid Leukemia (AML) with Normal Karyotype

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2518-2518
Author(s):  
Ulrike Bacher ◽  
Susanne Schnittger ◽  
Wolfgang Kern ◽  
Tamara Weiss ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Biological Entity ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Cox Regression Analysis ◽  
Multilineage Dysplasia ◽  
Acute Myeloid

Abstract Acute myeloid leukemia with mutated nucleophosmin (AML NPM1mut) represents about one-third of all adult AML and shows distinctive biological and clinical features. For this reason, AML NPM1mut is planned to be included as a separate category in the revised WHO classification. A yet controversial issue, however, is whether AML NPM1mut with or without multilineage dysplasia (MLD) may differ biologically and clinically, as the presence of MLD might confer a negative prognostic impact. A further feature that was suggested to be typical for NPM1 mutated AML is “cup-like” morphology of blasts. We here analyzed 128 pts with AML NPM1mut and normal karyotype at first manifestation (59 females, 69 males; median age 60.5 years; 23.5–79.3 y). We investigated in parallel cytomorphology from bone marrow and/or peripheral blood, chromosome banding analysis, and molecular analyses. Presence of dysplasia was defined by dysplastic features in ≥50% of cells in the respective hematopoietic lineage as defined by the WHO. A 5% cut-off was taken for the presence of “cup-like” morphology of blasts. All cases were additionally analyzed for the FLT3-ITD, and in 122 pts for the FLT3-TKD. Statistical analysis was performed for overall survival (OS), and event-free survival (EFS) according to Kaplan-Meier using the 2-sided log-rank test. Cox regression analysis related OS and EFS with the analyzed parameters. We found a predominance of the FAB M1 (21.3% of all cases), M2 (33.9%), and M4 subtypes (28.3%). Cup-like morphology in ≥5% of all blasts was observed in 39 of 127 evaluable cases (31.3%) confirming previous observations of an association of the NPM1mut and this specific blast appearance. Molecular characterization detected NPM1 mutation subtype A (n=90/122; 73.8%), B (15/122; 12.3%), and D (7/122; 5.7%), which was in accordance to previous studies. In 56 cases (43.8%) there was a coincidence with an FLT3-ITD. Dysplasia of granulopoiesis was detected in 28/126 (22.2%), of erythropoiesis in 28/104 (26.9%), and of megakaryopoiesis in 57/87 (44.5%) cases in which the respective cell lineage could be analyzed. MLD (≥2 dysplastic hematopoietic lineages) was detected in 28 of 105 evaluable cases (21.9%). Clinical follow-up was available in 104 pts. (median follow-up 12,7 months). CR rate was 83.1% in 77 evaluable pts., and median EFS was 42.1 months in 104 evaluable pts (median OS not reached). An additional FLT3-ITD had a significantly inferior OS (p=0.003) and EFS (p=0.007), confirming the present series being representative. However, the presence of MLD was not significantly related to any endpoint such as CR rate, EFS, or OS. There was no association between MLD and the NPM1-subtype. Also, there was no significant correlation of MLD and the presence of a FLT3-ITD. In conclusion, the presence of MLD in AML NPM1mut with normal karyotype had no impact on CR rate and outcome, whereas coincidence of FLT3-ITD significantly worsened prognosis. These results give further evidence that AML with NPM1mut AML is a unique biological entity with clinical course mainly influenced by FLT3-ITD coincidence. These data do not support any additional prognostic influence of MLD in this AML subtype.

Uptake and Outcome of Artificial Reproductive Techniques Following Allogeneic Stem Cell Tranplantation: A Single Centre Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2257-2257
Author(s):  
Anna Babb ◽  
Nadine Farah ◽  
Jane Apperley ◽  
John Goldman ◽  
Edward Kanfer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conflicts Of Interest ◽  
Ovarian Tissue ◽  
Median Number ◽  
Cell Transplant ◽  
Successful Pregnancy ◽  
Post Transplant ◽  
Co Morbidity ◽  
Reproductive Techniques ◽  
Insufficient Time

Abstract Abstract 2257 Poster Board II-234 Introduction: Infertility is common following allogeneic stem cell transplant (allo-SCT). Very little data are available on the use and success of artificial reproductive techniques in patients who have undergone allo-SCT as treatment for cancer. Patients and Methods: We have performed a retrospective survey to assess the uptake of gamete/embryo storage prior to SCT, their use following SCT and the success rate of these techniques. Two hundred patients (95 female) who received allo-SCT between 1979 and 2007 responded to a questionnaire at a median of 12 years (range 2-30 years) post transplant. The median age at SCT was 35 years (range 17-61 years). Results: Ninety-four men (90%) recalled being counselled about post transplant infertility. Seventy-two recalled being offered sperm storage and 36 men stored sperm prior to allo-SCT. Of the 68 men who did not store sperm, 43 did not wish to have children after SCT; 37/43 had completed their families or did not want children, 4/43 considered themselves too old and 2/43 were homosexual. Of the remainder the reasons were various; no semen storage available in country of residence (n=1), pre-pubertal at first allo-SCT (n=1), previous chemotherapy had induced infertility (n=4), sperm of insufficient quality to permit storage (n=7), insufficient time pre-transplant to arrange storage (n=5), unknown (n=8). Of the 36 men who stored sperm, 21 attempted pregnancy post SCT. 14 men fathered a total of 24 children (17 successful pregnancies including 7 twin pregnancies). In these men intracytoplasmic sperm injection (ICSI) was used in 12 pregnancies and inter-uterine insemination was used in 2 pregnancies. The method was not specified in 3 pregnancies. The median number of attempts for a successful pregnancy was 1 (range 1-10). The median number of attempts for men who were unsuccessful was 2 (1-4). In addition, three men fathered children with donated sperm and one man conceived naturally post transplant. Fifty-nine women (63%) recalled being counselled about post transplant infertility. Of these, 32 were offered storage of gametes/embryos. Ten patients undertook storage; oocytes (n=1), ovarian tissue (n=1), embryos (n=6) or a combination of these (n=2). The women who did not store gametes/embryos most had either completed their families (n=28), were too old (n=17) or there was insufficient time prior to transplant (n=13). In 6 cases, the technology was not available or insufficiently advanced to be successful at the time of SCT. Other given reasons included chemotherapy induced infertility, concerns about medical co-morbidity and worries about contamination of the stored tissue with malignant cells. Three women attempted to become pregnant with stored embryos. One was successful on her second attempt after a spontaneous abortion. One had 3 attempts and although succeeded in becoming pregnant unfortunately miscarried at 12 weeks. The third woman had one failed attempt. Of the other patients, one woman had 2 successful pregnancies with donated eggs and one woman adopted her child. Two women delayed their transplant in order to have children. Conclusions: The uptake of gamete storage was relatively high for male patients. Over half of men who had not already completed their families elected to store sperm. Subsequently two thirds of these men were successful in fathering children with stored sperm. Unfortunately the potential for women to store gametes/embryos is much lower. Less than a fifth of young women who had not completed their families undertook gamete / embryo storage prior to SCT and only one patient proceeded to have a successful pregnancy. Disclosures: No relevant conflicts of interest to declare.

Trisomy 8 in the Light of Recent Cytogenetic Classification Advances. A Study From the French Acute Myeloid Leukemia Intergroup.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2594-2594 ◽  
Author(s):  
Nicolas Boissel ◽  
Christine Terré ◽  
Pascale Cornillet-Lefebvre ◽  
Odile Maarek ◽  
Eric Lippert ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Prognostic Impact ◽  
Trisomy 8 ◽  
Factors Associated ◽  
Acute Myeloid ◽  
Similar Incidence

Abstract Abstract 2594 Poster Board II-570 Background: Trisomy 8 (+8) is one of the most common cytogenetical abnormality observed in acute myeloid leukemia (AML). The prognostic impact of +8 as sole aberration remains unclear and +8 may be classified either within intermediate- or high-risk subgroups. Recently, the prognostic impact of cytogenetic in AML has been refined by the identification of: 1) favorable genotypes in cytogenetically normal (CN) AML defined by the presence of either NPM1 gene mutation (NPM1m) or CEBPA gene mutation (CEBPAm) and the absence of FLT3 duplication (FLT3/ITD); 2) highly unfavorable AML with monosomal karyotype (MK). The aim of this study was to precise the prognostic impact of: 1) additional +8 in various cytogenetic risk subgroups; and 2) +8 as sole aberration when compared to different CN-AML genotypes. Patients: A total of 2087 patients with AML (AML-M3 excluded) were treated in the LAM-2001, LAM-SA-2002, ALFA-9802 and ALFA-9801 studies from the French AML Intergroup. After central review, cytogenetic analysis was considered successful in 1796 patients. Abnormalities were categorized according to the French AML Intergroup classification. All analysis (complete remission, CR; overall survival, OS; probability of continuous complete remission, %CCR) were stratified on studies. Results: +8 was present in 171/1796 (9.5%) with a similar incidence among the different cytogenetic subgroups: 22/243 fav-risk (9.1%), 99/1121 int-risk (8.8%), and 50/432 unfav-risk (11.6%). The incidence of +8 was significantly higher in MK-AML versus non MK-AML (30/223, 13.5%, p=.04). In none of these subgroups (fav, int, unfav, and MK), the presence of +8 was associated with a significantly different outcome (CR, OS, %CCR). When compared to patients with CN-AML, the 78 patients with +8 as sole anomaly had a similar age, a lower WBC (median WBC: 5 G/L vs 11.5 G/L, p=.004), a similar incidence of FLT3/ITD (22.2% vs 23.7%, 6/27 vs 101/426, p=.99), and a lower incidence of NPM1m (23.8% vs 46.5%, 5/21 vs 187/402, p=.05). In patients with +8 as sole anomaly, prognostic factors associated with a shorter OS were age (p=.01), high WBC (p=.01), and presence of +8 in all analyzed metaphases which was found in 1/3 of patients (p=.05). In those patients, when compared to CN-AML in general, CR rate was similar (88% vs 87%, p=.99), but %CCR and OS were shorter without, however, reaching significance (5y-%CCR: 31.8% vs 45.7%, p=.18). When compared to CN-AML patients with favorable genotypes (NPM1m or CEBPAm w/o FLT3/ITD), patients with +8 as sole anomaly had now a lower CR rate (87% vs 93%, p=.13) and significantly shorter %CCR and OS (5y-%CCR: 37.4% vs 57.8%, p=.05; 5y-OS 35.6% vs 59.0%, p=.05). Conversely, the prognosis of patients with +8 as sole anomaly appeared similar to that of patients with CN-AML w/o favorable genotypes (5y-OS: 32.6%). Conclusion: We report here the largest cohort of patients with +8. Additional +8 is equally distributed among cytogenetic risk subgroups and does not impact prognosis in each of these subgroups. Patients with AML with +8 as sole anomaly have an outcome comparable to that of CN-AML without favorable genotypes, suggesting that these patients should be managed similarly. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of a Novel Biomarker, Serum Soluble LR11 on Acute Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2717-2717
Author(s):  
Chikako Ohwada ◽  
Masahiro Takeuchi ◽  
Shio Sakai ◽  
Daijiro Abe ◽  
Yusuke Takeda ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Laboratory Data ◽  
Type I ◽  
Prognostic Impact ◽  
Soluble Lr11

Abstract Abstract 2717 Introduction: LR11 (also called SorLA or SORL1) is a type I membrane protein, from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding. LR11 plays a key role in the migration of undifferentiated vascular smooth muscle cells, and circulating sLR11 is known to be a biomarker of carotid intima-media thickness. Along with the fact that circulating sLR11 levels represent the accumulation of vascular immature cells, human CD34+CD38− immature hematopoietic precursors have been reported to express high levels of LR11 mRNA. We have recently found that LR11 is specifically and highly expressed on cell surface of acute leukemia cells in addition to normal leukocytes (unpublished data). These facts prompted us to evaluate the serum sLR11 level in patients with acute leukemia and other hematological malignancies to validate sLR11 as a novel circulating marker for treatment outcome and prognosis. Patients and Methods: Serum sLR11 levels were measured by ELISA method in 139 patients with acute leukemia and other hematological malignancies treated at a single institution from 1999 to 2010. Patients' laboratory data and treatment outcome were collected retrospectively in 43 acute myeloid leukemia (AML) and 23 acute lymphoblastic leukemia (ALL) patients. Results: sLR11 levels of acute leukemia patients were significantly increased [ALL, 73.5±93.5 ng mld−1 (range, 5.7–407.0), P<0.0001; AML, 26.8±29.1 ng ml−1 (range, 5.0–157.5), P<0.0001] in comparison to the control subjects (9.2±3.3 ng ml−1), while sLR11 levels in patients with chronic myeloid leukemia (17.9±11.1 ng ml−1), chronic lymphocytic leukemia (12.7±11.6 ng ml−1), multiple myeloma (10.5±4.8 ng ml−1), and POEMS syndrome (9.0±2.7 ng ml−1) were not significantly different from controls. sLR11 levels were significantly higher in ALL than those in other leukemias. Paired sample analysis of patients with AML and ALL at complete remission (CR) after chemotherapy showed significantly decreased sLR11 levels compared to the time of diagnosis (AML: 30.9±37.5 ng ml−1 vs. 10.4±4.3 ng ml−1, P=0.015, ALL: 39.1±126.0 ng ml−1 vs. 11.2±5.0 ng ml−1, P=0.0029). The multiple stepwise liner regression analysis showed that the peripheral blast proportion in both ALL and AML patients were independently associated with sLR11 at diagnosis (AML: r2= 0.21, P=0.0026, ALL: r2= 0.34, P=0.0043). Among 42 AML patients, sLR11 levels of subjects in the highest tertile of peripheral blast proportion (>67.5% of WBC) were 2.44- and 3.05-fold higher than those in the middle (23.0-64.0% of WBC) and lowest tertiles (<20.0% of WBC), respectively. Twenty out of 21 AML patients with <20 ng ml−1 sLR11 at diagnosis achieved CR after induction chemotherapy, and the CR rate was significantly higher in patients with <20 ng ml−1 sLR11 than in patients with ≥20 ng ml−1 (95.2% vs 65.5%, P=0.02). The probability of overall 5-year survival was significantly lower in AML patients with ≥20 ng ml−1 sLR11 at diagnosis than in those with <20 ng ml−1 [Figure1, 36.8% vs 63.7%, P = 0.04; hazard ratio (HR): 2.74; 95% confidence interval (CI): 1.04–8.01]. Conclusions: Serum sLR11 levels in patients with acute leukemia were significantly elevated and were associated with the peripheral blast population but not in other chronic proliferative hematological malignancies. These findings suggest that the serum sLR11 levels are predictive for pathogenic properties of immature blasts, including their migration and attachment activities, rather than simply associating with proliferating cell numbers. Especially in AML patients, serum sLR11 levels at diagnosis significantly affect CR rate and OS. Although larger scale studies including karyotype or FAB classification would be required for its patho-clinical significance, serum sLR11 is a promising novel biomarker for acute leukemia and it could play an important role as prognostic factor. Disclosures: No relevant conflicts of interest to declare.

DNMT3A mutations Predict for Inferior Outcome in NPM1-Wildtype and Molecular Unfavorable Cytogenetically-Normal Acute Myeloid Leukemia: A Study of the German-Austrian AMLSG

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 415-415 ◽  
Author(s):  
Verena I. Gaidzik ◽  
Richard F. Schlenk ◽  
Peter Paschka ◽  
Anja Stölzle ◽  
Andrea Corbacioglu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Negative Impact ◽  
Epigenetic Modification ◽  
Methylation Status ◽  
Prognostic Impact ◽  
Sequencing Analysis ◽  
Mutational Status ◽  
Acute Myeloid

Abstract Abstract 415 Background: Alteration of DNA methylation, a hallmark of epigenetic modification, is currently discussed as one important pathomechanism in leukemogenesis. Using a next-generation sequencing approach, a frameshift mutation of the gene encoding the DNA methyltransferase (DNMT3A) in an acute myeloid leukemia (AML) case was identified. DNMT3A catalyses the addition of a methyl group to the cytosine residue of CpG dinucleotides, thereby affecting promoter methylation status and gene expression. Subsequent sequencing analysis in an independent cohort of 288 AML patients (pts) revealed DNMT3A mutations (DNMT3Amut) in 22% of the pts; mutations were associated with intermediate-risk cytogenetics and poor outcome. Aims: To evaluate frequency and clinical impact of DNMT3Amut in pts with AML aged 18 to 61 years who were treated within AMLSG treatment trials AML HD98A (Schlenk et al., J Clin Oncol 2010;28:4642–8) and AMLSG 07–04 (NCT00151242). Methods: DNMT3A mutation analysis was performed in 1218 AML (HD98A, n=685; AMLSG 07–04, n=533; de novo AML, n=1102; s-AML, n=45; t-AML, n=69) using a DNA-based PCR assay for all coding exons (1 to 23) followed by direct sequencing. The median follow-up was 5.06 years. Results: DNMT3A mut were found with an overall frequency of 19.6% (239/1218); 189 mutations were located in the MTase domain clustering at amino acid R882 (79%). All but one mutation were heterozygous; only 4 cases had two mutations. DNMT3A sequence alterations included 17 frameshift, 4 nonsense, and 222 missense mutations. DNMT3A mut pts were significantly older (P=.01), more frequently females (P=.001), had higher white blood cell and platelet counts (both P<.0001), and higher bone marrow blasts percentage (P=.001). DNMT3Amut were associated with cytogenetically-normal AML (CN-AML, P<.0001), while DNMT3Amut were rare in favorable and adverse-risk karyotypes (P<.0001). Correlations with other molecular markers (NPM1, CEBPA, FLT3, IDH1/2, TET2, ASXL1) revealed a significant association with NPM1 (P<.0001), FLT3-ITD (P<.0001), and IDH1/2 (IDH1R132, P<.0001; IDH2R140, P=.0003; IDH2R172, P=.03) mutations, while co-occurrence of CEBPA (P=.02) and ASXL1 (P=.02) mutations was less frequent. DNMT3A mutational status did not impact complete remission (CR) rate, event-free (EFS) and relapse-free survival (RFS), neither in the whole cohort (P=.09, P=.98, P=.11; respectively) nor in the subgroup of CN-AML (P=.39, P=.79, P=.19, respectively). DNMT3Amut had a negative impact on overall survival (OS) in trend in the whole cohort (P=.07) and significantly in CN-AML (P=.02). In multivariable analyses, DNMT3Amut were in trend associated with a negative prognostic impact on OS (hazard ratio, 1.24; P=.06). In addition, we performed subgroup analyses according to (1) the NPM1 mutational status, and (2) the molecular risk groups of CN-AML (as defined by the European LeukemiaNet classification). DNMT3Amut did not impact OS in NPM1-mutated patients in the whole cohort as well as in CN-AML (P=.34; P=.22; respectively), while in NPM1-wildtype patients DNMT3Amut were associated with inferior OS in both, the whole cohort and in CN-AML (P=.001; P=.005; respectively). In molecular unfavorable CN-AML (NPM1-wildtype with or without FLT3-ITD, NPM1-mutated with FLT3-ITD, CEBPA-wildtype), DNMT3Amut were significantly associated with worse OS (P=.002) compared with DNMT3A-wildtype pts, even outweighing FLT3-ITD as an unfavorable prognostic marker. There was no effect of DNMT3Amut in molecular favorable-risk CN-AML. Conclusions: DNMT3A mutations are confirmed as frequent genetic aberrations in AML, associated with normal karyotype, NPM1, FLT3-ITD, and IDH1/2 mutations. DNMT3Amut predicts for inferior outcome in molecularly-defined subsets of AML, that is, NPM1-wildtype AML and molecular unfavorable CN-AML. As a single marker, DNMT3Amut only had a moderate effect on outcome. Disclosures: No relevant conflicts of interest to declare.

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