Frequent Mutation of the Polycomb-Associated Gene ASXL1 In Acute Myeloid Leukemia Secondary to Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2940-2940 ◽  
Author(s):  
Marta Fernandez-Mercado ◽  
Andrea Pellagatti ◽  
Janet Perry ◽  
Cristina Fernandez-Santamaria ◽  
Maria J. Calasanz ◽  
...  
Keyword(s):  
Disease Progression ◽  
Mutation Rate ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Common Mutation ◽  
Secondary Aml ◽  
Frequent Event ◽  
De Novo Aml

Abstract Abstract 2940 Recent studies have identified mutations of the ASXL1 gene in MDS and CMML. Mammalian ASXL proteins are believed to play a role in chromatin remodelling. We have previously reported that ASXL1 mutations are frequent in patients with MDS, CMML and AML. We observed that the mutation rate was relatively high in late MDS and AML with a lower frequency across early MDS. We found that the mutation is common in the normal karyotype group (especially AML secondary to MDS), occurring in 40% of all cases. ASXL1 mutations (including the common mutation c.1934dupG;p.Gly646TrpfsX12) were present in myeloid cells, but not in T-cells, indicating that they were acquired in all seven cases examined. The majority of the mutations identified were heterozygous frameshift mutations caused by deletion or duplication of a nucleotide. Given the high frequency of ASXL1 mutations in advanced MDS and AML in our earlier study, we have now screened a larger group of 143 AML samples, comprising 111 de novo AML and 32 AML secondary to either MDS or CMML, for mutations in the ASXL1 gene. In primary AML samples we found only 6/111 patients with ASXL1 mutations (5%), whereas the frequency of mutations was significantly higher in AML secondary to MDS (10/25, 40%) or CMML (5/7, 71%), strongly suggesting an association with disease progression in MDS and CMML. In order to determine the frequency of ASXL1 mutations in de novo and secondary AML patients with a normal karyotype and to identify cooperating mutations, we screened 85 samples for ASXL1 (all coding exons), NPM1 (exon 12), FLT3 (ITD and D835Y), TET2 (all coding exons), IDH1 (R132), IDH2 (R140 and R172) and RUNX1 (exons 3–7) mutations (Table 1). FLT3 and NPM1 mutations were more common in de novo AML (FLT3 51% and NPM1 58%) than in sAML (FLT3 9% and NPM1 12%), consistent with the role of NPM1 mutations as a hallmark of cytogenetically normal de novo AML. TET2 was mutated in 13% of primary AML, and in 28% of sAML, with most TET2 mutations found in AML secondary to CMML (5/7, 71%), as expected according to previous reports on higher mutation frequency in CMML patients. Mutations in IDH1 and in IDH2 were evenly distributed in primary and secondary cases. Similarly, RUNX1 mutation rate showed no significant differences between primary and secondary AML cases. Interestingly, ASXL1 mutations were mutually exclusive with NPM1 mutations, suggesting that they could be markers of different subgroups with a distinct aetiology. In conclusion, we have shown that mutation of ASXL1 is a very frequent event in AML secondary to MDS and CMML, but is much less frequent in de novo AML. Our data support a role for ASXL1 mutations in disease progression in MDS and CMML. Table 1. Mutation rate for genes screened in AML samples Primary AML Secondary AML From MDS From CMML ASXL1 5/53ü(9.4%) 10/25ü(40%) 5/7ü(71.4%) NPM1 31/53ü(58.5%) 3/25ü(12%) 1/7ü(14.3%) FLT3 26/51ü(51%) 3/25ü(12%) 0/7 TET2 7/52ü(13.5%) 4/25ü(16%) 5/7ü(71.4%) IDH1 7/52ü(13%) 3/25ü(12%) 0/7 IDH2 7/52ü(13%) 2/25ü(8%) 1/7ü(14.3%) RUNX1 6/53ü(11.3%) 4/25ü(16%) 1/7ü(14.3%) Disclosures: No relevant conflicts of interest to declare.

Bortezomib+Chemotherapy Based Salvage Combinations in Refractory AML, Preliminary Results

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4000-4000
Author(s):  
Miklos Udvardy ◽  
Attila Kiss ◽  
Bela Telek ◽  
Robert Szasz ◽  
Peter Batar ◽  
...  
Keyword(s):  
Cell Lines ◽  
De Novo ◽  
Case Reports ◽  
Fatal Outcome ◽  
Normal Karyotype ◽  
Secondary Aml ◽  
Poor Risk ◽  
Group 2 ◽  
De Novo Aml ◽  
Group 1

Abstract Bortezomib (Velcade) proved to be the standard element of refractory myeloma 2nd and 3rd line treatment, while many studies are suggesting excellent results in 1st line. Proteasome inhibition, the block of angiogenesis, modification of the NF-kappa-B system seems to be a challenging target in other malignant diseases, including refractory acute myeloid leukemia (AML), as well. In vitro data clearly support, that bortezomib exerts antiproliferative and pro-apoptotic effects in different AML cell-lines, along with human AML cell cultures, and moreover bortezomib was able to restore, or at least improve anthracyclin and possibly ARA-C sensitivity in different cell-lines (including AML). More recently, a Phase I trial showed bortezomib monotherapy efficient (only in few percents) in childhood refractory acute leukemia. Some case reports were shown at ASH 2007. We have tried bortezomib containing first or second line combinations in 27 (14 female, 13 male, mean age 57.6 years) patients with refractory or poor risk AML, in a small retrospective survey. The combinations were as follows: HAM or Flag-Ida, combined with bortezomib 1,3 mg pro sqm, day O and seven). The following groups were considered as refractory or poor risk AML: De novo AML, 2nd line: No response/remission to first line standard treatment (“3+7”), n=2 (Velcade- Flag-Ida treatment) De novo AML 1st line: bilineal or biphenotypic (flow-cytometry) n=2 (Velcade-Flag- Ida treatment) De novo AML with complex (numerical or more than 3 abnormalities) karyotype or normal karyotype with flt-3 TKD mutation, n=9, 1st line (Velcade-Flag-Ida n=6, Velcade- HAM protocol, n=3) Secondary AML or AML with evidence of previous more than 6 mo duration high grade MDS, n=14, 1st line: (Velcade-Flag-Ida n=9, Velcade-HAM n=5) RESULTS: Complete remission (CR) 12/27, partial remission (PR) 9/27, no remission 5/27, progression during treatment: 1/27.Best responses were seen in de novo cases. CR had been achieved in all patients of group 1 (two standard risk patients not responding to 3+7 protocol), and group 2 (biphenotypic, bilineal). The CR rate was quite appreciable in group 3, i.e. 6/9 (complex karyotype or normal karyotype with FLt-3 mutation – the response rate was excellent with flt-3 mutated cases). In group 4. (MDS, secondary AML) the results were less impressive. There were no major differences according to protocol (Flag-Ida or HAM) Allogeneous stem cell transplantation could have been performed in 1st CR in two patients (one from group 1. and another from group 2.). One of them died due to relapse, the other one is in CR since then. The combinations seem to be relatively safe. Induction related death rate was low (1 elderly patient acute thrombocytopenic bleeding with refractory MDS-AML). 5 other patients had severe neutropenic sepsis (2 with fatal outcome). Pulmonary syndrome, which may follow Velcade+ARA-C had not been documented. Other adverse events did not differ from the pattern observed with standard induction therapies.

Prognostic Implications of CD14 Positivity in Acute Myeloid Leukemia Arising From Myleodysplastic Syndrome,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3523-3523
Author(s):  
Yunsuk Choi ◽  
Sungdoo Kim ◽  
Young-Hun Park ◽  
Jae Seok Lee ◽  
Dae-Young Kim ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Free Survival ◽  
Secondary Aml ◽  
Hla Dr ◽  
Prognostic Implications ◽  
De Novo Aml

Abstract Abstract 3523 Introduction: Secondary AML that has evolved from MDS shows different clinical features and outcomes compared to de novo AML. Prognostic implications of immunophenotypes have been studied in de novo AML, whereas those have not well been defined in secondary AML from MDS. Methods: This retrospective study involved analysis of data from 65 adult patients, 37 males and 28 females, who were diagnosed with AML arising from MDS at a single institute. Data for baseline clinico-pathological features, treatments, and outcomes were collected from medical records of each patient. Immunophenotyping was performed for the markers including TdT, CD34, CD13, CD33, CD117, CD14, CD56, HLA-DR, CD3, CD7, CD10, and CD19 using flow cytometry. Results: At the time of MDS diagnosis, the WHO subtype was RA/RARS in 5, RCMD in 10, RAEB-1 in 17, RAEB-2 in 29, and unknown in 4. For the treatment of MDS, hypomethylating agents were given to 17 patients and 2 patients underwent allogeneic hematopoietic cell transplantation (HCT). Median duration of MDS prior to diagnosis of AML was 4.9 months (range, 0.3–91.1). At the time of AML evolution, median age was 50.7 years (range, 18–80), and cytogenetic risk group was good-risk in 1, intermediate-risk in 45, and poor-risk in 18. Proportion of positivity of each immunophenotype marker was as follows: TdT (5%), CD34 (65%), CD13 (98%), CD33 (97%), CD117 (90%), CD14 (22%), CD56 (10%), HLA-DR (93%), CD3 (2%), CD7 (35%), CD10 (8%), and CD19 (2%). After the evolution to AML, 52 patients received induction chemotherapy consisted of cytarabine plus idarubicin or daunorubicin and 8 patients underwent allogeneic HCT as initial treatment of AML. Complete remission (CR) was induced in 27 patients after treatment. At a median follow-up time of 29.2 months (range, 2.6–116.2) among surviving patients, 49 patients died, 13 relapsed, and 53 died or relapsed. Median overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) were 7.6, 26.1, and 5.4 months, respectively. Of immunophenotype markers, CD14 positivity only showed prognostic implications at the univariate analyses: lower CR rate after induction chemotherapy (P=0.034) and shorter survivals (OS, P<0.001; RFS, P=0.078, and EFS, P<0.001). Differences in OS and EFS remained significant after adjustment for other variables (OS, HR, 4.49, 95% CI, 2.16–9.87, P<0.001; EFS, HR, 4.06, 95% CI, 2.03–8.13, P<0.001). Other prognostic variables included age of 60 years or older (shorter OS [P=0.003] and EFS [P=0.020]), WBC over 60,000/mcl (shorter OS [P<0.001] and EFS [P=0.001]), and poor cytogenetic risk group (shorter OS [P=0.005]). Conclusions: Surface expression of CD14 on leukemic blasts was an independent prognostic factor for survivals in the patients with AML arising from MDS. Disclosures: No relevant conflicts of interest to declare.

IDH1/2, TET2 and DNMT3A Mutations Are Not Mutually Exclusive in Secondary Acute Myeloid Leukemias,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3556-3556
Author(s):  
Olivier Kosmider ◽  
Olivier LaRochelle ◽  
Marie-Magdelaine Coude ◽  
Veronique Mansat-De Mas ◽  
Eric Delabesse ◽  
...  
Keyword(s):  
Bone Marrow ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Remission Rate ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Myeloid Leukemias ◽  
Melting Analysis ◽  
De Novo Aml

Abstract Abstract 3556 IDH1/2, TET2 and DNMT3A mutations have been reported in myeloid malignancies including de novo AML. In this study, we have analyzed the frequency and prognostic impact of these mutations in a large retrospective cohort of patients (pts) with secondary AML (SA) which encompass myelodysplasia-related changes (MRC) AML and therapy-related (TR) AML according to the WHO classification. Bone marrow samples were collected from 247 pts at diagnosis with SA and the mutational status of IDH1/2, TET2 and DNMT3A genes together with other genes frequently mutated in AML (NPM1, FLT-3, N and K-RAS, WT1) was determined by Sanger sequencing or high resolution melting analysis. The cohort of 247 pts consisted in 201 MRC AML and in 46 TR AML, 39.5% of which with a normal karyotype (NK). The frequency of IDH1/2, TET2 and DNMT3A mutations was 12.6, 19.8 and 4.5%, respectively. Two pts had both TET2 and IDH1/2 mutations, 2 pts had TET2 and DNMT3A mutations and 5 pts had both IDH1/2 and DNMT3A mutations showing that these mutations were not mutually exclusive in SA. IDH1/2 and TET2 mutations were significantly more frequent in MRC AML (14.1 and 22.3%) than in TR AML (6.4 and 8.7%) (P =0.04 and P =0.03) while the frequency of DNMT3A mutations was identical in the two subgroups. The SA pts harbouring at least one IDH1/2 or TET2 or DNMT3A mutation were significantly older (P <0.0001) and presented higher leukocyte count and lower MCV (P <0.05) than unmutated pts. Percentage of blasts in the bone marrow was similar in the two groups. Karyotype was normal in 48% of the IDH1/2 or TET2 or DNMT3A mutated pts and 18% of the unmutated patients, indicating that these mutations were strongly associated with NK (P < 0.001). A statistically significant link was found between TET2 or IDH1/2 or DNMT3A mutations and NPM1 mutations, but not with FLT-3, N/K-RAS or WT1 mutations. Complete remission rate and overall survival were evaluated in a group of 158 pts which had received intensive chemotherapy at diagnosis, and were identical in the IDH1/2 or TET2 or DNMT3A mutated and unmutated groups. These mutations did significantly influence survival neither in the subgroup of pts with normal karyotype, nor in the subgroup of MRC-AML, or TR-AML which were of very poor prognosis. These data show that IDH1/2, TET2 or DNMT3A mutations could modify the clinical presentation without impact on prognosis. Disclosures: No relevant conflicts of interest to declare.

Poor Outcome in Secondary Acute Myeloid Leukemia (AML): A First Report From the Population-Based Swedish Acute Leukemia Registry

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 130-130 ◽  
Author(s):  
Soren Lehmann ◽  
Vladimir Lazarevic ◽  
Ann-Sofi Hörstedt ◽  
Erik Hulegårdh ◽  
Christer Nilsson ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Population Based ◽  
Induction Treatment ◽  
Secondary Aml ◽  
Male Predominance ◽  
Hematological Disorder ◽  
De Novo Aml

Abstract Abstract 130 Secondary AML comprises AML patients with an antecedent hematological disorder (AHD) or previous exposure to chemotherapy and/or radiation (therapy-related AML; tAML). Population-based data on this patient group are scarce. Here, we report for the first time, data on secondary AML from the Swedish Acute Leukemia Registry covering 98% of all AML cases diagnosed in Sweden between 1997 and 2006. In total, 3372 AML patients were registered during this period. Of these, 949 (28%) had secondary AML; 655 (19%) had a history of AHD and 294 (8.7%) had tAML. The proportion of secondary AML increased from 8% in patients below the age of 40 years to 36% in patients between 70–79 years. Of patients with AHD, 423 (65%) had previously been diagnosed with myelodysplastic syndrome (MDS) and 227 (35%) with various types of myeloproliferative disorders (MPN). AML with AHD showed male predominance (57%), whereas tAML showed female predominance (64%). This distribution was significantly different (p<0.001) compared to de novo AML with an equal gender distribution. Median and mean ages for patients with AML with antecedent hematological disorder were 73 and 71 years, which differed significantly from de novo AML with 70 and 66 years, respectively (p<10−11). For tAML, median and mean ages were 71 and 67 years, respectively, not significantly different from de novo AML. Patients with secondary AML had slightly worse WHO/ECOG performance status (WHO PS) with lower incidence of WHO PS 0 (10%: 14%: 18% for AML with AHD:tAML:de novo AML) and a higher incidence of WHO PS 3–4 (27%: 24%: 20%). The proportion of patients with PS 1 and PS2 was similar for secondary AML and de novo AML. Intensive induction treatment was given to 45% of all patients with AHD, to 57% of patients with tAML compared to 68% for patients with de novo AML. In patients below the age of 65, the proportion of intensively treated patients was 76, 85 and 98%, respectively. CR rates for in patients including all ages were 40% for AML with AHD, 54% for tAML and 72 % for de novo AML (p-values<0.0001 for all calculations). CR rates were lower in all cytogenetic risk groups in both AML with AHD and tAML compared to de novo AML (Low risk NA: 70%: 91%; intermediate risk 53%: 56%: 89%; high risk 30%: 43%: 76%). CR rates were lower for both secondary leukemia types within all WHO PS groups, despite similar early death rates in secondary and de novo AML. Median survival for all patients regardless of age or type of treatment was 4 mo, 4 mo and 9 mo respectively for patients with AML with AHD, tAML and de novo AML, respectively. For all patients receiving intensive induction treatment, corresponding figures were 7 mo, 9 mo and 17 mo, and for patients below 65 years of age 7 mo, 9 mo and 38 mo. We conclude that secondary AML is less common in younger patients and that the proportion increases to a third of patients above 70. Patients with AHD and tAML less often receive intensive induction treatment than those with de novo AML and treatment responses are poor regardless of cytogenetic risk group or performance status also in intensively treated patients. Disclosures: No relevant conflicts of interest to declare.

Comparing Outcomes of Patients with Secondary AML: Treatment-Related MDS/AML, AML Secondary to Myeloproliferative Neoplasms (t-MPN), and AML with Prior Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3557-3557 ◽  
Author(s):  
Cecilia Y Arana Yi ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
William G. Wierda ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Molecular Markers ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Secondary Aml ◽  
Flt3 Mutations ◽  
History Of ◽  
De Novo Aml

Abstract Abstract 3557 Background: Secondary Acute Myeloid Leukemia (AML) accounts for approximately 10% of AML's and are often associated with adverse outcomes compared to de novo AML. In addition to cytogenetics, multiple gene mutations have been incorporated in the de novo AML risk stratification as independent prognostic and predictive factors. Little is known about these molecular markers in secondary AML. We analyzed the characteristics and outcomes of AML patients arising from myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), treatment-related AML (t-AML), or with prior history of cancer not treated with chemotherapy or radiation compared to de novo AML, and investigated the frequency and prognostic relevance of molecular markers among those groups. Patients and Methods: We analyzed the outcomes of adult patients with AML receiving induction chemotherapy at MDACC (n= 248) from 2010 to 2012. Median age was 67 years (range 17–82) and 142 (57.2 %) patients were >60 yrs. 108 (44%) were female. 146 (59 %) had de novo AML, 43 (17%) had t-AML, 23 (9%) had post-MDS, 16 (7%) post-MPN, and 20 (8%) AML with antecedent cancer not treated with chemotherapy and/or radiation therapy. Median white blood cell count (WBC) at diagnosis was 4.45 × 109/L (r: 0.4–186.5), and 82 (33%) pts had WBC >10 x109/L. Cytogenetics were diploid in 91 (37%), inv 16 in 16 (7%), t(8;21) in 12 (5%), trisomy 8 in 10 (4%), chromosome −5 and/or −7 in 60 (24%), 11q in 11 (4%), miscellaneous in 30 (12%), and insufficient metaphases on 18 (7%). 43(17%) had FLT3 mutations including 26 (10%) with FLT3-ITD, 14 (6%) FLT3-D835, and 3 (1%) double mutant. 32 (13 %) had NPM 1, 15 (6%) CBFb-MYH1, 10 (4%) ABL1/ETO, 6 (2%) JAK2, 34 (14 %) RAS, 1 (0.4%) cKIT, 18 (7%) CEBPA, 10 (4%) IDH1, and 8 (3.2%) IDH2. The pts were treated with several different induction chemotherapies. Idarubicin and cytarabine (IA)-based were more frequent in de novo and in 2nd cancer groups, while hypomethylating agents were more common in post-MDS and post-MPN groups. CR rates were higher in de novo AML than the rest of the groups, and early deaths were more common in the post-MPN group. The frequency of mutations was similar among groups with the exception of JAK 2 mutation, which was more frequent in post-MPN (Table 1). In pts with secondary AML, FLT3 mutations do not seem to further worsen their outcome (median survival 6.2 months for FLT3 wt and 6.4 for FLT3 ITD in 2nd AML; corresponding values for de novo AML are not reached and 13.3 months, respectively). (Figure 1) EFS and OS was worse in the post-MDS and post-MPN groups compared to de novo AML and second cancer group (p>0.001). Conclusion: In patients with secondary AML, antecedent of MDS or MPN are associated with unique molecular signatures (eg, rare FLT3-ITD in post MDS, frequent JAK2 in post-MPN) and have an inferior outcome. In contrast AML in pts with history of previous cancers not previously exposed to chemotherapy or radiation therapy survival outcomes are similar to de novo AML. Mutational status may not be as predictive of outcome among patients with secondary AML as it is for de novo AML. Disclosures: No relevant conflicts of interest to declare.

AML in Israel: Younger Age at Diagnosis Does Not Improve Prognosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4130-4130
Author(s):  
Neta Goldschmidt ◽  
Sarah Cohen ◽  
Deborah Rund
Keyword(s):  
Supportive Care ◽  
De Novo ◽  
Tertiary Care ◽  
Normal Karyotype ◽  
Good Prognosis ◽  
Age At Diagnosis ◽  
Secondary Aml ◽  
Younger Age ◽  
Age Of Diagnosis ◽  
De Novo Aml

Abstract Abstract 4130 Introduction AML is generally considered a disease of the elderly, with a mean age of diagnosis in the Western world is approximately 60 years of age or older. Important prognostic parameters include: age, karyotype and new molecular markers (NPM1 and FLT3). Treatment in a tertiary care facility also may improve survival. We elected to examine these parameters and the long term outcome of AML patients (pts) treated in our institution which is an academic tertiary care center, among the largest in Israel. Methods We reviewed clinical data on pts with AML (de novo and secondary) treated at Hadassah in the years 1992-2009. Karyotype was determined by conventional cytogenetics and FISH analysis or molecular analysis when appropriate. Good prognosis karyotype was considered to include t(8;21), t(15;17) and inv16. FLT3 ITD (internal tandem duplications) and NPM1 analysis was determined on all pts for whom DNA was available, using PCR and either acrylamide gel electrophoresis (FLT3) or melting point analysis (NPM1). Kaplan Meier analysis determined duration of survival. Statistical significance was determined using Log rank and Chi square test, with significance set at a level of p<0.01. Results 293 patients were included, of which 236 (80%) had de novo AML and 57 (19.5%) had secondary AML, either following an antecedent hematological disease (AHD) such as MDS (n= 32, 11%) or therapy related AML (t-AML) (n=25, 8.5%). Our standard protocol for AML includes 7+3 induction and high dose Ara-C consolidations. Bone marrow transplantation (BMT), either allogeneic or autologous, is performed in high risk cases depending on donor availability. The mean age at diagnosis of the 293 pts was relatively young (all pts= 47.7±18.3 yrs; de novo AML= 45.6±17.6 yrs; secondary AML= 56.2±18.6 yrs; t-AML= 48.6±16.6 yrs). Mean age at diagnosis for Arab pts was 44.2±16.7, as compared to Jewish pts (49.4±18.6). For de novo AML Arab pts, mean age at diagnosis was 43.3±16.4 as compared to de novo Jewish pts (46.9±18). The male to female ratio was 60/29 (2.06) for Arab pts and 99/102 (0.97) for Jewish pts, 53/25 (2.12) and 80/78 (1.02) for de novo Arab and Jewish pts respectively. In the de-novo AML group, 58 (24%) had a good prognosis karyotype. In the entire group of pts, 108 (37%) had normal karyotype and 62 (21%) had FLT3 ITD. Of the 108 normal karyotype pts, 34 (31%) were found to have FLT3 ITD, and 17 (16%) were found to harbor NPM1 mutations; of the NPM1 positive patients, 12 (70%) were FLT3 ITD negative. Treatment with intention to cure was administered to 218 (92%) of the de novo AML and 36 (63%) of the secondary AML pts. Other pts received best supportive care. Eighty six (29%) pts underwent allogeneic BMT and 12 (4%) underwent autologous BMT. The 5 year survival was 35% and the 10 year survival was 17% with no difference between Arabs and Jews. Good prognosis karyotype significantly improved survival as did younger age, and absence of FLT3 ITD. Conclusions We conclude that in our institution, the median age of diagnosis of AML is more than two decades younger than that reported in literature. The reason for this may be demographic or related to environmental exposures such as smoking. The preponderance of male Arab pts is most likely due referral bias. The young age of the Arab male pts may be due to occupational or environmental exposures, such as smoking. Our treatment protocols and supportive care are similar to those used in Western countries. Despite these factors, survival was not as good as might be expected according to age, karyotype and FLT3 ITD status. Further studies are needed to elucidate the etiology of these findings. Disclosures: No relevant conflicts of interest to declare.

Low Prevalence of IDH1 gene Mutation In Childhood AML In Italy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1678-1678
Author(s):  
Martina Pigazzi ◽  
Giulia Ferrari ◽  
Riccardo Masetti ◽  
Brunangelo Falini ◽  
Francesco Martinolli ◽  
...  
Keyword(s):  
Gene Mutation ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Idh1 Mutation ◽  
Isocitrate Dehydrogenase 1 ◽  
Childhood Aml ◽  
Idh1 Mutations ◽  
Low Prevalence

Abstract Abstract 1678 Introduction: The IDH1 gene encodes for NADP+-dependent isocitrate dehydrogenase 1 enzyme, which catalyzes the oxydative decarboxylation of isocitrate to α-ketoglutarate. Acquired somatic mutations of the R132 residue of IDH1 have been detected in adults with de novo AML, while so far no IDH1 mutations were detected in a series of 257 children in USA. The role of IDH1 mutations in the pathogenesis of AML is still unclear. Material and Methods: From 01/12/2002 to 31/12/2007, 205 childhood AML patients were enrolled into the multicentric AIEOP-LAM 2001/02 protocol. Among them, we analyzed the prevalence of IDH1 mutations in 165 patients for whom material was available. IDH1 gene mutations have been analyzed by PCR amplification and sequencing of the exon 4. The clinical and biological features of the analyzed and not analyzed population were not statistically different. Results: In this series of childhood AML cases, 4 out of 165 cases (2.4%) were positive for IDH1 mutations. All patients were male, the age at diagnosis ranged from 3 to 14 years, while the WBC count at diagnosis ranged from 8750 to 233970 WBC/ml. Three of them had FAB M1 and one M2; none of them had localization in the central nervous system, while one had lymph nodes involvement. Two of the 4 children with the IDH1 mutation had a normal karyotype while two carried different clonal translocation. One patient carried the FLT3-ITD mutation at diagnosis, whereas no other known associated mutations were found. Based on cytogenetics, all of them were classified within the high risk group. Complete remission was achieved in all cases, and all but one received BMT. Two patients had a medullary relapse and all are alive, after 20, 26, 33 and 33 months from BMT. All patients carried the R132H IDH1 mutation. The mutation was specific of the leukemia cells, being absent in the remission phase of all patients. Interestingly, the R132H mutation was detected at the relapse stage of one patient, but not at the relapse of the second patient, suggesting that IDH1 mutations could represent a secondary lesion in the pathogenesis of leukemia. Because 2/4 IDH1 mutated cases in the sequential screening had a normal karyotype, we extended the mutational screening to all Italian childhood cases diagnosed as AML with normal karyotype from 13/10/2000 to 15/04/2010. Out of the additional 97 cases with normal karyotype, only 1 carried a IDH1 mutation (R132H). Conclusions: In summary, we showed that IDH1 gene mutation can be detected also in pediatric AML, with an estimate prevalence of 2.4% (4/165) in the Italian series. The low prevalence does not allow any prediction on the outcome, although all patients are alive at different time after BMT, even in the presence of FLT3-ITD mutation (one patient). The clinical and biological characteristics of the mutated patients seemed not to be different from the overall childhood AML population, and similar to the adult IDH1 mutated cases. The R132 mutation is the only pediatric mutation detected so far. The extended series to a total number of 186 childhood AML with normal karyotype identified 3/186 mutations (1.6%) in this specific subgroup. Therefore, it does not seem that IDH1 mutation is more prevalent in normal karyotype. In addition, even considering that the IDH1 mutation could not be present at the relapse (like it happens for FLT3 mutations), it is questionable the role of these abnormalities, and whether those mutations in ‘normal cytogenetic’ subgroup could be sufficient for the clinical disease emergence, or further events must be discovered in the complex and multistep pathogenesis of leukemia. Disclosures: No relevant conflicts of interest to declare.

Retrospective Comparison of Using or Not Using Donor Lymphocyte Transfusion in the Treatment of Hematological Relapse after Allogeneic Stem Cell Transplantation in 489 Adults with Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 298-298
Author(s):  
Christoph Schmid ◽  
Myriam Labopin ◽  
Juergen Finke ◽  
Gerhard Ehninger ◽  
Olle Ringden ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
De Novo ◽  
Patient Age ◽  
Entire Cohort ◽  
Post Transplant ◽  
Patient Âgé ◽  
Retrospective Comparison ◽  
De Novo Aml

Abstract Relapsed AML after allogeneic SCT has a poor prognosis. So far, no standard therapy could be defined. Donor lymphocyte transfusion (DLT) has been effective in a minority, however, no data is available to identify patients who will benefit from the procedure. Neither, the outcome of patients treated with or without DLT have been compared. We retrospectively evaluated overall survival (OS) of 489 adults with de novo AML in hematological relapse after SCT, receiving DLT (n=190) or not (n=299). DLT and noDLTgroups were well balanced in terms of patient age (median:37y in both groups), donor age, cytogenetics (good:5vs7%, intermediate:83vs79%, poor:12%vs14%), WBC at diagnosis, donor type (geno-id:71vs72%, MUD:18% both, mismatched:11vs10%), status at transplantation (CR1:38vs41%, CR2:13vs15%, advanced:49vs44%), conditioning, source of stem cells, and time from transplant to relapse (5vs4.5 months). However, DLT patients had a median of 39% BM blasts, as compared to 54% for the noDLT group (p=0.03). Follow-up was 32 and 30 months. Within the DLT group, chemotherapy was additionally given in 130 cases. Nevertheless, only 33% of patients received DLT in CR or aplasia, 67% had measurable disease. AGvHD developed in 41% of patients following DLT. CR and PR were achieved in 31.1% and 4.8% of DLT patients. In a multivariate analysis, younger patient age (&lt;36 years) (HR=1.53,p=0.02) and a longer interval (&gt; 5 months) from transplant to relapse (HR=7.74,p=0.002) were associated with better OS after DLT. When comparing the outcome of patients receiving or not DLT, OS at 2 years was 10±1% for the entire cohort, 18±3% for DLT and 6±1% for noDLT (p&lt;.0001). In a multivariate analysis, use of DLT (HR=2.11,p&lt;0.0001); recipient’s age&lt;36 y (HR=1.69, p&lt;0.001); longer interval (&gt;5 months) from transplant to relapse (HR=2.40, p&lt;0.0001) and number of BM blasts (&lt;48%) at relapse (HR=1.56,p=0.002) were favorable for OS. In this retrospective analysis the results suggest that DLT may be of advantage in the treatment of AML relapse post transplant, at least in younger patients with a longer post transplant remission and relapsing with smaller amounts of blasts in BM. However, patients receiving DLT might represent a positive selection among all relapsed cases, since a considerable number from the noDLT cohort had died too early to proceed to DLT. An intetion-to-treat analysis and further prospective studies should investigate the role of DLT and other approaches, such as second reduced intensity SCT.

Interim Anaiysis of Intention To Treat Analysis, “Multicenter AML-2000 Trial” Based on Cytogenetics Risk Factors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4618-4618
Author(s):  
Yeung-Chul Mun ◽  
S.M. Lee ◽  
S.M. Bang ◽  
S.H. Park ◽  
E.K. Cho ◽  
...  
Keyword(s):  
De Novo ◽  
Risk Groups ◽  
Good Prognosis ◽  
Remission Induction ◽  
Secondary Aml ◽  
Intention To Treat ◽  
Prognostic Groups ◽  
Prognosis Group ◽  
De Novo Aml ◽  
Treat Analysis

Abstract The result of cytogenetics is one of the most important prognostic factors on the prognosis of AML. HDAC, auto PBPCT and allogeneic BMT after 1 or 2 times of post remission therapy based on 4 prognostic groups(APL: Acute promyelocytic leukemia, GPG: Good prognosis group, IPG: Intermediate prognosis group, PPG: Poor prognosis group by MRC definition) were underwent based on cytogenetics data. We studied CR, relapse, toxic death, DFS and OS. Inclusion criteria were age<65, PS<3 with reasonable organ functions in de novo AML, secondary AML and RAEB-T. The aims of this prospective intention to treat analysis was to compare the CR, recovery kinetics, DFS and OS by giving different therapies of intensity in the different prognostic groups based on cytogentics data. Three plus seven(Idarubicin 12mg/m2(D1–D3), Ara-C 100mg/m2(D1–D7)) were given to de novo AML, secondary AML and RAEB-T. Intermediate dose(8gm/m2) of Ara-C was given followed by HDAC or auto PBPCT to the patients with GPG(t(8:21) & inv(16)). Three times of post remission therapy including HDAC, or auto PBPCT were given to the patients with IPG or PPG(−5, −7, del 5q, complex). If HLA-identical sibling was available, then allo BMT was underwent after 1st post-remission therapy. In cases of APL, three times of post-remission therapy with idarubicin alone were given. ATRA was given to APL group during remission induction therapy and after post-remission maintenance period for 2 years. Up to Mar., 2005, 422 patients(18 centers) were enrolled. Median follow-up was 48months. Among them, 92.3% was de novo AML, and APL, GPG, IPG and PPG were 10.0%, 21.6%, 51.4%, and 14.7% respectively. Overall CR after 1st induction(3+7) were 69.9%(APL: 87.2%, GPG: 84.7%, IPG: 63.8%, PPG: 55.66%, P<0.01). Relapse rate was 12.8%(APL), 40.5%(GPG), 40.5%(IPG) and 45.6%(PPG) respectively(P<0.01). Toxicities profiles including mucositis, hepatic, cardiac and bleeding episodes were similar on 3 different therapy modalities(HDAC, auto PBPCT and allo BMT). In conclusions, this trial seems to be tolerable in terms of toxicities after induction and during post remission therapies. Among GPG, there were no significant statistical differences on OS and LFS in all the therapy modalities(ie, HDAC, Auto, Allo). In IPG, auto arm had a tendency of superior OS and LFS comparing to HDA & allo arm. In PPG, there was significant surperior LFS in allo arm. There were no statistical differences on OS in all the therapy modalities in PPG. This intention to treattrial, which had started in Jan, 2000, has been going on until now. Through this risk based trial using cytogenetics, we might be able to find optimal post-remission therapies for different risk groups with less toxicities.

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