NPM1 Mutations Have a High Impact On the Development of Secondary AML.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 999-999
Author(s):  
Susanne Schnittger ◽  
Tamara Weiss ◽  
Frank Dicker ◽  
Jana Sundermann ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
De Novo ◽  
Myeloproliferative Neoplasms ◽  
Blast Crisis ◽  
Nras Mutation ◽  
Npm1 Mutation ◽  
Secondary Aml ◽  
Second Hit ◽  
Total Cohort ◽  
Equity Ownership ◽  
De Novo Aml

Abstract Abstract 999 Poster Board I-21 NPM1 mutations are frequently reported to be typical for de novo AML and are regarded as prognostically favorable if not associated with FLT3-ITD. These mutations have rarely been reported in secondary AML after myelodysplastic syndrome (MDS) or after myeloproliferative neoplasms (MPN). We have detected NPM1 mutations in 37/283 patients with AML after a previous MDS (s-AML) (13.1%) and in 6/67 after a previous MPN (9%). Here we describe the characteristics of these 43 NPM1 mutated s-AML cases to show the involvement of NPM1 mutations in development of secondary AML. The total cohort of 43 cases was composed of 22 males and 21 females with a median age of 71.3 years (range: 29.3-87.7 years). Cytogenetics was available in 40 of the 43 cases (93%). 27 of these had a normal karyotpye whereas 13 revealed one of these aberrations: +4 (n=3), t(1;14)(p34;q32) (n=1); -7 (n=1), del(9q) (n=2), +13 (n=1); +21 (n=1), -Y (n=1); i(X)(p10) (n=1), [+1,der(1;13)(q10;q10),+i(5)(p10),+8] (n=1) and a t(5;12)(q33;p13) (n=1). All 43 samples were analysed for MLL-PTD, FLT3-ITD, FLT3-TKD, NRAS, CEBPA, RUNX1 mutations as well as for KITD816 and JAK2V617F mutations. The incidence of additional cooperating mutations was similar to de novo AML. FLT3-ITD was detected in 14/37 AML after MDS (37.8%) and only once (1/6) after MPN. FLT3-TKD was observed in 3/37 case after MDS (8.1%) and never after MPN. In addition there was one case with RUNX1 and 4 cases (10.8%) with NRAS mutation after MDS. In none of the cases a CEBPA mutation or MLL-PTD was observed. Thus a total of 18/37 cases (48.8%) after MDS revealed a further molecular mutation in addition to NPM1. Of those without additional molecular mutations (only NPM1) 4 cases revealed cytogenetic aberrations resulting in 22/37 cases (59.5%) with additional cytogenetic or molecular mutations. Also in the 6 cases with NPM1 after MPN we detected a high proportion of additional mutations. Two of these 6 cases defined to be after MPN had a history of KITD816V mutated mastocytosis. Two further cases had preceding JAK2V617F mutated MPN and one additional carried an ETV6-PDGFRB rearrangement. In all these 5 transformed MPN cases the initial typical MPN mutation was retained in AML (blast crisis) whereas the NPM1 mutation was acquired and may have served as a second hit in the development to AML. One of the two JAK2+/NPM1+ cases in addition also acquired an FLT3-ITD. From 11 of the s-AML cases a paired sample from the timepoint of MDS was available. Retrospectively the NPM1 mutations was retraced by mutation specific realtime PCR and also all other markers were analysed. Three different patterns were observed: 1) in two cases the NPM1 mutation was not detectable in MDS (analysed 35 and 11 months before diagnosis of s-AML). In one case an NPM1/ABL1 level of 1.6% was detectable 6 months after diagnosis of MDS and a level of 2129% eleven months after diagnosis of MDS. 2) In six cases the NPM1 mutation was not detectable with standard methods in MDS, but with sensitive Real time PCR a ratio of 1-4 log below the s-AML level was already detectable 6-17 months before onset of s-AML. 3) In three further cases a high NPM1 level comparable to that in s-AML was already detectable in MDS 2-12 months before s-AML evolved. These three cases gained an FLT3-ITD at the time point of transformation from MDS to AML. These pattern show that NPM1 can be an early or a late event in transformation to s-AML and although the acquisition of mutations seems to be important in the transformation to AML the sequence of the single events seem to be secondary. As NPM1 have a favourable prognosis in de novo AML if not associated with FLT3-ITD we did a respective analysis for overall survival (OS) and (EFS) for our cohort of s-AML after MDS. For this analysis 278 s-AML patients were available: NPM1-/FLT3- (n=223); NPM1+/FLT3- (n=20), NPM1-/FLT3+ (n=20) and NPM1+/FLT3+ (n=12). The total cohort revealed a bad outcome (median OS: 56.6 days and median EFS: 43.5 days; range 2-1049 days for both). The median time for MDS until transformation to AML was 316 days (range: 15-6310 days). No difference with respect to outcome was detected between the four different molecular genetic subgroups. In conclusion, these data 1) show that NPM1 mutations play a major role in the evolution of AML following MDS or MPN. 2) NPM1 mutations can be the first as well as the second hit during transformation. 3) Support the theory of a multistep genetic principle in development of secondary AML. 4) s-AML with a NPM1+/FLT3-ITD- status can not be regarded as prognostically favorable. Disclosures: Schnittger: MLL Munich Leukemia Lab: Equity Ownership. Weiss:MLL Munich Leukemia Lab: Employment. Dicker:MLL Munich Leukemia Lab: Employment. Sundermann:MLL Munich Leukemia Lab: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Lab: Equity Ownership. Haferlach:MLL Munich Leukemia Lab: Equity Ownership.

Fusion Gene Detection Using Whole Transcriptome Analysis in Patients with Chronic Myeloproliferative Neoplasms and Secondary Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4093-4093 ◽  
Author(s):  
Fiorella Schischlik ◽  
Jelena D. Milosevic Feenstra ◽  
Elisa Rumi ◽  
Daniela Pietra ◽  
Bettina Gisslinger ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Fusion Gene ◽  
Myeloproliferative Neoplasms ◽  
Chronic Phase ◽  
Loss Of Function ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Whole Transcriptome

Abstract Fusion oncogenes resulting from chromosomal aberrations are common disease drivers in myeloid malignancies. The most prominent example is BCR-ABL1 fusion present in chronic myeloid leukemia, which together with essential thromobocythemia (ET), primary myelofibrosis (PMF) and polycythemia vera (PV) belongs to the classic myeloproliferative neoplasms (MPN). The BCR-ABL1 negative MPNs are driven by somatic mutations in JAK2, MPL and CALR. MPN patients can progress to acute myeloid leukemia (AML) but the transformation process is not well understood. Studies using standard karyotyping and SNP microarrays have shown that disease progression is characterized by an increase in karyotype complexity. We aimed to identify novel fusion oncogenes in patients with BCR-ABL1 negative MPN during chronic phase and disease progression in high-throughput and cost-efficient manner using RNA-seq technology. In addition this approach enabled us to perform RNA-seq variant calling for identification of gene mutations on the same cohort of patients. Whole transcriptome sequencing was performed on 121 patients (112 chronic phase MPN and 9 secondary AML samples) and 23 healthy controls in a 100 base pair paired-end manner. The cohort consisted of 44% PMF, 22% ET, 12% PV and 6% secondary AML patients. The output of three fusion detection tools (Defuse, Tophat-fusion and SOAPfuse) was combined in order to increase sensitivity. Extensive filtering steps were applied in order to enrich for cancer specific fusion events, including filtering for fusions appearing in healthy individuals, filtering for read-throughs and false positives with external databases and manual inspection of sequencing reads. The outcome of analysis for Defuse, Tophat-fusion and SOAPfuse resulted in the total of 52, 54 and 38 candidate fusions, respectively. Candidate fusions were Sanger-sequenced and for Tophat-fusion and Defuse the validation rate was 60%, while for SOAPfuse only 20% could be validated. Approximately 70% of the fusion candidates were not shared among the 3 tools which underlines the importance of selecting the union of all calls from each tool rather than the intersect. We did not observe clustering of breakpoints along the genome. Most fusion candidates could be detected in PMF which corresponds to the disease entity that was most represented in the cohort (44% of patients). No enrichment for fusions was found in 7 triple negative (no JAK2, CALR, MPL mutations) cases. 42% of chromosomal aberrations were translocations, followed by duplication (31%), inversion (14%) and deletion events (11%). Among the intragenic fusions, approximately half had genomic breakpoints less than 1 Mb apart. 70% of validated fusions were out of frame, while 28% were in frame. In the leukemic samples a higher abundance of fusions was found (4/9). Typical fusions for de novo AML were not detected within secondary AML (sAML) samples. We did not detect a recurrent fusion oncogene in our patient cohort. In a PMF patient with JAK2-V617F mutation we identified a BCR-ABL1 fusion, indicating a clonal exchange which was consistent with patient's phenotype. Another PMF patient exhibited an inversion event involving the first exon of CUX1, causing a CUX1 loss of function. Other fusions in chronic MPN patients affected genes involved in histone modifications (SMYD3-AHCTF1, KDM4B-CYHR1). In post-MPN AML patients we identified a somatic in frame-fusion involving INO80D and GPR1 and a fusion truncating the first 3 exons of RUNX2 (XPO5-RUNX2). The high quality of RNA sequencing data, allowed us to set up a variant detection workflow that will be compared with matched samples that have been exome sequenced. Preliminary results could demonstrate that mutations in the JAK2 gene in a cohort of 96 patients were all correctly recalled, emphasizing its sensitivity. Fusion events among patients in chronic phase MPN are rare and the majority of these events imply loss of function of both fusion gene partners. This approach adds valuable information on the true frequency of inactivation of genes such as CUX1 in patients, as small inversions like the one described above would not be detectable by other methods. Detection of a subclone with BCR-ABL1 fusion underlines the strength of the fusion detection workflow for diagnostic purposes. Typical de novo AML fusions were not found in sAML and further suggests that de novo AML and sAML are distinct disease entities on a genetic level. Disclosures Gisslinger: Janssen Cilag: Honoraria, Speakers Bureau; Sanofi Aventis: Consultancy; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Factors Affecting the Survival of Therapy Related AML/MDS, Secondary AML and De Novo AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5199-5199
Author(s):  
Rao Mushtaq ◽  
Faisal Akbar ◽  
Israa Khan ◽  
Scott Isom ◽  
Timothy Pardee ◽  
...  
Keyword(s):  
Median Survival ◽  
De Novo ◽  
Cytotoxic Agents ◽  
Smoking History ◽  
Risk Category ◽  
Npm1 Mutation ◽  
Factors Affecting ◽  
Secondary Aml ◽  
Risk Of Death ◽  
De Novo Aml

Abstract Introduction: Patients exposed to cytotoxic agents are at a higher risk of developing therapy related AML and MDS (tAML/tMDS), and have poor survival as compared to de novo AML due to high risk of adverse features. Secondary AML (sAML)includes patients with progression from myeloproliferative neoplasms (MPN) and myelodysplastic syndrome (MDS) to AML, considering this progression could be natural history of disease process. Patients with tAML are considered to have an inferior outcome compared with de novo AML. In this retrospective chart review study, we aimed to look at factors affecting the survival of tAML/tMDS, sAML and de novo AML. Method: This retrospective analysis included 219 AML patients treated at Wake Forest Baptist Medical Center between January 2010 and December 2016. Kaplan-Meier estimation was used to evaluate survival at one and two-year period in these three types of AML. Multiple Cox proportional hazards models were used to examine the interaction between baseline characteristics (Table 1) and AML type (tAML/tMDS, sAML, de novo AML) on survival. Backward selection method was used to identify important predictors for a final model. Hazard ratios and 95% CI of all-cause mortality were based on the final Cox model. Results: We analyzed 219 patients with AML diagnosis. Of those 151 (69%) were de novo AML, 25 (11%) sAML and 43 (20%) tAML/tMDS, with mean age of 60.7, 70.7, and 69.7 years respectively. 88% of sAML and 72% of tAML/tMDS were ≥ 65 years compared to 50% of de novo AML patients (p=0.0009). More patients were in underweight/normal BMI (< 24.9) category of sAML (50%) compared to 36% of de novo AML and 21% of tAML/tMDS although this was not statistically significant (p=0.10). There were more females with tAML/tMDS (51%) compared to de novo AML (48%) and sAML (40%) (p=0.52). Most patients in all three groups of AML were white with 79% of de novo AML, 88% of sAML and 88% of tAML/tMDS. Almost one-third of sAML (33%) and tAML/tMDS (38%) were in adverse risk category group with 24% of de novo AML in this category. Most of de novo (62%), sAML (67%) and tAML/tMDS (45%) were in intermediate risk category. There were 5 patients with tAML/tMDS in favorable risk category with zero sAML and 18 de novo AML in this category. 54% of our patients had ECOG performance score of 0-1. A majority of sAML (63%) had a positive smoking history compared to 47% of de novo AML and 44% of tAML/tMDS. Majority of patients in the three categories denied any alcohol use. Incidence of FLT-3 mutation was 23% in de novo AML, 0% in sAML and 9% in tAML/tMDS (p=0.0001). NPM1 mutation was present in 19% of de novo AML, none of sAML and 5% in tAML/tMDS (p = 0.0016). CEBPa mutation was present in 6% of de novo AML, 4% of sAML and 2% of tAML/tMDS. Median survival was 18.5 months for de novo AML (95% CI 14.9- 23.7), 7.2 months for tAML/tMDS (95% CI 3.3- 11.5) and 7.0 months for sAML (95% CI 3.4-15.6). The median survival was longer among males, compared to females with de novo AML (23.2 months in males; 95% CI 18.3-37.1 vs. 14.6 months in females; 95% CI 10.3-19.0) compared to sAML (13.5 months in males; 95% CI 3.8-55 vs, 3.3 months in females; 95% CI 0.2-8.1) and tAML/tMDS (6.3 months in males; 95% CI 4.5-17.8 vs. 7.2 months in females; 95% CI 2.3-11.5) p=0.06. Patients with adverse risk category had a shorter median survival compared to those with favorable risk category, especially in tAML/tMDS but this was not significant. After adjusting for age, risk category and FLT-3 status, the type of AML was not a significant predictor of survival. However, when compared with de novo AML, patients with sAML and tAML/tMDS appear to have a somewhat increased risk of death (HR 1.3; 95% CI 0.7-2.4 and 1.6; 95% CI 0.9, 2.7 respectively). Mortality was 4.5 (95% CI 1.8, 11.3) and 9.3 (95% CI 3.6, 24.0) times higher in patients with intermediate and adverse risk category respectively, when compared to the favorable risk group. Patients with positive FLT-3 had 1.6 times mortality compared to negative FLT-3 (95% CI 1.0, 2.7). Conclusion: We found that median survival was better in de novo AML compared to sAML and tAML/tMDS. There was no difference in survival between sAML and tAML/tMDS. Advancing age increases the odds of death across three types of AML. It is important to note that the effect of patient characteristics on survival is mostly consistent across the AML types and that once the major survival predictors are accounted for, the type of AML is no longer significant. Disclosures Pardee: Amgen: Speakers Bureau; Karyopharm: Research Funding; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Rafael Pharmaceuticals: Employment. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Outcome of Myelodysplastic Syndrome Treated with Intensive Chemotherapy within the AMLCG99 Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2773-2773
Author(s):  
Utz Krug ◽  
Carsten Muller-Tidow ◽  
Matthias Stelljes ◽  
Maria Cristina Sauerland ◽  
Achim Heinecke ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Allogeneic Transplantation ◽  
Intensive Chemotherapy ◽  
Employment Equity ◽  
Term Survival ◽  
Secondary Aml ◽  
Equity Ownership ◽  
De Novo Aml

Abstract Abstract 2773 Introduction: For patients with high-risk myelodysplastic syndromes an epigenetic therapy with hypomethylating agents is considered standard of care. Intensive chemotherapy can be offered to a subset of patients; however, data about the long-term outcome of MDS patients receiving intensive chemotherapy are scarce. Methods: For this evaluation, 104 adult patients with IPSS intermediate-2 or high-risk MDS with at least 10% bone marrow blasts of all age groups treated within the AMLCG1999 trial were included. Patients were randomized upfront to receive 1. double induction therapy with either standard-dose containing TAD - versus high-dose containing HAM–HAM, 2. TAD consolidation therapy followed by either a monthly maintenance therapy for 3 years after achievement of CR or an autologous stem cell transplantation (patients aged ≥ 60 years were all assigned to maintenance therapy), and 3. blast priming with filgastrim starting on day -1 of chemotherapy in selected centers. Results: Fifty-four patients had IPSS Score intermediate-2 and 50 patients were IPSS high risk. Median bone marrow blast count at diagnosis was 15%. The median age was 63.5 years (range: 27–76 years), 39 patients (37.5 %) were female. Median lactate dehydrogenase (LDH) serum level was 296 U/l, median leukocyte count at diagnosis was 5,950 per μl. The cytogenetic risk groups were as follows: favorable 3, intermediate 57, unfavourable 37, missing 7. Among 38 patients with normal karyotype, NPM1/FLT3 mutational status was available for 22 with 5 patients having the combination NPM1 mutated/FLT3 wildtype. Comparison with 2051 patients with de novo AML within the same trial revealed the following significant differences: patients with MDS were older, had a higher male to female ratio, a lower LDH serum level at diagnosis, a lower leukocyte count at diagnosis and were more likely to have adverse cytogenetic risk. Compared to 636 patients with secondary AML after MDS, cytotoxic therapy or irradiation, the cohort of patients with MDS did not display any significant differences except the sex distribution. Patients with MDS displayed a CR rate of 48% (50/104 patients), which was significantly lower than de novo AML patients (67%) and not different to secondary AML patients (47%). Median overall survival in MDS patients was 320 (95% CI: 236 to 505) days with a 2-year and 5-year survival of 33.4% (95% CI: 23.6% to 43.2%) and 22.7% (95% CI: 13.5% to 31.9%), respective, which was significantly (p=0.03) lower than in patients with de novo AML (median 484, 95% CI 435 to 541 days) and comparable to patients with secondary AML (median 282, 95% CI 224 to 311 days, p=0.13). Median relapse-free survival in responding MDS patients was 536 (95% CI: 264 to 1299) days with no significant differences of RFS compared to de novo or secondary AML patients. In multivariate analyses, the diagnosis of MDS remained an independent prognostic factor for CR probability but had no independent influence on survival compared with de novo AML patients. Nine patients proceeded to allogeneic stem cell transplantation in first complete remission of whom six remain in first complete remission between 1354 and 1911 days after achievement of CR. In addition, 16 patients remained in CR for more than one year without allogeneic transplantation. Discussion: Taken together, outcome of patients with intermediate-2 or high-risk MDS after intensive chemotherapy is comparable to the outcome of patients with secondary AML. Adjustment for known risk factors such as age, cytogenetic risk and LDH revealed that inferior outcome of MDS patients compared to patients with de novo AML is attributable to the higher incidence of adverse risk factors. CR-rates appear to be higher compared to hypomethylating therapy and a fraction of MDS patients experiences long-term survival by intensive chemotherapy. Allogeneic transplantation can improve long-term survival for patients achieving remission. Disclosures: Krug: MedA Pharma: Honoraria; Novartis: Honoraria; Alexion: Honoraria; Boehringer Ingelheim: Research Funding; Sunesis: Honoraria. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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.

Patients with Therapy-Related Myeloid Disorders Share Genetic Features but Can Be Separated by Blast Counts and Cytogenetic Risk Groups Into Prognostically Relevant Subgroups,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3583-3583
Author(s):  
Ulrike Bacher ◽  
Claudia Haferlach ◽  
Susanne Schnittger ◽  
Tamara Alpermann ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
De Novo ◽  
Risk Group ◽  
Risk Groups ◽  
Employment Equity ◽  
Total Cohort ◽  
Myeloid Neoplasms ◽  
Equity Ownership ◽  
De Novo Aml ◽  
Group 1

Abstract Abstract 3583 Background: In the WHO classification of 2008, patients with therapy-related acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) following cytotoxic therapy/radiation are combined to the category “therapy-related myeloid neoplasms”. To contribute to the discussion whether blast percentage or other subclassification are prognostically relevant in therapy-related myeloid disorders, we evaluated this combined group for clinical/genetic aspects. Study design: A total of 520 pts (242 m/278 f; median, 67.4 years; r. 18.0–91.5 yrs) with therapy-related myeloid malignancies (253 pts with ≥20% bone marrow blasts termed “t-AML”, 267 with <20% BM blasts: “t-MDS”) were investigated by cytomorphology, chromosome banding analysis, molecular genetics, and for clinical outcomes. Results: When biological characteristics of pts with ≥20% (“t-AML”) and <20% (“t-MDS”) BM blasts were compared, t-AML had higher mean WBC counts (17.7 vs 5.8×10(9)/L; p<0.001) and lower Hb (94 vs 103 g/L; p=0.003) and platelet level (81 vs 115 x10(9)/L; p=0.027) than t-MDS. Mean age was equal in t-AML/t-MDS (64.5 vs 64.6 years). Male/female ratio was lower in t-AML (0.6 vs 1.3 in t-MDS; p<0.001). Aberrant karyotypes (KTs) were more frequent in t-AML than t-MDS (175/253; 69.2% vs 147/267; 55.1%; p=0.001). NPM1 mut were similar in t-AML and t-MDS (23/197; 11.7% vs 6/54 investigated; 11.1%; p=n.s.). When only normal KTs were considered, NPM1 mut were detected in 20/65 (30.8%) t-AML (which is less than the NPM1 mut rate known in de novo NKT-AML) and were similar in NKT t-MDS (6/17; 35.3%; p=n.s.). FLT3 -ITD were less frequent in t-AML (19/210; 9.0%) compared to data on de novo AML, but more frequent than in t-MDS (2/112; 1.8%; p=0.016). Frequencies of FLT3 -ITD in normal KT were 8/66 (12.1%) in t-AML and 2/36 (5.6%) in t-MDS (p=n.s.). RUNX1 mut (t-AML: 11/81; 13.6%; t-MDS: 5/69; 7.2%), CEBPA (t-AML: 6/104; 5.8%; t-MDS: 0/10; 0.0%), FLT3- TKD (t-AML: 3/120; 2.5%; t-MDS: 0/23; 0.0%), NRAS (7/64; 10.9% vs 6/82; 7.3%), IDH (11/86; 12.8% vs 1/13; 7.7%), and MLL -PTD (7/200; 3.5% vs 5/109; 4.6%) did not differ significantly between t-AML/t-MDS. Patients with <20% BM blasts had better overall survival (OS) than pts with ≥20% BM blasts (median 43.8 vs 18.2 months; p=0.003). According to MRC cytogenetic risk groups (Grimwade et al., 2010), only 35 (6.7%) of all pts had favorable, 303 (58.3%) intermediate (t-AML: 144/253; 56.9%; t-MDS: 159/267; 59.6%), but 182 (35.0%) had adverse KTs (t-AML: 79/253; 31.2%; t-MDS: 103/267; 38.6%). In the total cohort, favorable KTs (group 1) had better OS than intermediate (group 2) and adverse (group 3) KTs (median n.r. vs 43.8 vs 16.2 months; p=0.002 comparing all 3 groups; group 1 vs 2: p=0.011; 1 vs 3: p=0.001; 2 vs 3: p=0.048). This holds true as well when t-AML pts (p=0.002 comparing different MRC groups) or t-MDS (p=0.003) were investigated separately. OS of NPM1 mut/FLT3 -ITD-neg. pts did not differ significantly from other genotypes in the total cohort (median n.r. vs 20.9 months) nor in normal KT t-AML (16.9 vs 11.0 months). In t-AML, MLL -PTD+ had worse OS than MLL -PTD-neg. pts (median 3.8 vs 16.9 months; p=0.001). In the total cohort, univariable Cox regression for OS was significant for age (p<0.001), WBC counts (p=0.016), Hb level (p=0.025), BM blasts both by a threshold of ≥20% vs <20% (p=0.003) or as continuous parameter (p=0.002), and MRC risk group (p=0.001). No significant differences were found for gender, platelets, NPM1 mut/FLT3 -ITD-negative status, or MLL -PTD+. By multivariable Cox analysis for OS age (p<0.001), WBC count (p=0.042), BM blasts by a threshold of 20% (p<0.001), and MRC risk group (p=0.002) were significant. Conclusions: In this study, patients with t-AML or t-MDS separated by a BM blast threshold of 20% showed significant differences in clinical outcomes and biological parameters. This emphasizes maintaining both subtypes within the WHO defined combined cohort of “therapy-related myeloid neoplasms”. Within both morphologically defined subentities, the karyotype is an excellent parameter for further prognostic predictions and shows similar patterns. The underrepresentation of the FLT3 -ITD and NPM1 mut in t-AML compared to de novo AML, and the similar frequency of NPM1 mut in t-AML and t-MDS suggests common molecular characteristics of both categories irrespective of blast percentages and strongly supports to combine them as therapy-related myeloid neoplasms as suggested by the WHO. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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.

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.

Epigenetic Therapy with 5-Azacitidine, Valproic Acid, and ATRA in Patients with High-Risk AML or MDS: Results of the French VIVEDEP Phase II Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 763-763 ◽  
Author(s):  
Emmanuel Raffoux ◽  
Adrienne de Labarthe ◽  
Audrey Cras ◽  
Christian Recher ◽  
Pascal Turlure ◽  
...  
Keyword(s):  
Valproic Acid ◽  
High Risk ◽  
Response Rate ◽  
De Novo ◽  
Expression Profiles ◽  
Intensive Therapy ◽  
Epigenetic Therapy ◽  
Median Response ◽  
Secondary Aml ◽  
De Novo Aml

Abstract Introduction: Promising results have been reported last year with a combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with AML/MDS treated at MDACC in a Phase I/II study (Soriano et al. Blood 2007). We report here on a similar study conducted in 9 centers between 7/2006 and 8/2007. Methods: Patients with high-risk AML (AML in patients aged 70y+ unsuitable for intensive chemotherapy or early relapsing/refractory AML) or MDS (int-2/high IPSS without possibility of allogeneic SCT) were eligible. Treatment consisted of 6 cycles with AZA 75 mg/m2/d SC (d1-7), VPA 35 to 50 mg/kg/d PO (d1-7), and ATRA 45 mg/m2/d PO (d8-28). Cycle 1 was initiated at the hospital but cycles 2–6 were planned monthly in out-patients. Response was assessed after cycle 1, 3, and 6 (IWG AML criteria). VPA was started at 35 mg/kg/d and then increased at 50 mg/kg/d if well tolerated. Sixty-three patients were enrolled and 51 are evaluable. Results: Patients characteristics were: M/F, 27/24; median age, 73y (50–87); median WBC, 2.3 × 109/L; PS 0-1/2, 45/6 patients; median follow-up, 13 months. Forty-two patients had AML (31 de novo, 9 therapy-related, 2 post-MDS/MPD) and 9 had MDS. Only 6 patients had received prior intensive therapy. Cytogenetics was available in 46 patients with high-risk features in 26 of them (complex, -7). Twenty-nine patients stopped the treatment after 1–5 cycles: 13 due to disease progression, 11 due to toxic events (mostly infection), and 5 due to physician decision despite stable disease. VPA was associated with notable CNS toxicity at 50 mg/kg, but not at the 35 mg/kg dose level. ATRA-related symptoms (headaches, mucosal dryness) were noted. In the 22 patients who received the 6 cycles, re-hospitalization rate was 27, 41, 23, 18, 20, and 14% after cycle 1 to 6, respectively. Among these patients, 11 reached CR (6 after cycle 3) and 5 reached PR (4 after cycle 3). The CR/PR rate was thus 31%, reaching 35% in the 46 patients who did not interrupt the treatment in the absence of progression or toxic event. Table 1 gives CR/PR rate according to various patient subsets. In patients with de novo AML, CR/PR rate was 45%. Advanced age and high-risk cytogenetics did not influence the response rate. In multivariate analysis, cytogenetics but not age remained, however, a poor risk factor for OS (PS, WBC, and MDS/secondary AML being other significant factors). Ten of the 16 responders relapsed after a median response duration of 10.6 months. Median OS was 12 months (not reached in the responders). Results of sequential DNA methylation and gene expression profiles monitoring (#17 patients) will be presented. Conclusion: This study confirms that epigenetic therapy with AZA, VPA, and ATRA yields a 35% response rate in patients with high-risk AML/MDS. Although randomized studies are needed (AZA ± HDAC inhibitors), this combined approach appears to be a good option to treat older patients with low WBC and favorable PS, whatever their cytogenetics. Maintenance options should be investigated in responding patients. Table 1 CR/PR No CR/PR P values Age < 75y 7 (27%) 19 Age ≥ 75y 9 (45%) 11 0.23 Standard-risk cytogenetics 8 (44%) 10 High-risk cytogenetics 7 (29%) 17 0.35 De novo AML 13 (45%) 16 MDS/secondary AML 3 (18%) 14 0.11 PS 0-1 16 (40%) 24 PS 2 0 (0%) 6 0.08 WBC < 5.109/L 15 (43%) 20 WBC ≥ 5.109/L 1 (9%) 10 0.07

TET2 and ASXL1 Mutations in Leukemic Transformation of Chronic Myeloproliferative Neoplasms.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2894-2894 ◽  
Author(s):  
Omar Abdel-Wahab ◽  
Taghi Manshouri ◽  
Jay Patel ◽  
Kelly Harris ◽  
Jin Juan Yao ◽  
...  
Keyword(s):  
De Novo ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Leukemic Transformation ◽  
Exact Test ◽  
Chronic Myeloproliferative Neoplasms ◽  
Secondary Acute Myeloid Leukemia ◽  
Paired Samples ◽  
Mutational Status ◽  
De Novo Aml

Abstract Abstract 2894 Poster Board II-870 Recent studies have identified TET2 and ASXL1 mutations in myeloid malignancies, suggesting that acquisition of these mutant alleles might precede the acquisition of JAK2 in some myeloproliferative neoplasm (MPN) patients. Moreover, the observation that JAK2 mutations are observed in minority of patients with leukemic transformation of JAK2-mutant MPNs suggests the possibility that JAK2 mutations are dispensable for leukemic transformation. However the role of TET2 and ASXL1 mutations in leukemic transformation has not been evaluated. We therefore investigated the mutational status of JAK2, TET2, and ASXL1 in 63 patients with leukemic transformation from a pre-existing MPN, including 49 unpaired secondary acute myeloid leukemia (sAML) samples and 14 patients for whom paired MPN and sAML samples were available. Mutations of TET2 and ASXL1 were found at a higher frequency in sAML samples transformed from MPNs than reported for sporadic MPNs (9/46 (19.6%) and 7/46 (15.2%), respectively). This was also higher than the mutational frequency of TET2 and ASXL1 in de novo AML (6.4% (3/47) and 4.3% (2/47), respectively) but similar to that of AML transformed from MDS (12.8% (5/39) and 15.4% (6/39)). All possible genetic combinations of JAK2, TET2, and ASXL1 status were observed in sAML patients. Analysis of paired samples reveal that TET2 mutations are far more likely to occur at leukemic transformation of MPN than at MPN diagnosis (p=0.013, Fisher's exact test) whereas ASXL1 mutations were equally likely to occur at MPN or sAML. Although mutations in JAK2 and in TET2 may not be retained at leukemic transformation from MPN, mutations in ASXL1 at MPN diagnosis were consistently retained at leukemic transformation. In addition, individual cases were observed where TET2 and/or ASXL1 mutations were found before acquisition of JAK2 mutations or clinical evidence of MPN, as well as cases where TET2 and ASXL1 mutations were acquired during leukemic transformation of a JAK2V617F-positive clone. These data suggest the mutational order of events in MPN and sAML pathogenesis might vary in different patients, and that TET2 and ASXL1 mutations might contribute in different patients to the development of MPN and/or to leukemic transformation. In addition, the identification of transformed AML cases with no evidence of pre-existing JAK2, TET2, and ASXL1 mutations indicates the existence of other, not yet identified, mutations necessary for leukemic transformation of MPNs. Disclosures: Levine: Novartis: Research Funding; TargeGen: Consultancy. Verstovsek:Incyte: ; Exelixis: ; Cephalon: ; SBIO: ; AstraZeneca: .

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