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

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

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

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

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

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

EZH2 Mutations Are Associated with Low Blast Percentage in Bone Marrow and −7/Del(7q) Karyotype in De Novo Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2544-2544
Author(s):  
Xiuli Wang ◽  
Haiping Dai ◽  
Qian WANG ◽  
Qinrong Wang ◽  
Yang Xu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Myelogenous Leukemia ◽  
Prognostic Impact ◽  
Coding Region ◽  
Acute Myeloid

Abstract Abstract 2544 Somatic mutation of the EZH2 gene is seen in myelodisplastic syndrome, myelofibrosis, and chronic myelomonocytic leukemia patients. The prevalence and prognostic impact of somatic mutations of EZH2 in patients with acute myelogenous leukemia (AML) remains unknown. In this study, we sought to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo AML by PCR amplification of the entire coding region followed by direct bidirectional DNA sequencing. EZH2 mutations were identified in 13/714 (1.8%) of AML patients and occurred almost exclusively in males (11/13, P=0.033). In univariate analysis, the presence of EZH2 mutations was significantly associated with lower blast percentage (21–30%) in bone marrow (P=0.0001) and −7/del(7q) (P=0.025). There was no difference in the incidence of mutations in 13 genes, including ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. Complete remission, event-free survival or overall survival was similar between AML patients with and without EZH2 mutation (p>0.05). These results demonstrated EZH2 mutation as a recurrent genetic abnormality associated with lower blast percentage in BM and −7/del(7q) in de novo acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1492-1492
Author(s):  
Guadalupe Oñate ◽  
Ana Garrido ◽  
Jordi Esteve ◽  
Rosa Coll ◽  
Montserrat Arnan Sangerman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Mutational Status ◽  
De Novo Aml ◽  
Acute Myeloid

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

scholarly journals Prognostic Implication of Therapy-Related Acute Myeloid Leukemia after Comparative Analysis with De Novo acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4884-4884
Author(s):  
Jae-Ho Yoon ◽  
Byung-Sik Cho ◽  
Hee-Je Kim ◽  
Seung-Ah Yahng ◽  
Seung-Hwan Shin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Survival Outcome ◽  
Poor Survival ◽  
Poor Survival Outcome ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background: Therapy-related acute myeloid leukemia (t-AML) is regarded as a complication after cytotoxic chemotherapy and/or radiation therapy, and also considered to have a poor survival outcome compared to de novo AML. We still have a question whether t-AML itself indicates a poor prognosis or whether the inferior outcome results from the association with such an adverse characteristics including cytogenetic risk or age or underlying malignancies. Methods: In this single center retrospective study, 1825 patients (median 46 years old [range, 17-92]) with variable karyotypes were enrolled from 2002 to 2013. Fifty-four (3.0%) patients had previous malignancies or autoimmune diseases, and all of them were treated with radiation or toxic chemotherapy before diagnosis of t-AML with a median duration of 36.3 months (range, 2.9-280.5). We analyzed clinical outcomes compared to 1771 de novo AML patients who were not related with any toxic therapies before. Results: Among 54 t-AML patients, 42 (77.8%) was in remission of prior malignant disease and 8 were in stable disease and 4 were in relapsed disease. In t-AML subgroup, median age was older (50 vs. 46 years old, p =0.119), leukocyte and bone marrow blast counts were significantly lower than de novo AML subgroup. There were more female patients in t-AML subgroup (70.3% vs. 45.4%, p=0.003). Among 38 female t-AML patients, 13 (34.2%) patients had breast cancer, 10 patients had hematological malignancies (i.e. APL in 5, lymphoma in 3, multiple myeloma in 2), and 8 (21.1%) had gynecological malignancies (i.e. ovarian and cervical cancer etc.). One or more chromosomal abnormalities (82.6% vs. 68.3%, p=0.015) and more adverse-risk karyotypes (41.2% vs. 20.0%, p<.001) were in t-AML subgroup. Especially, t-AML had more 5 or 7 chromosomal abnormalities (7.8% vs. 2.0%, p=.004) and complex karyotypes (27.5% vs. 7.6%, p<.001) which also included abnormal 5 or 7 chromosomes. Smaller number of t-AML patients received induction chemotherapy (74.1% vs. 87.6%, p=0.006) and early death rate was higher in t-AML group (22.2% vs. 13.7%, p=.083). After median follow-up of 70 months (range: 5.6-165.0), t-AML showed inferior 5-year overall survival (OS) compared to de novo AML (23.8% vs. 39.0%, p <.001). The result was more significant in intermediate to poor-risk group (9.2% vs. 30.0%, p<.001), but it was similar in favorable-risk group (75.0% VS. 62.8%, p=.532). In treated cohort, however, remission rate (70.0% vs. 79.3%, p =.149) and relapse rate (28.8% vs. 35.9%, p =.544) was not different, and multivariate analysis showed t-AML did not affect OS (HR=1.25, p=.185), while age >50 years old (HR=1.48, p<.001), hematopoietic cell transplantation (HCT, HR=0.37, p<.001), favorable-risk karyotype (HR=0.48, p<.001), and post-induction remission status (HR=0.26, p<.001) did. Five-year OS of t-AML patients treated with HCT (n=16) was 50.0%, and for intermediate to poor-risk subgroup treated with HCT, 5-year OS was 33.3%. Conclusion: In this study, t-AML was related with a larger proportion of adverse-risk karyotype, and many patients could not start induction chemotherapy due to old age, and remained prior malignant disease, which might result in poor survival outcome. On the other hand, response to induction chemotherapy of t-AML was similar with de novo AML consistent with a recent report (Kayser et al. Blood 2011). Therefore, if previous malignancy is in remission or in stable disease, aggressive treatment strategy using HCT may overcome poor survival outcome of t-AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Pegylated Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory and/or Elder Acute Myeloid Leukemia: The Preliminary Result of Phase II Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 984-984
Author(s):  
Hui-Jen Tsai ◽  
Ming-Chung Wang ◽  
Sheng-Fung Lin ◽  
Ya-Ping Chen ◽  
Hui-Hwa Hsiao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Phase Ii Trial ◽  
Arginine Deiminase ◽  
Arginine Deprivation ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background: Deprivation of circulating L-asparagine by L-asparaginase, which can lead to the inhibition of RNA and DNA synthesis and subsequent apoptosis of blastic cell, has been implemented as part of multidrug chemotherapy for acute lymphoblastic leukemia since decades ago. Arginine, a semi-essential amino acid in human, is involved in diverse aspects of tumor metabolism and plays critical role for the growth of human cancers. Deficiency of argininosuccinate synthase (ASS), the rate-limiting enzyme for endogenous arginine production in urea cycle, has been found in various cancer tissues. In preclinical studies, pegylated arginine deiminase (ADI-PEG20), which can rapidly convert arginine into citrulline and serve as an arginine depriving agent, was shown to exert in vitro and in vivo anti-proliferative effect on ASS-deficient cancers, such as hepatocellular carcinoma, melanoma, small cell lung cancer, lymphoma and acute myeloid leukemia (AML). The efficacy of ADI-PEG20 is currently under evaluation for various solid tumors in clinical trial setting, including a global phase III trial for hepatocellular carcinoma. Absence of ASS expression has been noted in 87% (46/53) of bone marrow biopsy samples of patients with AML.1 In xenograft model, ADI-PEG20 could reduce the leukemic burden in mice transplanted with primary AML cells.2Herein, we reported the preliminary result of a phase II trial evaluating the therapeutic efficacy of ADI-PEG20 in relapsed/refractory and/or elderly AML patients. Patients and Methods: Patients ≥ 18 years with ASS deficient (by western blotting of bone marrow leukemia cells and/or immunohistochemical staining of bone marrow biopsy), relapsed/refractory or poor-risk AML were eligible. The poor-risk AML includes treatment-related AML, antecedent hematologic disease, unfavorable cytogenetics and de novo AML ≥ 70 years of age. Patients received ADI-PEG20 at 320IU/m2IM weekly (4 weeks as one cycle). Bone marrow aspiration was performed at the time of enrollment, and after the first and second cycle of treatment to evaluate the response. Treatment was continued for each patient until the occurrence of disease progression, development of unacceptable toxicity, death, or withdrawal of consent for any reason. If patients achieved complete remission (CR) or CR with incomplete blood count recovery, the treatment was finished after another 4 cycles of ADI-PEG20. Results: Between October 2013 and May 2014, 9 patients were enrolled, with a male/female ratio of 5/4 and a median age of 62 years (ranged 27 to 79 years old). They were all de novo AML except for 1 with blast-transformed chronic myelomonocytic leukemia. All patients received at least one prior treatment regimen, except for two treatment-naïve elderly patients. After a mean 1.5 cycles of ADI-PEG20 treatment, 2 of 8 evaluable patients achieved CR after 3 and 1 cycles of ADI-PEG20, respectively, while 6 patients had disease progression after an average of 1 cycle of treatment. One patient was not evaluable for response due to withdrawal of consent after the first 2 doses of treatment. Two patients, who died within 2 weeks after the first dose of ADI-PEG20, were considered to have progressive disease. Of the 2 CR patients, 1 was 79 years old with chemo-naïve acute megakaryocytic leukemia (M7) and the other was 69 years old with low-dose Ara-C refractory M2. The most common treatment-related severe adverse events (AE) included grade 4 tumor lysis syndrome, grade 4 infection and treatment-related grade 4 neutropenia occurring in one patient each. The episode of grade 4 neutropenia occurred in the ADI-PEG20 responsive M7 patient. Minor AE included grade 1 hyperuricemia and skin rash in 2 and 1 patients, respectively. Conclusions: ADI-PEG20 is an effective treatment for some patients with ASS-deficient AML with minimal toxicities. Further investigation with genetic and epigenetic profiling to identify patients who will benefit from arginine deprivation therapy is warranted. References. Szlosarek P, et al. Pegylated arginine deiminase (ADI-PEG 20) as a potential novel therapy for argininosuccinate synthetase-deficient acute myeloid leukemia. (AACR Abstract # 467, 2012). 2. Miraki-Moud F, et al. Arginine deprivation with pegylated arginine deiminase induces death of acute myeloid leukaemia cells in vivo. Blood 2012 122:1458. Disclosures Tsai: TWD Pharmaceuticals, Inc: Honoraria.

The Prognostic Role of Smac/DIABLO Protein Expression in Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2626-2626
Author(s):  
Agnieszka Pluta ◽  
Agata Wrzesien-Kus ◽  
Barbara Cebula ◽  
Anna Wolska ◽  
Anna Szmigielska-Kaplon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Protein Expression ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
De Novo ◽  
Intracellular Expression ◽  
De Novo Aml ◽  
Acute Myeloid ◽  
Active Caspase

Abstract Abstract 2626 Poster Board II-602 Background: Smac/DIABLO (second mitochondrial derived activator of caspase/direct IAP binding protein with low pI), an antagonist of inhibitor of apoptosis proteins (IAP) family, was shown to trigger both external and internal apoptosis pathways in acute leukemia cell lines. The role, pathway of action and prognostic significance of Smac/DIABLO protein is not clearly determined in acute myeloid leukemia (AML) patients. Aims: The main objective of this study was to verify whether expression of Smac/DIABLO protein has a prognostic impact on response to induction chemotherapy and overall survival (OS) of adult AML patients. Additionally, we aimed to analyse the apoptotic pathway potentially activated by Smac/DIABLO in AML patients. Material and Methods: Intracellular expression of Smac/DIABLO protein was examined in leukemic blasts isolated from bone marrow or peripheral blood of 89 de novo AML patients with median age 54 (range 23-82). Simultaneously, intracellular expression of active caspase-3 was investigated in 30 de novo AML patients with median age 57 (range 23–79). All measurements were done using multi-colour flow cytometry. In parallel, isotype controls were performed for all measurements. The percentage of Smac/DIABLO- and caspase-3-positive cells was assessed. According to median protein expression the patients were divided into “low-expressers” and “high”-expressers groups. Results: The median of intracellular expression of Smac/DIABLO protein was 65,8% (ranged 0–99,8%) and the median of cleaved caspase-3 was 4,95% (ranged 0,5–40,8) of leukemic blasts. Sixty four out of 89 AML patients received standard induction chemotherapy with daunorubicine and cytarabine (Ara-C) (“3+7”), 24/89 were treated with low dose Ara-C and 2/89 received best supportive care. Forty two (47%) of all patients achieved complete remission (CR). It was found that lower CR rate was associated with poor karyotype and low expression of Smac/DIABLO protein (p<0.01, p<0.01, respectively). The median time of the follow up reached 6 months (range 0.1–68.9). It has been shown that the high expression of Smac/DIABLO (above the median value) and percent of leukemic blast in bone marrow less than 50% were associated with significantly better OS in both univariate (p<0.001, p<0.001, respectively; Figure1) and multivariate (p=0.03, p=0.01, respectively) analyses. However, disease free survival was not influenced by baseline expression of Smac/DIABLO protein in AML cells. Additionally, it has been observed that patients with good and intermediate karyotype according to SWOG classification showed significantly higher expression of Smac/DIABLO protein, compare to poor risk group (median 74,7% vs 37,7% respectively; p< 0.01). Expression of Smac/DIABLO as well as caspase-3 did not correlate with tumour burden-associated risk factors as: number of white blood cells (WBC), percentage of leukemic blasts in bone marrow and serum LDH levels. Furthermore, analyses did not show any correlation between expression of Smac/DIABLO protein and cleaved caspase-3. Conclusions: These data demonstrate that high Smac/DIABLO protein expression is associated with higher sensitivity to standard chemotherapy, favorable karyotype and longer OS in AML patients. The lack of the correlation between expression of Smac/DIABLO and active caspase-3 may be due to low number of patients with examined expression of caspase-3 or activation different way of cell death by Smac/DIABLO. Further investigations evaluating the relationship between Smac/DIABLO as well as the other pro- and anti-apoptotic proteins should be undertaken to better demonstrate its pathways of action as well as prognostic and potentially therapeutic value in AML. Disclosures: No relevant conflicts of interest to declare.

Characteristics and Outcome Of Acute Myeloid Leukemia Following Breast Cancer: Analysis Of 408 Cases and Controls

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1408-1408
Author(s):  
Marine Gilabert ◽  
Jean-Baptiste Micol ◽  
Austin G Kulasekararaj ◽  
Stephane de Botton ◽  
Claude Chahine ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Biological Data ◽  
Matched Pair ◽  
Npm1 Mutation ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background With the improvement of cancer therapy, long term survivors are more exposed to the risk of secondary myeloid neoplasm including myelodysplasia and acute leukemias. The WHO 2008 classification individualize the therapy related acute myeloid leukemia (AML) as a specific entity and highlight the role of chemotherapy/radiotherapy in the pathogenesis of the disease. There is a demonstrated link between specific therapeutic agents, recurrent genetic lesions (such as t(15;17), CBF AML, monosomy 7, …), and outcome. However, most of the published series include multiple types of primary cancer and treatments. This heterogeneity may represent a problem as only limited data are available in patients with specific cancer subtypes, such as the most frequent one, breast cancer. This may be important at a public health level but also to homogenize age and types of prior treatment. Moreover, the complexity of t-AML could not be resumed to the association between treatment and karyotype, as some patients developed AML without chemotherapy, suggesting a potential predisposition to AML. In the present report, we focused on AML arising after breast cancer (BC) and describe the characteristics and outcome of this population. Patients and Methods This is a retrospective multicenter study. Patients were included if they had the diagnosis of breast cancer preceding diagnosis of acute myeloid leukemia whatever may be the interval between the 2 cancers and whatever treatment was administered for BC. All patients with AML were treated with induction chemotherapy. Clinical and biological data for both cancers were collected. Patient’s characteristics and results were compared with age, cytogenetic risk, and optionally sex matched (if possible) de novo AML with a 2/1 ratio. Results 408 patients were analyzed, including 136 AML associated with BC and 272 de novo AML. The median age at diagnosis of BC was 50 years. 47% of patients had invasive ductal carcinoma. Treatment of BC included chemotherapy in 81% of cases, radiotherapy in 91% of cases, and surgery in 99% of cases. The median time between BC and AML was 2.8 years. Median WBC was 3.4G/l and median platelets count was 49G/l. For AML-BC, Cytogenetics were abnormal in 82% of cases including 12% Complex Karyotype, 12% t(15;17), 17% CBF, and 20% MLL translocations. The recent introduction of taxanes in the treatment of BC did not seem to change the frequencies of these aberrations. With the exception of sex ratio, there was no significant difference of baseline characteristics as compared to control group. Regarding induction chemotherapy, CR rate was 81% and 8-week mortality 11.6%. In the control cohort, CR rate was 83% (p=NS) and 8 week mortality 7% (p=NS). Allogeneic transplantation was performed in 21% and 17% of patients respectively. In cytogenetic adjusted survival analysis, median overall survival and relapse free survival were similar between AML-BC and de novo AML for favorable risk (OS and RFS not reached for both groups; p=0.06 and p=0.3 respectively), and unfavorable risk (OS 12m vs. 13m p=NS, RFS 8m vs. 9m p=NS) groups. Interestingly, there was a difference for intermediate cytogenetics group, with median OS (21 months vs. 38 months p=0.01) and median RFS (14 vs. 25 months p=0.04). Difference was also confirmed for cumulative incidence of relapse (1 year probability 41% vs. 22%, p=0.04). Frequency of FLT3, NPM1, and CEBPA mutations were only available in a subset of patients. Only 1/12 pts in the intermediate AML-BC group was FLT3 mutated and 1/12 pt had isolated NPM1 mutation. In the de novo cohort, 11/28 pts had FLT3 mutations and 8/21 pts had isolated NPM1 mutation. Conclusion Our data showed that in AML arising after BC, the prior BC do not appear to impact the outcome in favorable and unfavorable cytogenetic risk groups. However, this is different for intermediate risk cytogenetics, our data suggesting a poorer outcome of AML-BC and potentially a different mutational profile. Regarding AML susceptibility, a matched pair analysis comparing the AML-BC and BC without AML will also be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

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

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

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

The Prognostic Impact of the Revised IPSS Cytogenetic Scoring System for Patients with MDS Allows a Risk-Stratification for Patients with MDS-Derived Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1715-1715
Author(s):  
Friedrich Stölzel ◽  
Michael Kramer ◽  
Brigitte Mohr ◽  
Martin Wermke ◽  
Martin Bornhäuser ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Scoring System ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Poor Risk ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 1715 Besides cytopenias and the medullary blast count, cytogenetic risk groups (good vs. intermediate vs. poor) according to IPSS are of main prognostic relevance for overall survival (OS) in patients with myelodysplastic syndrome (MDS). Recently, the revised IPSS (rIPSS) was introduced involving 5 (very good vs. good vs. intermediate vs. poor vs. very poor) instead of 3 cytogenetic risk groups, which better predict disease progression to MDS-derived acute myeloid leukemia (mdsAML) and OS of MDS patients receiving supportive care only. We analyzed the impact of the rIPSS-based cytogenetic scoring systems on the outcome of patients with AML undergoing intensive chemotherapy within the AML96, AML2003, and AML60+ trials of the Study Alliance Leukemia (SAL). This was done in an intention to compare its general prognostic influence as well as between patients with mdsAML and those with a de novo disease (dnAML). A total of 258 patients (median age 63 years, range 24 – 82) with mdsAML were identified and 258 patients with dnAML were matched with regards to age, gender, clinical trial, induction and consolidation therapy, respectively. Distributions of the cytogenetics in both groups according to MRC, IPSS and rIPSS score are shown in Table 1. Expectedly, the MRC cytogenetic scoring system revealed a stratification into two risk groups for patients with mdsAML with intermediate (3-year OS 27%) and adverse (3-year OS 10%), p=.004, and stratification into three groups for dnAML with favorable (3-year OS 50%), intermediate (3-year OS 32%) and adverse (3-year OS 10%), p=.001. When using the new rIPSS, this allowed a stratification of mdsAML patients with a 3-year OS of 28% for good+intermediate, 12% for poor, and 2% for very poor, p<.001, compared to 28% for good, 22% for intermediate, and 7% for poor risk cytogenetics according to the IPSS, p=.002. Importantly, the rIPSS allowed for a refined subdivision of patients within the poor and very poor group. By applying the rIPSS in dnAML patients we observed a 3-year OS of 34% for good+intermediate, 22% for poor, and 11% for very poor, p<.001, compared to 37% for good, 23% for intermediate, and 19% for poor risk cytogenetics according to the IPSS, p=.028. In conclusion, the rIPSS and IPSS-based classifications are feasible for prognostic risk stratification of patients with both dnAML and mdsAML. Interestingly, the rIPSS-based good and intermediate risk groups do not separate patients in both groups sufficiently. Furthermore, the rIPSS as compared to the current MRC-based cytogenetic scoring system allowed for a more concise distribution of mdsAML patients with the detection of a very poor (rIPSS) risk group with a dismal outcome. Table 1. dnAML, n=258 (%) mdsAML, n=258 (%) Cytogenetics MRC AML Good 16 (7) 0 Intermediate 210 (81) 179 (69) Poor 32 (12) 79 (31) Cytogenetics IPSS Good 158 (61) 121 (47) Intermediate 59 (23) 79 (31) Poor 41 (16) 58 (22) Cytogenetics rIPSS Very good 0 0 Good 167 (65) 131 (51) Intermediate 47 (18) 53 (20) Poor 18 (7) 34 (13) Very poor 26 (10) 40 (15) Disclosures: Platzbecker: Novartis: Consultancy; Celgene: Consultancy; GlaxoSmithKline: Consultancy; Amgen: Consultancy.

Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study

2015 ◽  
Vol 33 (31) ◽  
pp. 3641-3649 ◽  
Author(s):  
Lene Sofie Granfeldt Østgård ◽  
Bruno C. Medeiros ◽  
Henrik Sengeløv ◽  
Mette Nørgaard ◽  
Mette Klarskov Andersen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Intensive Therapy ◽  
Risk Groups ◽  
Population Based ◽  
National Population ◽  
De Novo Aml ◽  
Acute Myeloid

Purpose Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age. Patients and Methods In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs. Results Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61). Conclusion Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.

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