ASXL1 Mutations in AML: Molecular Biomarker for Secondary AML?

Abstract Background: Additional sex combs like transcription factor 1 (ASXL1) is a member of the polycomb group protein. ASXL1 mutation has been implicated in myeloid malignancy transformation. It is hypothesized that mutated ASXL1 leads to the loss of polycomb repressive complex 2 (PRC2) mediated gene repression and subsequent transforming events. Recent studies identify ASXL1 mutation as a poor prognostic marker in patients (pts) with de novo acute myeloid leukemia (AML) who present with intermediate–risk cytogenetic lesions (Patel, NEJM 2012; Schnittger, Leukemia2013). To study the impact of ASXL1 mutations in an unselected AML population, we analyzed clinical and molecular characteristics of patients with untreated AML who express ASXL1 mutation at presentation. Methods: Using next generation sequencing, 254 adult patients with AML seen at the Hospital of the University of Pennsylvania were analyzed for mutations, including ASXL1, using a 33-gene hematologic malignancy panel. Clinical characteristics were obtained from retrospective chart review. Kaplan-Meier estimates were used to calculate overall survival (OS) from time of diagnosis. Living patients were censored at date last seen. Results: ASXL1 mutations were detected in 36/254 (14%) AML pts. There were 29 known pathologic mutations, 1 benign, 1 probable pathologic, and 9 variants of unknown clinical significance (VUS). In 6/36 (16.7%) pts, ASXL1 was the sole mutation identified. Of the 30 pts with additional mutations (Figure 1), 6/30 (20%) pts harbored 2 independent ASXL1 mutations. When the 27 patients with pathologic ASCL mutations were analyzed for co-mutations, TET2 (13/27, 48%) was the most frequent ASXL1 co-mutation. FLT3 (0/27, 0%) and NPM1 (1/27, 3.7%) were notable for their absence. Median age of pts at diagnosis was 69 years (range 23-80). Prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) was noted in 9/36 (25%) and 11/36 (30.6%) pts, respectively. Four pts (11.1%) had received chemotherapy and/or radiation therapy for a prior non-myeloid neoplasm. Karyotype was normal in 18/36 (50%) pts, and 7 additional pts had intermediate cytogenetic lesions. There were 7 pts (19.4%) with unfavorable cytogenetics (complex karyotype (3 pts), 7q- (3 pts), and 5q- (1 pt)). Four pts (11.1%) had a favorable karyotype, with t(8;21) in 3 pts and t(15;17) in 1 pt. At presentation, median white blood cell count (WBC) was 6.4x103/uL (1.0 x -103). In pts whose AML transformed from prior MPN, median WBC was 50 X103/uL (3.3-140). Standard induction chemotherapy with an anthracycline and cytarabine was given to 17/36 (47%) pts. An additional 3/36 (8.3%) pts underwent induction therapy with clofarabine. Complete remission (CR) was documented in 14/20 (70%) evaluable pts. Of the remaining pts, 11 received a hypomethylating agent, and 5 received other therapies. Thirty-day treatment mortality for all 36 pts and for 27 pts with known ASXL1 pathologic mutation was 13.4% and 18.5% respectively. Kaplan-Meier estimate showed a median overall survival of 349 days (median follow up of 107 days (range 15-1570)). For the 27 pts with a pathologic ASXL1 mutation, the OS was 276 days (Figure 2, median follow up of 145 days (range 18-1570)). Conclusion: ASXL1 mutations in de novo AML with intermediate-risk cytogenetics is associated with poor clinical outcome in cooperative group trials. Strikingly we demonstrate in a single institution, retrospective analysis that 66.7% of pts who present with ASXL1 mutations in the setting of previously untreated AML had documented MDS, MPN and/or prior chemotherapy/radiation. Further studies are necessary to evaluate if ASXL1 mutation has independent prognostic significance in AML or if it is primarily a marker for secondary leukemia. Figure 1: ASXL1 and co-mutations Figure 1:. ASXL1 and co-mutations Figure 2: Overall survival for AML patients with ASXL1 pathologic mutation Figure 2:. Overall survival for AML patients with ASXL1 pathologic mutation Disclosures No relevant conflicts of interest to declare.

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Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia

Blood ◽

10.1182/blood-2011-06-357764 ◽

2011 ◽

Vol 118 (15) ◽

pp. 4188-4198 ◽

Cited By ~ 40

Author(s):

Sebastian Schwind ◽

Guido Marcucci ◽

Jessica Kohlschmidt ◽

Michael D. Radmacher ◽

Krzysztof Mrózek ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Older Patients ◽

Myeloid Leukemia ◽

Hox Genes ◽

De Novo ◽

Prognostic Significance ◽

The Impact ◽

Favorable Group ◽

Acute Myeloid

AbstractLow MN1 expression bestows favorable prognosis in younger adults with cytogenetically normal acute myeloid leukemia (CN-AML), but its prognostic significance in older patients is unknown. We analyzed pretherapy MN1 expression in 140 older (≥ 60 years) de novo CN-AML patients treated on cytarabine/daunorubicin-based protocols. Low MN1 expressers had higher complete remission (CR) rates (P = .001), and longer overall survival (P = .03) and event-free survival (EFS; P = .004). In multivariable models, low MN1 expression was associated with better CR rates and EFS. The impact of MN1 expression on overall survival and EFS was predominantly in patients 70 years of age or older, with low MN1 expressers with mutated NPM1 having the best outcome. The impact of MN1 expression was also observed in the Intermediate-I, but not the Favorable group of the European LeukemiaNet classification, where low MN1 expressers had CR rates and EFS similar to those of Favorable group patients. MN1 expresser-status-associated gene- and microRNA-expression signatures revealed underexpression of drug resistance and adverse outcome predictors, and overexpression of HOX genes and HOX-gene–embedded microRNAs in low MN1 expressers. We conclude that low MN1 expression confers better prognosis in older CN-AML patients and may refine the European LeukemiaNet classification. Biologic features associated with MN1 expression may help identify new treatment targets.

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Incidence and characterization of venous thromboembolic events (VTE) in patients with pancreatic cancer: Effect of timing of VTE on survival.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4037 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4037-4037

Author(s):

Maithili A Shethia ◽

Aparna Hegde ◽

Xiao Zhou ◽

Michael J. Overman ◽

Saroj Vadhan-Raj

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Survival Analysis ◽

Kaplan Meier ◽

Hazard Ratios ◽

Venous Thromboembolic Events ◽

Venous Thromboembolic ◽

One Year ◽

The Impact

4037 Background: Patients (pts) with pancreatic cancer are at high risk for VTE, and the occurrence of VTE can affect pts’ prognosis. The purpose of this study was to evaluate the incidence of VTE and the impact of timing of VTE (early vs. late) on survival. Methods: Medical record of 260 pts with pancreatic cancer, newly referred to UT MDACC during one year period from 1/1/2006 to 12/31/2006, were reviewed for the incidence of VTE during a 2-year follow-up period from the date of diagnosis. All VTE episodes were confirmed by radiologic studies. Survival analysis was conducted using Kaplan-Meier analysis and Cox proportional hazard models. Results: Of the 260 pts, 47 pts (18%) had 51 episodes of VTE during the 2-year follow-up. The median age of the pts with VTE was 61 years (range: 28-86) and 53% were males. Of the 47 pts with VTE, 27 (57%) had PE, 19 (40%) had DVT and 1 had concurrent PE/DVT. Three pts had recurrent VTE during the study period. Median follow-up time for OS was 192 days (range: 1-1652 days). Kaplan-Meier Survival analysis showed that those who developed VTE earlier (within 30 or 90 days) had shorter median overall survival (OS) compared with those who had VTE beyond these time points. The hazard ratios, 95% CI, and median OS at 1 year are summarized in the table below. Conclusions: The incidence of VTE is high in pts with pancreatic cancer. The timing of VTE had a significant impact on OS; pts who had an early development of VTE had a shorter overall survival. [Table: see text]

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Impact of Early Switching to Nilotinib As Second Line TKI in Patients with Chronic Myeloid Leukemia Who Were Intolerant to, Suboptimal to and Failed Imatinib: The Thai Multi-Centered Study

Blood ◽

10.1182/blood-2018-99-117787 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4267-4267

Author(s):

Pongtep Viboonjuntra ◽

Arnuparp Lekhakula ◽

Kanchana Chansung ◽

Chittima Sirijerachai ◽

Pimjai Niparuck ◽

...

Keyword(s):

Overall Survival ◽

Adverse Events ◽

Real Life ◽

Progression Free Survival ◽

Second Line ◽

Free Survival ◽

Kaplan Meier ◽

Grade 3 ◽

The Impact

Abstract Introduction : To date, the ELN recommendation and NCCN guidelines are the principle mile stones to follow up the treatment response and to make the decision of TKIs switching. However, in real life practice, many factors influence changing the real switching date from the date had an indication. This study aims to analyze the impact of early switching to second line TKI, nilotinib, in real life practice, for the CML patients who failed, had sub-optimal response or were intolerant to imatinib. Methods : This prospective study was conducted through 7 medical centers in Thailand between 1st of September 2009 and 31st of August 2011. Adult CML patients of age ≥ 18 years old, in chronic and accelerated phase, who had failure, suboptimal response or intolerance to imatinib, based on ELN 2009 guideline, were included and were eligible with nilotinib 400 mg twice daily. Prospective data collection for 24 months of each patient was performed. The main objective was to identify the impact of early switching to nilotinib on major molecular response (MMR). The other objectives were to observe the efficacy of nilotinib including overall survival, progression free survival and the safety. The survival results were presented as Kaplan-Meier survival curves. For the comparison of the treatment groups, the Kaplan-Meier estimator with the corresponding log-rank test for equality of survivor functions across treatment group was applied. Results : The final 108 cases were analysed. The median age was 47 (17-79) years with the proportion of male to female of 1.4:1 respectively. The median duration of the prior imatinib treatment was 18 months (2-142 months). The median duration between the date of indication and the date of real switching was 3.1 months (0-62.8 months) with 50% changing less than 3 months, 26.9% between 3 months and 12 months, and 23.1% changing longer than 12 months. The indication of switching included 63.6% failure to imatinib, 29% intolerance to imatinib and 7.4% suboptimal to imatinib. On the nilotinib switching, 70.4% completed 24 months follow-up, and 29.6% discontinued treatment mostly because of unsatisfactory results or adverse events. Evaluation was made every 3 months based on 2009 ELN recommendation. At 3 months, 57%, 20%, and 8% of the patients achieved CHR, CCyR and MMR, respectively. Those who did not achieve CHR at 3 months never achieved MMR, while 86 % of those who achieved CCyR at 3 months achieved MMR. All CML achieving MMR at 3 months had sustained MMR throughout the study period (24 months). Imatinib suboptimal response had better outcome than imatinib failure and imatinib intolerance groups. A preliminary analysis of BCR-ABL mutation was performed on 90 cases, and mutations were found on 21 cases. Two of them were T315I which were excluded from the study. The cases with mutation had poorer response to treatment than those without mutation. There was one case with initial G250E mutation developing T315I mutation after treatment with nilotinib. At 24 months, one case progressed to accelerated phase and 3 cases progressed to blastic transformation. The 2-year overall survival and 2-year progression-free survival and were 98.9% and 96.9% (figure 1 and 2), respectively. The interquatile analysis was done to identify the groups of cumulative MMR according to the duration between the date of indication and the date of real switching to nilotinib. The patients who switched to nilotinib within 12 months after date of indication could have a greater chance to achieved MMR than those who switched treatment later than 12 months (p(log-rank) = 0.002) (figure 3). Skin rash, musculoskeletal pain, and infection were the three most common non-hematologic adverse events, However, most of them were grade 1-2, except for 4 cases with grade 3-4 infections. Grade 3-4 hematologic adverse events included thrombocytopenia (12%), neutropenia (11%), anemia (5%) and leucopenia (4%), and most of them were manageable. Although biochemical abnormalities were commonly found, most of them were mild. Conclusions : Nilotinib, as a second line treatment showed excellent efficacy and tolerability. Indication for nilotinib treatment, initial mutation status and depth of response at 3 months after treatment can predict outcomes of the patients. However, the patients will have a greater chance to achieve MMR if they switched to nilotinib within 12 months after the date of indication for changing. Disclosures No relevant conflicts of interest to declare.

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Impact of Early Immune Reconstitution after Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood-2018-99-119601 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2118-2118

Author(s):

Nieves Dorado ◽

Ana Pérez-Corral ◽

Mi Kwon ◽

Laura Solán ◽

Rebeca Bailén ◽

...

Keyword(s):

Nk Cells ◽

Lymphocyte Count ◽

Immune Reconstitution ◽

Conflicts Of Interest ◽

Conditioning Regimen ◽

Prognostic Significance ◽

Disease Free Survival ◽

Haploidentical Transplantation ◽

The Impact

Abstract Introduction: Immune reconstitution (IR) has a significant impact in HSCT outcome with a role against opportunistic infections and in disease control. In the setting of unmanipulated haploidentical transplantation (Haplo-HSCT), some groups have identified the absolute leukocyte count on day +30 (ALC30) as an independent prognostic factor in terms of overall survival (OS), disease free survival (DFS) and infection related mortality (IM). The aim of this study was to evaluate the impact of early IR on different HSCT outcomes in patients who underwent Haplo-HSCT with postransplant cyclophosphamide (PTCy) at our institution. Patients and methods: Eighty-eight patients received a Haplo-HSCT from 2011 to 2016. Thirty-six percent of the patients received myeloablative conditioning regimen and 64% received reduced intensity regimen. Graft-versus-host disease (GVHD) prophylaxis was based on PTCy, cyclosporine and mycophenolate mofetil. Early IR was assessed through the analysis of different lymphocyte subpopulations at days +30 and +90 after transplantation, including ALC30 (cellular analyzer DXH, Beckman Coulter®); CD3+ lymphocyte count and their different subpopulations (CD4+ and CD8+ lymphocytes, naive and memory T cells) and NK cells count. Lymphocytes subpopulations were determined by multiparametric flow cytometry (FC500 and Navios, Beckman Coulter®). ROC curves were used to determine the optimal cut-off values for each of the studied variables. Results: Eighty-one patients were studied, excluding 7 who died before day +30. Median follow-up was 26 months (10-43). Patient´s characteristics are shown in Table 1. CMV reactivation was documented in 76% (62) of the patients, 4% (3) developed a proven invasive fungal infection, and 31% (25) presented hemorrhagic cystitis. Median OS and DFS were 26 months (10-43) and 24 months (9-39), respectively. IM rate and NRM rate were 10% and 24%, respectively, at the end of follow up. Median lymphocyte populations counts at day +30 are shown in Table2. ALC30 below 100 cells/uL (p= 0.027) and CD4+ naïve lymphocytes below 12 cells/uL (p=0.033) (both corresponding to the 25 percentile) were associated with lower OS compared to patients with higher counts at day +30 (Figure 1). Patients with ALC30 lower than 300 cells/uL (p=0.026) showed significantly higher NRM; CD8+ count lower than 20 cells/uL (p=0.022) also showed higher NRM. NK cells counts at day +30 lower than 14 cells/uL (p=0.014), near to percentile 25, predicted higher IM (62.5% vs 37.5%). We did not identify any lymphocyte subpopulation that could predict DFS. Patients with acute GVHD grades II-IV showed values of ALC30 lower than 200 cells/uL (p=0.051), although non-statistically significant. No relationship was found between lymphocytes subpopulations at day +90 and HaploSCT outcomes. Conclusions: Our study supports the prognostic significance of early IR after unmanipulated haploidentical transplantation with PTCy, as previously described by other groups. ALC30, CD4+ naïve lymphocytes, and CD8+ lymphocyte count at day +30 may be good early predictors for OS and NRM in this setting. On the other hand, low NK cells counts (lower than percentile 25) predicted higher IM. Patients with very low lymphocyte counts should be monitored closely as they are at high risk for infectious complications, NRM and OS. Disclosures No relevant conflicts of interest to declare.

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Time Dependent Platelet Attrition Identifies Biological Subgroup In Intermediate But Not Low-Risk Myelodysplastic Syndrome (MDS) Revised-IPSS (R-IPSS) Exhibiting Distinct Overall Survival

Blood ◽

10.1182/blood.v122.21.5233.5233 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5233-5233

Author(s):

Gustavo A. Rivero ◽

Maria Otazo ◽

Sarvari Venkata Yellapragada ◽

Ang Li ◽

Matthew Zheng ◽

...

Keyword(s):

Overall Survival ◽

Platelet Count ◽

Low Risk ◽

Time Dependent ◽

Biological Behavior ◽

Intermediate Risk ◽

Term Survival ◽

Disease Initiation ◽

The Impact

Abstract Background Low-risk MDS (LR-MDS) is a clinically, genetically and epigenetically diverse disease characterized by progressive cytopenias. Within LR-MDS subsets have been identified as having aggressive biological behavior and shorter overall survival (OS). Fixed single time point covariates contained in R-IPSS prioritizes MDS risk prediction based on novel redefined blast percentage, 5 cytogenetic subgroups and depth of cytopenias at disease initiation, and time-dependent IPSS/WPSS facilitates prediction of survival during disease evolution. Given the role thrombocytopenia and neutropenia in predicting survival at disease initiation, we sought to investigate whether time –dependent platelet count worsening could segregate patient (pts) with inferior outcome in low and intermediate risk MDS. Method From 2000-2012, 30/124(24%) and 32/124 pts (26%) with confirmed diagnosis of intermediate and low-risk R-IPSS MDS, respectively, were identified from the Michael E. Medical Center Cancer Registry. Pts were included for analysis if: (1) ≥ 2 follow up sequential platelet counts values were available; (2) at time of recording counts no clinical or laboratory evidence of sepsis, infection or disseminated intravascular coagulation (DIC) was observed. An initial exploratory percentile level decline in platelet count (30th vs. 20th vs. 10th) strategy aimed at identifying statistically significant correlation between platelet reduction and survival identified 10th percentile as strong predictor of long-term-survival. Median survival was calculated for pts whose platelet count has fallen within ≥ or ≤ 10th percentile from baseline at predetermined time points. Multivariate Cox regression analysis was performed to assess the impact of multiple independent variables on clinical outcomes including blast count, cytogenetic risk, R-IPSS, WHO 2008 category, MDS directed therapy and age. Results 21 pts (median age 72 years, range, 53-82) in intermediate risk and 18 pts (median age 75, range, 53-88) in low-risk matched study criteria. Characteristics of pts with platelet count achieving ≥ or ≤ 10th percentile from baseline are summarized in table 1. In Intermediate R-IPSS group, 7 pts experienced reduction of platelet count falling below 10th percentile (median baseline and 6 months platelet count were 309000 and 160000, respectively, P=0.10). With a median follow- up of 16.1 m for intermediate risk, 3-y estimate OS was 60%. For intermediate risk pts experiencing ≥ or ≤ 10% percentile reduction, median OS at 6m was 303 days (d) vs 786 d, respectively, P=0.02 (Fig.1) No statistically significant differences were detected at 6 m OS survival median in low-risk subsets (Fig.2). Univariate analysis identified only higher proportion of blast at disease initiation with trend toward risk factor for unfavorable outcome (P=0.06).This correlation was not observed by multivariate analysis. Conclusion Our study showed that progressive thrombocytopenia in intermediate-risk MDS could suggest feasibility of group disease heterogeneity. 10% platelet count reduction in intermediate-risk but not low-risk R-IPSS MDS could identify pts with inferior outcome. Larger coalesced studies including intermediate risk MDS pts with steady/progressive platelet attrition could facilitate recognition of variable involved in faster disease progressors and assist in identification of pts suitable for investigational interventions. Disclosures: No relevant conflicts of interest to declare.

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Cytogenetic Evolution in Patients with IPSS Low and Intermediate-1 Risk. Study from the Spanish Group of Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v124.21.4649.4649 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4649-4649

Author(s):

Brayan Marcel Merchán ◽

Margarita Ortega ◽

María José Llamas-Poyato ◽

Montserrat Cortés ◽

Montserrat Arnan ◽

...

Keyword(s):

Overall Survival ◽

Population Distribution ◽

Risk Group ◽

Univariate Analysis ◽

Normal Karyotype ◽

Molecular Diagnostic ◽

Kaplan Meier ◽

Cytogenetic Analyses ◽

The Impact

Abstract Cytogenetic abnormalities (CA) are the most important prognostic factor in MDS patients, nevertheless the incidence of CA at diagnosis is not higher than 50% and even less in lower risk patients. The acquisition of CA (ACA) has recently been reported as a frequent and poor prognostic event in patients with normal karyotype at diagnosis (Jabbour et al 2013). The aim of our study was to analyze in a large cohort of patients the incidence, characteristics, and prognosis of the ACA in patients with low and intermediate-1 IPSS risk at diagnosis. We retrospectively reviewed 254 adult patients from the Spanish Registry of MDS with IPSS low or intermediate-1 risk diagnosed between 1995 and 2013. In total 121 patients had at least two consecutive cytogenetic analyses during the follow up. The main end points were overall survival (OS) and AML evolution (TFS). Cytogenetic analyses were conducted on unstimulated bone marrow cells after culture (24–72 hours). The ISCN 2005 criteria were used for identification of abnormal clones. ACA was defined by structural change or gain in at least 2 metaphases and loss in 3 metaphases as proposed in previous reports. Differences among variables were evaluated by non-parametric tests. OS and TFS were analyzed by Kaplan-Meier curve. The median follow-up was 25 months (0-155). The median age at diagnosis was 71 years (26-87) and 28% of the patients were female. The IPSS risk group was low in 43% and intermediate-1 in 57% of the population. Distribution as the IPSS-R was very low 20%, low 42%, Intermediate-1 30%, poor 6%, and there were no cases with very poor risk. At diagnosis, 34.7% of patients had abnormal karyotype. ACA was detected in 16 patients (13,2%) after a median of 30 months (range, 5-165). The most common ACA identified were trisomy 8 as sole abnormality followed by chromosome 7 abnormalities in in 25% and 12.5% of patients, respectively. Of the 42 patients with CA at diagnosis, 12% developed new ACA while among 79 patients with normal karyotype at diagnosis, 14% developed ACA (p=0,7). The presence of ACA changed the IPSS-R risk group in 14 out 16 patients. Compared with patients without ACA, the presence of ACA was significantly associated with a lower hemoglobin level (Table 1). In univariate analysis, ACA was not apparently associated with a higher incidence of AML evolution as there were 2 out of 16 patients (12,5%) with ACA that developed AML while between the 105 patients without ACA, 11 developed AML (11,5%) (P=NS). At last follow-up, 34 (28%) patients died and the median OS for the entire cohort was 67 months (IC 95% 34-99). In Kaplan-Meier curve, the presence of ACA was associated with lower overall survival (median 67 months (95% CI: 34-99) than patients without ACA (median 140 months (95% CI 36,9.243) (P =0.01). In summary, the present analysis shows that, the ACA occurs in around 13% of cases, which is a lower frequency than previously reported in other series, and it may have impact in overall survival. Future studies should address the impact molecular alterations and somatic point mutations; molecular diagnostic may allow identified patients with higher risk to transformation. Table 1. Hematologic parameters at the time for the cytogenetic control. ACA (n= 16) NO ACA (n=105) P Hb g/dL 9,1 (5.8-11.9) 10,3 (5.6-17.7) 0.04 WBC × 109/L 3,15 (0.7-24.1) 4,1 (0.9-32) 0.85 Pla × 109/L 71 (16-127) 93,5 (4-574) 0.38 Blast × 109/L 6 (1-15) 2.4 (0-19) 0.09 Disclosures Valcárcel: Celgene: Honoraria, Speakers Bureau.

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Glutathione S-Transferases (GSTT1 and GSTM1) Genes Polymorphisms and Response and Prognosis of Chinese Patients with De Novo Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v110.11.4293.4293 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4293-4293

Author(s):

Lin Yang ◽

Zhijian Xiao ◽

Jianxiang Wang ◽

Yushu Hao

Keyword(s):

Overall Survival ◽

Induction Therapy ◽

De Novo ◽

Prognostic Significance ◽

Disease Free Survival ◽

Chinese Patients ◽

Lower Probability ◽

Acute Monocytic Leukemia ◽

Monocytic Leukemia

Abstract The GSTT1 and GSTM1 genes are polymorphic in humans, with the phenotypic absence of enzyme activity caused by a homozygous inherited deletion of the gene. A number of prior studies have reported on GST genotype and outcome of therapy for AML. In this study, we analyzed the prognostic significance of gene polymorphism of GSTT1, GSTM1 in Chinese patients with de novo AML other than M3. A total of 254 cases were entered. There are 157 males and 97 females, ranging in age from 15 to 75 years (median: 32 years). Patients were diagnosed following WHO criteria, 81 were AML with t(8;21) AML1/ETO, 54 were AML with inv(16) or t(16;16) CBF-β/MYH11, 4 were AML with 11q23 abnormalities (MLL), 1 was minimally differentiated, 3 were AML without maturation, 44 were AML with maturation, 17 were acute myelomonocytic leukemia, 42 were acute monocytic leukemia, and 8 were acute erythroid leukemia. All the patients were treated with HAD regimen (Homoharringtonine, HHT, 2.5mg/m2 intravenously on days 1 to7; Ara-c, 150 mg/m2/d continuous infusion on days 1 to 7, and DNR,45 mg/m2 intravenously on days1 to 3.) as induction therapy. Postremission therapy consisted of HA regimen (HHT and Ara-c)(course 1 and 4), DA regimen (DNR and Ara-c)(courses 2 and 5), and MA regimen (MTZ and Ara-c) or HAM (Ara-c 1g/m2,q12h, intravenously on days 1 to 4, combined with MTZ 8mg/m2, intravenously on days 5 to 7(courses 3 and 6). The multiplex PCR method was used to simultaneously amplify and analyze GSTM1,GSTT1, and β-globin from patients. 21 patients died before marrow recovery or adequate assessment of response. 165 (68.5%) achieved a CR after the first course of chemotherapy and 194 (80.5%) achieved a CR after the second course of chemotherapy. Median follow-up was 36 months (11 to 111 months). 104 patients were last known to be alive after entering the study, the other 138 patients are now decease. Twelve patients lost to follow-up are censored at the date they were last known to be alive. Median OS and median RFS was 22 months and 19 months, respectively. OS rates at 3 years and 5 years were 38.9%±3.5% and 25.2%±6.5%, respectively. RFS rates at 3 years and 5 years were 32.8%±3.9% and 22.4%±5.2%, respectively. The rate of early death after the initiation of chemotherapy was similar between the GSTT1+/ GSTM1+ group and GSTT1− / GSTM1- group. The CR rates was higher in GSTM1+ group(71.9%) than GSTM1− group(60.8%) (OR=1.882; P =0.034) after the initiation of chemotherapy, and The CR rates was higher in GSTT1+ group(82.6%) than GSTT1− group (70.75)(OR=2.204; P =0.024) after the second course of chemotherapy. Overall survival and disease-free survival of patients who achieved complete remission (CR) in GSTT1 and GSTM1 double present group(50.1%±9.6% and 43.1%±9.6% at 5 years, respectively) was better than GSTT1- and/or GSTM1- group(27.2%±4.6% and 15.7%±6.3% at 5 years, respectively) (p=0.03 and p=0.022, respectively). For patients with AML with inv(16)(p13q22) or t(16;16)(p13;q22)(CBFβ/MYH11), Overall survival was better in GSTT1+ group than GSTT1− group(69.7%±10.5% v 27.5%±13.0% at 5 years)(p=0.013). Our data showed AML patients with deletions of GSTM1 or GSTT1 or both had a lower probability to achieve CR on induction therapy as compared to patients with intact GST genes and a shorter survival.

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AML1/RUNX1 Mutations in 470 Adult Patients with De Novo Acute Myeloid Leukemia: Prognostic Implication and Interaction with Other Gene Alterations.

Blood ◽

10.1182/blood.v114.22.1564.1564 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1564-1564 ◽

Cited By ~ 1

Author(s):

Hsin An Hou ◽

Jih-Luh Tang ◽

Liang-In Lin ◽

Chien-Yuan Chen ◽

Wen-Chien Chou ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Conflicts Of Interest ◽

Adult Patients ◽

Poor Prognostic Factor ◽

The Impact ◽

Runx1 Mutation ◽

Acute Myeloid

Abstract Abstract 1564 Poster Board I-587 Somatic mutation of AML1/RUNX1 (RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 individuals (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male gender, older age, lower LDH value, FAB M0/M1 subtypes and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19 and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD (P=0.0061), but negatively associated with CEBPA (P=0.0057) and NPM1 mutations (P=0.0001). AML patients with RUNX1 mutations had a significantly lower complete remission rate, shorter disease-free and overall survival than those without the mutation (P=0.0087, P<0.0001 and P=0.012, respectively). Subgroup analysis of patients with normal karyotype showed that RUNX1-mutation was also closely associated with worse OS and DFS (P= 0.001 and P=0.001, respectively). Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival (hazard ratio 1.874, 95% CI, 1.101- 3.189, P=0.021). Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidences that RUNX1 mutations are associated with distinct biological and clinical characteristics and poor prognosis in patients with de novo AML. Disclosures No relevant conflicts of interest to declare.

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Salvage Autologous Hematpoeitic Stem Cell Transplants (AHSCT2) for Myeloma: Single Center Experience.

Blood ◽

10.1182/blood.v116.21.4591.4591 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4591-4591

Author(s):

Bishoy Faltas ◽

Jane L. Liesveld ◽

Michael Becker ◽

Jainulabdeen J. Ifthikharuddin ◽

Gordon L. Phillips

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Stem Cell ◽

Median Overall Survival ◽

Progressive Disease ◽

Conflicts Of Interest ◽

High Dose ◽

The Impact

Abstract Abstract 4591 Although the role of AHSCT1 is well established in multiple myeloma therapy, the role of the salvage (not “tandem”) AHSCT2 is less clear. However, most pts. undergo initial stem cell harvests with plans for eventual AHSCT2. To clarify the indications, the prognostic factors and the outcomes of AHSCT2 in relapsed myeloma, we analyzed our experience in 19 pts. (pts.) who underwent salvage AHSCT2 between the 1994–2008. Mean age at AHSCT1/2 was 54.58 (SD 7.96)/57.03 (SD 8.10) respectively; 15 (79.0%) were males. At the time of diagnosis, 7 (36.8%) pts. had ISS stage I, 6 (31.6%) stage II, 3(15.8%) stage III and in 3 (15.8%) the ISS stage could not be determined. Isotypes: IgG 11 (57.9%), IgA 4 (21.1%), 1 (5.3%) pt. had IgM and 3 (15.8%) had light chain myeloma. Cytogenetics were normal in 6 (31.6%), abnormal in 5 (26.3%) and unavailable for 8 (42.1%) pts. The most common therapy received prior to AHSCT1 was Vincristine/Adriamycin/Dexamethasone in 11 (57.9%) pts.; 7 pts. were exposed to novel agents. One pt. achieved complete response (CR), 15 (79.0%) pts. achieved partial response (PR) and 3 (15.8%) pts. had stable or progressive disease after receiving the initial treatment. All pts. proceeded to receive high dose therapy with Melphalan (MEL), 2 pts received fTBI in addition to MEL. Mean MEL dose was 190.00 mg/m2 (SD 23.01); 15 pts. received 200 mg/m2. All pts. received >2×10e6/kg of CD34+ cells in the first and second transplants. At D+100 after AHSCT1, responses were: 4 (21.1%) CR, 1 (5.3%) VGPR, 8 (42.1%) PR and 6 (31.6 %) with lesser responses. Therapy to prolong response or for salvage after AHSCT1 was given in all pts before AHSCT2, including Thalidomide in 6 (31.6%), Bortezomib in 4 (21.1%) and Lenalidomide in 2 (10.5) pts. Median time to progression after AHSCT1 was 318 days [95 % CI 110– 573]. Median interval between AHSCT1 and AHSCT2 was 896.74 days (SD: 698.34 days). At the time of AHSCT2, 4 (21.1%) were in PR, 15 (79.0%) had progressive disease. For AHSCT2, all pts. Received MEL, one pt. received MEL + Cytoxan and one pt. received MEL + Bortezomib. The median MEL dose/m2 was 175.56 (52.04).All pts. survived AHSCT2 to D+100, responses were as follows: 3 (15.8%) VGPR, 9 (47.4%) in PR; 7 (36.9) pts. had lesser responses. After AHSCT2, nine (47.4%) pts. had grade III toxicity and only one pt. had grade IV toxicity (avascular necrosis). Maintenance therapy after AHSCT2 included Bortezomib in 7 (36.8%) pts., Lenalidomide in 5 (26.3%) pts. and Thalidomide in 4 (21.1%) pts. After AHSCT2, the median overall survival (OS) was 658 days [95 % CI 326–1330] and progression free survival (PFS) after AHSCT2 was 237 days [95 % CI 121– 397] (Figure 1). OS probability at 6, 12, 24 months after AHSCT2 was 81.3, 75.0, 39.3 % respectively. For all pts., the median OS time (i.e. time from diagnosis to death or last follow-up) was 2187 days [95% CI 1413– 4126]. At the end of the follow up period, a total of 14 pts. had died. Causes of death were progression in 12 (63.2%) and sepsis in 2 pts. (10.5%). The number of previous lines of chemotherapy, interval between transplants, disease status at the time of AHSCT1/2, type of myeloma and MEL dose were not predictive of OS and PFS. In the multivariate analysis, only age by decade at AHSCT2 and male gender were independent predictors of OS after AHSCT2 (HR 4.037, P= 0.01), (HR 3.74, P=0.07) respectively. Similarly, in the multivariate analysis for PFS after AHSCT2, age at AHSCT2 was an unfavorable independent predictor (HR 3.48, P=0.009) whereas relapse free response more than 18 months after AHSCT1 was an independent favorable predictor (HR 0.198, P=0.007).Our results are consistent with the few studies examining the impact of salvage transplants for myeloma which report a median overall survival ranging from 20.7 to 38.1 months from the time of AHSCT2.We conclude that salvage AHSCT2 can positively impact PFS and OS but efforts to improve outcomes are mandatory.FigureSEQ Figure ≂,* ARABIC 1Figure. SEQ Figure ≂,* ARABIC 1 X-axis represents time from AHSCT2 in days. Y axis represents survival distribution. Blue line = OS, Red = PFS. Disclosures: No relevant conflicts of interest to declare.

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Prognostic Significance of Karyotype in Octogenarian Patients (Pts) with Acute Myeloid Leukemia (AML)–An International Study

Blood ◽

10.1182/blood.v118.21.2521.2521 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2521-2521

Author(s):

Meir Wetzler ◽

Jessica Kohlschmidt ◽

Krzysztof Mrózek ◽

Herve Dombret ◽

Hartmut Döhner ◽

...

Keyword(s):

Overall Survival ◽

Molecular Markers ◽

De Novo ◽

Prognostic Significance ◽

Disease Free Survival ◽

Molecular Testing ◽

Npm1 Mutation ◽

Significant Difference ◽

The Impact ◽

Disease Free

Abstract Abstract 2521 We asked whether a modified European LeukemiaNet (ELN) karyotype-based classification without molecular markers has prognostic significance in AML pts aged 80 to 89 years (y). We queried the German-Austrian AML Study Group (AMLSG; 7 pts), the Acute Leukemia French Association Group (ALFA; 17 pts), the German AML Cooperative Group (AMLCG; 35 pts) and the Cancer and Leukemia Group B (CALGB; 81 pts) for pts treated with intensive induction (7+3 or similar) on whom conventional karyotype analyses were completed and reviewed centrally. Of the 140 pts, including 82 (59%) men and 58 (41%) women, with a median age of 82 y (range, 80–89), 117 pts had de novo and 23 had secondary or therapy-related AML (s-AML/t-AML). There were 2 pts in the modified Favorable Group [t(8;21) and inv(16)], 67 pts in the modified Intermediate I Group [cytogenetically normal (CN-AML) pts], 44 pts in the ELN Intermediate II Group [t(9;11) and abnormalities (abn) classified as neither favorable nor adverse] and 27 pts in the ELN Adverse Group [inv(3) or t(3;3), t(6;9), t(v;11)(v;q23), -5 or del(5q), -7, abn(17p) and complex karyotype (≥3 abn)]. In order to assess the impact of karyotype on outcome, we eliminated early deaths. The complete remission (CR) rate for all 92 (66%) pts surviving beyond 30 days (d) was 46% and their median disease-free survival (DFS) was 6 months (mo); 35% were disease-free at 1 y and 12% at 3 y. Similarly, the median overall survival (OS) for pts surviving beyond 30 d was 6 mo, with 35% alive at 1 y and 11% at 3 y. There was no difference in DFS or OS based on AML type (de novo v s-AML/t-AML; Table 1). As shown in Table 2, pts in the modified Intermediate I Group had better OS than pts in the Adverse Group (P=0.03). Among CN-AML pts with molecular testing completed, 9/21 (43%) were NPM1-mutated (mut), 8/25 (32%) had FLT3-internal tandem duplication (ITD) and 1/12 (8%) was CEBPA-mut. Interestingly, FLT3-ITD did not have prognostic significance in the CN-AML cohort alive beyond 30 d (data not shown), but NPM1 mutation resulted in trends for higher CR rates (67% v 25%, P=.09) and longer OS (91 v 10 mo, P=0.07) in the CN-AML cohort alive beyond 30 d (Figure). Of note, there was no difference between the 2 larger cohorts (AMLCG and CALGB) in regards to pt characteristics or outcome in de novo pts; there were insufficient numbers of pts with s-AML/t-AML to compare the 2 cohorts. We conclude that there is a difference in accrual to clinical trials of octogenarian AML pts among the different cooperative groups. Further, CN-AML pts had better OS in octogenarian AML, and NPM1 mutation may be of prognostic significance among the CN-AML pts.Table 1:Treatment outcome by disease presentation for 92 pts alive beyond 30 dEnd Pointde novo AML (n = 78)s-AML/t-AML (n = 14)All pts (n = 92)P de novo v s-AML/t-AMLCR, no. (%)35 (45)7 (50)42 (46).78DFS.76 Median, y0.50.60.5.27 % Disease-free at 1 y36 (26–51)29 (4–61)35 (21–49) % Disease-free at 3 y14 (5–29)012 (4–24)OS Median, y0.50.60.5 % Alive at 1 y35 (24–46)36 (13–59)35 (25–45) % Alive at 3 y14 (6–23)011 (5–19)Table 2:Disease outcome by ELN karyotype-based classification without molecular markers for 92 pts alive beyond 30 dEnd PointIntermediate I (n = 43)Intermediate II (n = 29)Adverse (n = 20)PCR, no. (%)23 (53)13 (45)6 (30).23DFS.17* Median, y0.60.40.3 % Disease-free at 1 y36 (17–56)40 (16–63)17 (1–52) % Disease-free at 3 y23 (8–41)00OS.03† Median, y0.90.40.3 % Alive at 1 y43 (28–57)33 (16–50)21 (7–41) % Alive at 3 y17 (8–31)5 (0–20)5 (0–22)*Only Intermediate I compared to Intermediate II (too few pts in the Adverse Group)†This is overall P-value. Adjusted P-values were not significant for the differences between Intermediate-I and Intermediate-II Groups (P=.26) and between Intermediate-II and Adverse Groups (P=.87). There was a statistically significant difference between Intermediate-I and Adverse Groups (P=.03)Figure.Overall survival by NPM1 status in CN-AML ptsFigure. Overall survival by NPM1 status in CN-AML pts Disclosures: Krug: MedA Pharma: Honoraria; Novartis: Honoraria; Alexion: Honoraria; Boehringer Ingelheim: Research Funding; Sunesis: Honoraria.

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