Clinical Impact of TERT A1062T Mutations in Younger Patients with Acute Myeloblastic Leukemia

Abstract Abstract 1381 Background: Acute myeloid leukemia (AML) is a heterogenous disease. In addition to cytogenetic aberrations, somatic mutations in several genes (e.g. NPM1, FLT3, DNMT3A, WT1) have been identified which are involved in the pathogenesis of AML and affect the prognosis of these patients. Recently, it was shown that also germline mutations in the gene encoding the reverse transcriptase component of the human telomerase complex (TERT) are associated with AML and occur with a frequency of approximately 3–5% (Calado et al. Proc Natl Acad Sci USA 2009; 106:1187–92). These mutations lead to a reduced enzymatic activity of the telomerase complex. The most frequent of these mutations is an G>A conversion in codon 1062 in exon 15 of TERT which leads to an alanine>threonine substitution (A1062T). Telomerase complex mutations had previously been described in patients with bone marrow failure or other organ dysfunction such as liver cirrhosis or pulmonary fibrosis. The impact of such mutations on the clinical course and prognosis of AML patients, however, is unknown. Aims: We wanted to analyze the clinical and prognostic impact of the most common TERT mutation A1062T in younger AML patients treated within two prospective multicenter trials. Methods: The mutational hotspot in exon 15 of the TERT gene was analyzed by direct sequencing in 420 patients (age 16–60 years) with AML treated with intensive double induction and consolidation therapy within the AMLSG 295 and 0199 trials (NCT00209833). The patients were also analyzed for mutations/aberrations in the genes NPM1, FLT3, WT1 and DNMT3A. Median follow up was 79 months. Results: Fifteen of the 420 analyzed patients (3.3%) carried a TERT A1062T mutation. In the four patients of whom remission bone marrow or blood samples were available, the mutation was also detected in complete remission suggesting a germline origin of the mutation. Patients with TERT mutations had a trend (p = 0.06) towards less favorable (13% vs. 42%) and more intermediate-2/adverse karyotypes/genotypes (60% vs. 31%) according to the ELN classification. Other clinical and molecular parameters did not differ from wildtype patients. In univariate analysis, patients with TERT mutations had a significantly inferior overall survival (OS) compared to wildtype patients (HR 2.31; 95% CI 1.29 – 4.13, p = 0.005; 3year OS 20% vs. 46%). Also, in multivariate analysis TERT mutations were an independent negative factor for OS when analyzed together with age, leukocytes/peripheral blasts, platelets, extramedullary disease, de novo vs. secondary AML, ELN risk classification, WT1 SNP rs16754 and mutations in NPM1, FLT3 and DNMT3A. In addition to a high relapse rate, TERT mutated patients also showed a high rate of treatment related mortality: 5/15 (33%) of the mutated patients died during induction therapy or in CR as compared to 62/405 (15%) of the wildtype patients (p = 0.07). Of note, three of four TERT mutated patients who received an allogeneic stem cell transplantation in first CR died in CR. Therefore, we also analyzed treatment related toxicity during induction therapy. In the TERT mutated patients, 14/15 (93%) suffered from non-hematological/non-infectious grade 3 or 4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wildtype patients (p = 0.006). In multivariate analysis, TERT mutations were an independent risk factor predicting for adverse events during induction (OR 9.6; 95% CI 1.24 – 75.23, p = 0.031) when analyzed together with age, ELN risk classification, other gene mutations, blood counts, extramedullary disease, ECOG performance status, response to first induction therapy, and de novo vs. secondary AML. Conclusions: TERT A1062T mutations are an independent negative prognostic factor in younger patients with AML. These mutations seem to predispose AML patients to treatment-related toxicity and mortality. Disclosures: No relevant conflicts of interest to declare.

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Prognostic Impact of the Levels of Expression of Cell Surface Proteins Commonly Expressed by Blasts and Hematopoietic Precursor Cells in De Novo AML Patients: A Report From the Spanish Cetlam Study Group

Blood ◽

10.1182/blood.v120.21.1452.1452 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1452-1452

Author(s):

Maria Concepcion Garcia-Dabrio ◽

Montserrat Hoyos ◽

Ana Garrido ◽

Salut Brunet ◽

Rafael F Duarte ◽

...

Keyword(s):

Bone Marrow ◽

Multivariate Analysis ◽

Cell Surface ◽

De Novo ◽

Genetic Alterations ◽

Cell Phenotype ◽

Prognostic Impact ◽

Sm Proteins ◽

Increased Risk ◽

De Novo Aml

Abstract Abstract 1452 Introduction: Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders characterized by the presence of acquired genetic alterations in hematopoietic progenitor and stem cells. The prognostic impact of immunophenotypic markers has long been controversial. Despite this, only a very limited number of studies have investigated the prognostic impact of the levels of cell surface membrane (Sm) proteins commonly expressed on AML blasts. In this study we analyzed the prognostic impact of the levels of expression of several markers associated with AML blasts and normal hematopoietic precursors, as asessed by Multiparameter Flow Cytometry (MFC) in de novo AML patients (pts). Methods: Overall, 122 adult de novo AML pts diagnosed between 12/2003 and 08/2011 were studied, after excluding acute promyelocytic leukemia. All cases were diagnosed and classified according to the WHO criteria and they were immunophenotyped using an extensive 4-color panel of monoclonal antibodies by MFC, as previously described. Patients were treated according to the multicenter CETLAM AML-03 trial. Blast cells were gated after excluding all other cell populations, as well-delineated clusters of SSC low/int/CD45dimevents (“blast gate”) using the merge function of the Infinicyt software (Cytognos SL, Salamanca, Spain). For each case, the reactivity for the following markers was evaluated in terms of mean fluorescence intensity (MFI; arbitrary units) in bone marrow samples: CD123, CD117, CD34 and CD7. Normal residual bone marrow lymphocytes were used as reference for internal quality control purposes. Cytogenetic and molecular risk stratifications were based on the European LeukemiaNet (ELN) recommendations and the molecular lesions were investigated using well established protocols. Overall survival (OS), disease-free survival (DFS) and relapse rate (RR) were measured by the Kaplan–Meier method and curves were compared with the log-rank test. Multivariate analysis was performed using the Cox regression model. P-values ≤0.05 were considered to be statistically significant. Results: Median AML patient age was of 54 years (range: 20–70 y) with a M/F ratio of 63/59. Twelve pts (10%) had good cytogenetic/molecular risk, 83 (68%) intermediate, 17 (14%) high risk and 10 (8%) pts were unknown. Fifteen cases (12%) had NPM1mut, 33 (27%) showed FLT3-ITDmut, 5 (4%) pts carried CEBPAmut, 41 (33.6%) pts with no mutations and 28 (23%) pts were unknown. The median follow-up of pts alive was 19 months (range 0–97 months) and the 5-year OS of all pts was 42±5%. Univariate analysis of prognostic factors showed an association between higher CD45 (MFI >232; p=.01), CD117 (MFI>259; p=.008), CD34 (MFI >242; p=.007) and CD7 (MFI> 19; p=.03) expression and both a shorter OS and DFS. In addition, high CD123 expression (MFI >248; p=.04) was associated with a shorter DFS. In multivariate analysis only a high CD45 (p=.03) and a high CD34 (p=.03) expression were identified as independent predictors for a shorter OS. In turn, higher levels of CD123 (p=.03) and of CD34 (p=.02) were independent predictors for DFS and relapse, even when age, gender and WBC were taken in account. Conclusion: In this study, we show that higher levels of expression of immunophenotypic markers associate with immature myeloid precursors (CD45, CD117, CD34 and CD7) as assessed by MFC, have a significantly adverse prognostic impact in AML, both as regards OS and DFS. Accordingly, higher levels of CD45 and CD34 were independent predictors for both a shorter OS whereas, greater CD123 and CD34 values were associated with an increased risk of relapse and a shorter DFS, supporting the adverse prognostic impact of a more immature blast cell phenotype in de novo AML. Disclosures: No relevant conflicts of interest to declare.

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The Impact of Therapy-Related and Secondary AML in Relation to Karyotype and Molecular Markers: A Study of the AMLSG.

Blood ◽

10.1182/blood.v110.11.881.881 ◽

2007 ◽

Vol 110 (11) ◽

pp. 881-881

Author(s):

Sabine Kayser ◽

Konstanze Döhner ◽

Jürgen Krauter ◽

Daniela Späth ◽

Silja Groner ◽

...

Keyword(s):

Molecular Markers ◽

Regression Model ◽

Induction Therapy ◽

De Novo ◽

Survival Rates ◽

Prognostic Impact ◽

Complex Karyotype ◽

Secondary Aml ◽

De Novo Aml ◽

The Impact

Abstract Background: Patients (pts) with therapy-related AML (t-AML) or secondary AML (s-AML) after a myelodysplastic syndrome are considered to have an inferior outcome compared to de novo AML. Whether this is due to an adverse cytogenetic risk profile or by the fact of t/s-AML per se has not yet been determined. Aims: To evaluate the frequency and prognostic impact of cytogenetic abnormalities and molecular markers in t/s-AML in comparison to de novo AML in a large cohort of adult AML pts. Methods: Patients were entered on seven AMLSG treatment trials. The key inclusion criteria for this analysis were availability of cytogenetics and molecular markers. Genotypic groups were defined as follows: Acute promyelocytic leukemia (APL) [t(15;17)], core binding factor (CBF)-AML [t(8;21), inv(16)/t(16;16)], cytogenetically normal (CN)-AML, t(11q23), adverse cytogenetics outside a complex karyotype (AC) [abn(3q), −5/5q-, -7/7q-, abn(12p), abn(17p)], complex karyotype (CK, ≥3 aberrations) and all remaining aberrations (various). Results: Between 1993 and 2006, 3083 adults (age range: 16–85 years) were registered and in 2604 karyotype and information about the type of AML were available; 196 (7.5%) had t-AML, 374 (14.5%) s-AML, and 2034 (78%) de novo AML. The median age was lower in de novo AML (50 years) compared to t-AML (58 years) and s-AML (57 years) (p<0.0001). Median WBC and LDH levels were higher (p<.0001) in de novo AML compared to t/s-AML. The distribution of genotypic groups according to type of AML revealed highest incidences of t-AML in the groups t(11q23) (23%), CK (17%), AC (14%), and of s-AML in the groups CK (23%), various (22%), and AC (21%), whereas incidences of de novo AML were highest in APL (92%), CBF (87%) and CN (82%). Response to induction therapy was higher in de novo AML (CR 72%) compared to t-AML (59%) and s-AML (52%). The logistic regression model for response to induction therapy revealed s-AML (OR, 0.53; p<0.001), age diff: of 10 years (OR, 0.71; p<0.0001), log10(WBC) (OR, 0.74; p<0.0001), and cytogenetics with CBF (OR, 2.77; p<0.0001), CK (OR, 0.22; p<0.0001), AC (OR, 0.29; p<0.0001), and various (OR, 0.69; p=0.01) in comparison to CN-AML as significant variables. Cox regression model on overall survival (OS) revealed s-AML (HR, 1.29; p=0.0004), age diff: of 10 years (HR, 1.40; p<0.0001), log10(WBC) (HR, 1.33; p<0.0001), and cytogenetics with CBF (HR, 0.53; p<0.0001), CK (HR, 3.20; p<0.0001), t(11q23) (HR, 1.76; p<0.0001) and AC (HR 1.97, p<0.0001) in comparison to CN-AML as significant variables. To better define the role of t/s-AML, subgroup analyses were performed according to genotypic groups. Of note, survival rates of de novo AML, t- and s-AML were almost identical in the genetically defined groups APL (p=0.93), CBF-AML (p=0.34), CK (p=0.33), AC (p=0.38) and t(11q23) (p=0.23), whereas differences were found in the groups various (p=0.0005) and CN-AML (p=0.02). Analyses of CN-AML including the FLT3-ITD and NPM1 status revealed significant differences in the subgroups defined by FLT3-ITDpos (p=0.05) and double negative (p=0.05), whereas in the group with a favorable genotype NPM1mut/FLT3-ITDneg survival rates were nearly identical (p=0.65). Conclusions: The prognostic impact of t/s-AML is restricted to patients with CN-AML exhibiting an unfavourable genotype and patients within the heterogeneous group exhibiting various aberrations.

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AML: Negative Prognostic Impact of Early Blast Persistence Can be Overcome By Subsequent Remission Induction

Blood ◽

10.1182/blood-2019-127174 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1324-1324

Author(s):

Jana Ihlow ◽

Sophia Gross ◽

Leonie Busack ◽

Alma Herneth ◽

Igor-Wolfgang Blau ◽

...

Keyword(s):

Decision Making ◽

Bone Marrow ◽

Induction Therapy ◽

Remission Induction ◽

Prognostic Impact ◽

First Line ◽

Allogeneic Hsct ◽

Entire Cohort ◽

Remission Status

Introduction: In acute myeloid leukemia [AML] intensive treatment usually includes an interim bone marrow assessment in the context of the first induction chemotherapy cycle. Early blast clearance has been shown to predict for achievement of a complete remission [CR], which makes the interim bone marrow result a widely used additive for further therapy decision making. However, there is an ongoing debate on the prognostic role of early blast clearance (day 14 - 21) and consistent clarification of this issue is still lacking. Here, we provide monocentric data from a large intensively treated AML cohort addressing the prognostic impact of early remission status on long-term survival. Methods: Data of 1008 intensively treated AML patients who were diagnosed between 2000 and 2017 and aged between 18 and 86 years were retrieved from our local AML database. Evaluation of bone marrow aspirates and / or biopsies was conducted by cytologic, flow cytometric and histopathological methods. Remission status was determined in accordance with the European-Leukemia Net [ELN] criteria of 2017. Patients were grouped according to their remission status after induction 1 (day 14 - 21) and prior to further therapy (chemotherapy and / or allogeneic hematopoietic stem cell transplantation [HSCT]). Baseline characteristics of the two groups such as age, cytogenetic / molecular risk according to ELN 2010, performance score according to Eastern Cooperative Oncology Group [ECOG] and Charlson Comorbidity Index [CCI] were compared using chi-square test and Kruskal-Wallis H test followed by post-hoc testing. Overall- and relapse-free-survival [OS, RFS] were analyzed using Kaplan-Meier- and Cox regression models. Results: In 57 % (n = 572) of the entire cohort, complete / incomplete remission [CR / CRi] or at least morphologic leukemia free state [MLFS] were observed after the first cycle of induction therapy. Partial response [PR] was found in 19 % (n = 196) and persistent disease [PD] in 24 % (n = 240) of all patients. The three different groups (CR / CRi / MLFS vs. PR vs. PD) did not significantly differ in age, ECOG-score or CCI, but - as expected - substantially with regard to ELN risk classification. Of the entire cohort, 62 % (n = 626) received a double induction, 61 % (n = 617) consolidation chemotherapy and 47 % (n = 477) allogeneic HSCT as a part of first-line therapy. Prior to HSCT, 85 % (n = 406) of the patients were in first CR / CRi / MLFS. Amongst these 406 patients, 51 % (n = 243) had only achieved PR / PD in early bone marrow puncture on day 14 - 21 of induction therapy. 71 % of these patients (n = 173) were converted into CR / CRi / MLFS prior to HSCT by additional chemotherapy. Within the non-transplanted group, 58 of 130 patients (44 % with initial PR / PD) achieved CR / CRi / MLFS after an additional cycle of induction chemotherapy. Early blast persistence and refractory disease were generally associated with inferior OS as compared with blast clearance (p < 0.001). Interestingly, early PR lost its negative prognostic impact on survival after conversion into CR / CRi / MLFS by additional therapy prior to post-induction therapy. This could particularly be observed in patients undergoing HSCT, but also in non-transplanted patients receiving a second cycle of induction therapy. In patients without allogeneic HSCT, early PR with blast clearance beyond induction 1 resulted in impaired RFS (p = 0.045) but not OS, possibly due to the influence of subsequent salvage therapy. Early PD remained prognostically unfavorable for OS and RFS in both transplanted and non-transplanted patients even after subsequent conversion into CR / CRi / MLFS (p = 0.002 and p = 0.021). Conclusion: Our results show that the achievement of CR / CRi / MLFS prior to post-remission therapy overrides the negative impact of an early partial response on OS, irrespective of the favorable prognostic impact that early blast clearance generally has on OS. With regard to OS, our results suggest a predominant role of the final remission quality after induction therapy. However, the adverse impact of achieving no response at interim bone marrow assessment can apparently not be attenuated by a later remission induction. On the assumption that the final depth of remission after induction therapy is predictive for OS, MRD-guided decision making prior to consolidation treatment might further improve first-line AML therapy, particularly in the intermediate ELN risk group. Disclosures Bullinger: Abbvie: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Menarini: Honoraria; Janssen: Honoraria; Hexal: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Bayer: Other: Financing of scientific research; Seattle Genetics: Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria.

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Acute Myeloid Leukemia in the Elderly: Assessment of Multidrug Resistance (MDR1) and Cytogenetics Distinguishes Biologic Subgroups With Remarkably Distinct Responses to Standard Chemotherapy. A Southwest Oncology Group Study

Blood ◽

10.1182/blood.v89.9.3323 ◽

1997 ◽

Vol 89 (9) ◽

pp. 3323-3329 ◽

Cited By ~ 379

Author(s):

Catherine P. Leith ◽

Kenneth J. Kopecky ◽

John Godwin ◽

Thomas McConnell ◽

Marilyn L. Slovak ◽

...

Keyword(s):

Myeloid Leukemia ◽

De Novo ◽

The Elderly ◽

Drug Efflux ◽

Younger Patients ◽

High Frequencies ◽

Secondary Aml ◽

Elderly Aml ◽

Mdr1 Expression ◽

Acute Myeloid

Abstract Compared with younger patients, elderly patients with acute myeloid leukemia (AML) respond poorly to conventional chemotherapy. To determine if this poor response is due to differences in the biologic characteristics of AML in the elderly, we studied 211 patients (161 de novo, 50 secondary AML) over 55 years of age (median, 68 years) registered to a single clinical trial for previously untreated AML (SWOG 9031, Phase III randomized trial of standard dose cytosine arabinoside and daunomycin ± rhG-CSF ). Pretreatment leukemic blasts were karyotyped and were also analyzed for intrinsic drug resistance by quantitating expression of the multidrug resistance glycoprotein MDR1 and functional drug efflux using sensitive flow cytometric techniques. Results were correlated with clinical variables and outcome. These elderly AML patients had a high frequency of unfavorable cytogenetics (32%), MDR1 protein expression (71%), and functional drug efflux (58%); each of these factors occurred at high frequencies in both de novo and secondary AML patients and was associated with a significantly poorer complete remission (CR) rate. In multivariate analysis, secondary AML (P = .0035), unfavorable cytogenetics (P = .0031), and MDR1 (P = .0041) were each significantly and independently associated with lower CR rates. Resistant disease was associated with unfavorable cytogenetics (P = .017) and MDR1 expression (P = .0007). Strikingly, elderly MDR1(−) de novo AML patients with favorable/intermediate cytogenetics had a CR rate of 81%; with increasing MDR1 expression, CR rate decreased in this cytogenetic group. MDR1(+) secondary AML patients with unfavorable cytogenetics had a CR rate of only 12%. Thus, AML in the elderly is associated with an increased frequency of unfavorable cytogenetics and MDR1 expression, both of which independently contribute to poor outcomes. The high frequencies of these features in both de novo and secondary elderly AML patients suggest a common biologic mechanism for these leukemias distinct from that in younger patients. Investigation of biologic parameters at diagnosis in AML in the elderly may help identify patients with a high likelihood of achieving CR with conventional regimens, as well as those who may require alternate regimens designed to overcome therapy resistance.

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Study of Sequential Treatment of Newly Diagnosed De Novo AML Patients with DA and CAG Regimens as Remission Induction Therapy.

Blood ◽

10.1182/blood.v106.11.4630.4630 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4630-4630

Author(s):

Hui ping Sun ◽

Wei Hong Liu ◽

Jun min Li ◽

Qiu sheng Chen ◽

Yu Chen

Keyword(s):

Bone Marrow ◽

Induction Therapy ◽

Peripheral Blood ◽

De Novo ◽

Classification Criteria ◽

Sequential Treatment ◽

Remission Induction ◽

Newly Diagnosed ◽

Fab Classification ◽

De Novo Aml

Abstract Objectives To evaluate the efficacy and safety of sequential treatment of newly diagnosed de novo AML patients with DA and CAG regimens as induction therapy. Methods Those who were newly diagnosed as de novo AML (FAB classification criteria) were enrolled and DA regimen chemotherapy were administered. Bone marrow aspirates were performed and BM smears were examined at 48 hours since the end of chemotherapy. If severe hypocellularities were not achieved, the percentage of blasts in BM was between 20%–60% and peripheral WBC was in the range of (0.5–10) x109/L, the patients would receive CAG regimen therapy since 72 hours. Patients’ general status and the important parameters, such as peripheral blood count, liver function, renal function, thrombosis and hemostasis parameters were monitored throughout the course of the treatment and thereafter. When the clinical symptoms were relieved and peripheral blood counts returned to normal, or it was the end of the second or third week since the end of the CAG regimen, Bone marrow were examined again to evaluate the efficacy of the sequential therapy. Results 14 patients consisted of 9 male and 5 female patients were enrolled. Out of them, 2 were M1, 5 M2, 4 M4 and 3 M5 according to FAB classification criteria. Median of blasts in BM were 38.5%(20%–60%) before CAG regimen. Of the 14 patients, 10 reached CR, 2 PR and 2 NR. CR rate was 71.4% (10/14) and total response rate was 85.7%(12/14). Time to achieve CR was on 15th(14th–29th)day medianly since the end of the treatment. During the CAG therapy courses, the nadir of peripheral blood cell counts and the time when it occurred were as follows: WBC 1.0(0.2–3.5)(x109/L),10(1–23)(d); Hb 57.5(44–69) (g/L), 10(1–27)(d)and PLT 11.5(10–65)(x109/L), 12(3–23)(d), respectively. Neutropenia (WBC<1.0x109/L) and thrombocytopenia (PLT<20.0x109/L) were lasted for 0(0–24) and 11(0–21)days, respectively. Median units of transfusions of platelets and red blood cells required by each patient were 3(0–10)(u) and 4(0–12)(u), respectively. The most commonly observed side effect of the regimen was bone marrow proliferation inhibition. Infections, usually respiratoy tract infections, were the second. However, sepsis was rare, which appeared in 1 out of 14 patients. Conclusions DA and CAG regimens sequential treatment as remission induction chemotherapy in patients with newly diagnose de novo AML was highly effective and well tolerated. It would be beneficial for those who might not be sensitive enough to DA regimen chemotherapy only.

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Absolute Lymphocyte Count Is a Novel Prognostic Indicator in Acute Leukemia: Implications for Risk Stratification and Future Studies.

Blood ◽

10.1182/blood.v108.11.2276.2276 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2276-2276

Author(s):

Guillermo R. De Angulo ◽

Carrie Yuen ◽

Shana Palla ◽

Peter M. Anderson ◽

Patrick A. Zweidler-McKay

Keyword(s):

Bone Marrow ◽

Young Adults ◽

Multivariate Analysis ◽

Risk Stratification ◽

Acute Leukemia ◽

Induction Therapy ◽

Age At Diagnosis ◽

Acute Leukemias ◽

Children And Young Adults ◽

Current Risk

Abstract Background: Despite improving outcomes, 25–50% of children and young adults with acute leukemia still relapse and most salvage rates are discouraging. Additional prognostic factors, particularly those that represent host factors, may further stratify patients and decrease relapse rates. Purpose: To determine if absolute lymphocyte counts (ALC) during induction chemotherapy can improve current risk stratification and predict relapse-free survival (RFS) and overall survival (OS) in children and young adults with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Methods: We analyzed 160 consecutive cases of de novo ALL and AML patients 1–21 years of age, treated at the University of Texas M. D. Anderson Cancer Center from 1995–2005. Age at diagnosis, initial WBC, bone marrow blast % on days 0 and 7, were analyzed with ALC on days 0, 15, 21 and 28 of induction therapy. Results: ALC during induction therapy is a significant independent predictor of RFS and OS in young adults and children with either ALL or AML. Specifically, an ALC <350 cells/mcL on day 15 of induction therapy for ALL significantly predicts poor 6-year OS (52% vs. 87%, p=0.015; HR=4.2, Figure 1A) and RFS (46% vs. 80%, p=0.001; HR=4.8, Figure 1B). Similarly, an ALC of <350 cells/mcL on day 15 of induction therapy for AML predicts poor 6-year OS (35% vs. 86%, p=0.033; HR=4, Figure 1C). ALC-15 remains a significant predictor of OS and RFS after adjusting for age at diagnosis, initial WBC and bone marrow response on day 7 (p=0.013; HR=6.3, and p=0.003; HR=6.3, respectively) in multivariate analysis (Table 1). Importantly, ALC-15 defines a subgroup of half of our AML patients and predicts an excellent 5-year OS of 86% (p=0.033, Figure 1C). Conversely, prolonged lymphopenia predicts that 16% of young AML patients will have a dismal 5-year RFS of 14% (p=0.004, Figure 1D). Finally, ALC-15 <350 cells/mcL is able to predict 70% of relapses in both ALL and AML patients. One possible algorithm could identify half of AML patients with a predicted OS of 86% simply by measuring the ALC-15. Those patients with a low ALC on day 15 would be assessed at day 21 and 28 and those with persistent lymphopenia would be predicted to to have an RFS of 14% and would be stratified to receive intensified and/or experimental therapy. Conclusion: We demonstrate that ALC can identify patients at high and low risk for relapse early in the course of treatment for ALL or AML. Our data indicates that ALC is both independent of and a more powerful predictor than age at diagnosis, initial WBC and bone marrow response on day 7. This routine measurement could enhance current risk-stratification and lead to improved outcomes in young patients with acute leukemias. Figure 1 Figure 1. Table 1 Multivariate Analysis of ALC, Age, WBC, Bone marrow response and Survival

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The Outcome in AML Is Predicted by Cytogenetics, NPM1/FLT3 Mutation, Age and Sex, but Not by Treatment Variables.

Blood ◽

10.1182/blood.v110.11.593.593 ◽

2007 ◽

Vol 110 (11) ◽

pp. 593-593 ◽

Cited By ~ 1

Author(s):

Thomas Buchner ◽

Wolfgang E. Berdel ◽

Utz O. Krug ◽

Torsten Haferlach ◽

Claudia Haferlach ◽

...

Keyword(s):

Predictive Factor ◽

De Novo ◽

Normal Karyotype ◽

Prognostic Impact ◽

Mutation Status ◽

Younger Patients ◽

Female Sex ◽

Flt3 Mutation ◽

Mutation Age ◽

Age And Sex

Abstract In order to test current risk factors in a prospective multicenter setting we evaluated the AMLCG 99 trial. Patients were randomly assigned to induction by TAD-HAM (HAM with araC 3 for age <60y and 1 for age ≥60y g/m2 × 6), or HAM-HAM, and also to TAD consolidation and maintenance or (age <60y) myeloablative chemotherapy and autologous SCT. Patients with histocompatible family donors preferentially underwent allogeneic SCT. Since any randomization was done up-front, informations from completely unselected patients were available. 2547 patients of 16–85 (median 61) y entered the trial. 1858 pts had de-novo and 689 pts secondary AML. The CR rate was 61%, 54% in older (60) and 69% in younger patients. The overall survival (OS) at 4 years was 27%, 15% in older and 41% in younger patients. The relapse risk (RR) was 65%, 80% in older and 50% in younger patients and the relapse-free survival (RFS) was 30%, 14% and 44%, respectively. In the entire patients complete outcome (CR, OS, RR, RFS) was predicted by favorable and unfavorable karyotype. Among patients with any abnormal karyotype complete outcome was predicted by unfavorable karyotype in the older and favorable karyotype in the younger age group. In both age groups with normal karyotype outcome for the complete parameters was predicted by the NPM1+/FLT3- ITD- mutation status. As a new finding in patients of <60 years with normal karyotype female sex turned out being an independent predictive factor for longer OS (HR 1.45;95%CI 1.04–2.03), longer RFS (HR1.64;95%CI 1.10–2.44), and lower RR (HR 0.59;95%CI 0.38–0.92). Female sex was the only predictive factor besides the NPM1/FLT3 mutation status in this group. The OS at 4 years in patients of <60y with normal karyotype is 52% in women and 40% in men (log-rank P=0.047), the RR is 37% and 52% (P=0.016), and the RFS is 55% in women and 42% in men (P=0.025). Furthermore, the favorable NPM1+/FLT3- mutation status was more frequent in women than in men (35% vs 26%; P=0.0075). Remarkably, the NPM1+/FLT3- mutation status was equally predictive in patients of ≥60y as in those of <60y with HR for OS of 2.51 (95% CI 1.75–3.61) and 3.27 (95%CI 2.11–5.05) and HR for RR of 0.33 (95% C 0.21–0.51) and 0.29 (95%CI 0.17–0.49). The difference in the OS at 4 years between patients with NPM1+/FLT3- mutation and those with other NPM1/FLT3 combinations was 42% vs 18% (P=<0.001) in the older, and 69% vs 34% (P<0.001) in the younger patients. The related differences in RR were 58% vs 84% (P<0.001) in the older, and 22% vs 59% (P<0.001) in the younger patients. Among the NPM1/FLT3 mutations the favorable +/− constellation accounted for 27% of older, and 35% of younger patients (P=0.0197). Besides karyotypes and mutations, also age, de-novo AML, blast clearance, LDH and WBC partly predicted outcomes. In contrast no prognostic impact was found by multi-and univariate analyses of treatment alternatives. Conclusion: As from a large multicenter prospective trial the outcome in AML is mainly determined by cytogenetics, NPM1/FLT3 mutation, age and sex, but not by the assigned treatment variables.

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The Interaction of Response and FISH-Based Risk Stratification to Better Define Clinical Outcome in Myeloma

Blood ◽

10.1182/blood.v118.21.1823.1823 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1823-1823

Author(s):

Kevin D Boyd ◽

Fiona M Ross ◽

Mark T Drayson ◽

Roger G Owen ◽

Alex J Szubert ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

High Risk ◽

Prognostic Factor ◽

Induction Therapy ◽

Response Rates ◽

Phase Iii ◽

Prognostic Impact ◽

Cell Transplant ◽

Important Prognostic Factor

Abstract Abstract 1823 Background: The achievement of a complete response (CR) is an important prognostic factor in myeloma. The international staging system (ISS) and tumor genetic lesions detected by FISH also impact survival. It is not known whether response rates are adversely affected by these factors, whether achieving CR overcomes the adverse prognosis associated with these factors, or if achievement of CR is more important in a specific biological subgroup. We have examined the importance of CR in the context of these other prognostic factors in the intensive arm of a phase III randomized trial, MRC Myeloma IX, in which all patients were planned to proceed to autologous stem cell transplant (ASCT) after induction. Patients and Methods: Patients were randomized to a conventional or thalidomide-based induction regimen followed by ASCT, with a second randomization to maintenance thalidomide versus no maintenance. Response was assessed after completion of induction therapy and 100 days post-ASCT. iFISH was performed on diagnostic bone marrow samples and genetic lesions associated with adverse progression free survival (PFS) were defined as t(4;14), t(14;16), t(14;20), +1q and 17p-. Results: To confirm that CR was prognostically important in the data set, patients with a CR at 100 days post-ASCT (N=355) were compared to non-CR (N=344) (comprising VGPR, PR and SD). CR was strongly associated with improved PFS (median 30.8 months vs 38.7 months, P<0.001) but was not associated with improved OS at median follow-up of 3.7 years. Response rates were assessed in the context of other prognostic factors. Interestingly, the presence of high risk FISH lesions was not associated with impaired CR rates following induction therapy (P=0.584) or following ASCT (P=0.314). Patients without adverse genetic lesions had a CR rate of 11.1% post-induction which improved to 48.3% post-ASCT. In comparison, patients with adverse FISH lesions had a 13.3% CR rate, rising to 44.9% post ASCT. Similarly, there was no correlation between ISS stage and response. The absence of adverse FISH lesions (hazard ratio (HR) 2.68 (1.94-3.70) P<0.001) and achievement of CR (HR 1.58 (1.15-2.17) P=0.005) were independently associated with improved PFS in multivariate analysis. The prognostic impact of achieving CR was assessed in various prognostic groups. CR was associated with improved PFS in patients with no adverse FISH lesions (N=179)(median PFS 58.4 vs 37.1 months, P=0.031), and in ISS I (N=182)(median PFS 51.2 vs 33.2 months, P=0.008). In patients with adverse FISH lesions, and in ISS II and III, there was a trend towards improved PFS with CR that was not significant. For patients achieving CR as their maximum response (N=398), in a multivariate analysis including the ISS, the presence of high risk FISH lesions was the most significant factor associated with impaired PFS and OS. Patients with more than 1 adverse FISH lesion were associated with an especially high risk of progression or death (PFS HR 6.63 (3.23-13.53) P<0.001; OS HR 5.35 (1.98-14.45) P=0.001). Conclusion: These data show that attainment of CR is an important prognostic factor associated with improved PFS in patients treated with ASCT, and this benefit was most significant in patients with favorable prognostic factors such as lack of adverse FISH lesions and ISS I. The presence of t(4;14), t(14;16), t(14;20), +1q or 17p- was also strongly associated with PFS, and the impaired outcome associated with these adverse genetic lesions was not overcome by achievement of CR, within the context of the therapies used in this trial. The presence of more than 1 adverse FISH lesion identified a patient group with an especially poor prognosis, despite achieving CR. However, CR rates within these high risk patients were similar to patients without adverse genetic features, showing that they were sensitive to chemotherapy, but progressed quickly after therapy was stopped. The implication of these data is that it may be possible to improve the poor outcome of this genetically-defined high risk group with an alternative treatment strategy aimed at maintaining these responses. Disclosures: Gregory: Celgene: Honoraria. Child:Celgene: Honoraria.

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

Blood ◽

10.1182/blood.v120.21.2544.2544 ◽

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.

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Extramedullary Disease Is Common In Newly Diagnosed AML But Has No Independent Prognostic Significance, Including CNS Involvement: Analysis Of 3,522 AML Patients Treated On Consecutive ECOG Trials 1980-2008

Blood ◽

10.1182/blood.v122.21.63.63 ◽

2013 ◽

Vol 122 (21) ◽

pp. 63-63

Author(s):

Chezi Ganzel ◽

Judith Manola ◽

Dan Douer ◽

Jacob M. Rowe ◽

Hugo F Fernandez ◽

...

Keyword(s):

Clinical Trials ◽

Multivariate Analysis ◽

Proportional Hazards ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Cns Involvement ◽

Proportional Hazards Models ◽

Extramedullary Disease ◽

Nerve System ◽

Univariate Analyses

Abstract Background Extramedullary disease (EMD) of acute myeloid leukemia (AML) was described decades ago but the incidence of this phenomenon and its prognostic impact are not clear. It is also uncertain whether every site of EMD has the same significance. This study explored these questions using a large cohort of AML patients treated on consecutive Eastern Cooperative Oncology Group (ECOG) frontline clinical trials. Methods For AML patients enrolled into ECOG clinical trials, the presence of EMD was captured at baseline on case report forms. From patients with newly diagnosed AML, age 15 and above, who were treated on 11 consecutive different clinical trials, we identified those with or without EMD, defined by physical examination, laboratory findings and imaging, without necessarily a biopsy. We used descriptive statistics to summarize patient and disease characteristics. Univariate analyses of potential prognostic factors were done. The Kaplan-Meier method was used to estimate median overall survival (OS) within each prognostic category and differences were explored using the log-rank test. Cox proportional hazards models were used to examine the effect of one-unit increases in continuous variables on OS and for multivariable analyses. Multivariate models were built using backward selection. Factors (or groups of factors) significant at the 0.10 level in univariate analyses were tested for inclusion in the model, and retained if they were significant at the 0.05 level. Results Of the 3,522 patients enrolled in 11 different AML clinical trials, we excluded 281; for diagnosis of other types of leukemia (n=220), no EMD evaluation at baseline (n=41) or no survival data (n=20). The overall incidence of EMD was 23.8% (770 out of the remaining 3,241 patients). The sites involved were: lymph nodes 367 (11.3%) patients, spleen 234 (7.2%), liver 173 (5.3%), skin 146 (4.5%), gingiva 104 (3.2%), central nerve system (CNS) 32 (1%), peripheral nerve system (PNS) 8 (0.2%) and other sites 134 (4.1%). In 65 cases (8.4%) EMD was confirmed by biopsy. Most of the patients (64.4%) had only one site of EMD, 163 (21.2%) had 2 sites, 75 (9.7%) - 3 sites, 28 (3.6%) - 4 sites, and 4 patients (0.5%) each had 5 or 6 sites. EMD patients compared to those without EMD; tend to be younger (median age 45.7 vs 52.9 years); male (57.7% vs 52%); poorer ECOG performance status (76.4% with ECOG 0-1 vs 85.9%) and with higher white blood cell count (WBC) at diagnosis (median of 41.6/µl vs 10.2/µl). In univariate analysis, having EMD was associated with a shorter OS (P=0.006). Examination of individual EMD sites revealed that skin (P=0.002), spleen (P=0.0002) and liver (P=0.0007) but not CNS (P=0.35), PNS (P=0.53), nodal involvement (P=0.85) and gingival hypertrophy (P=0.14), were associated with poorer OS. Using proportional hazards models for continuous factors, each additional site of EMD conferred a 9.4% increase in the risk of death. In a multivariable model, after adjusting for known prognostic factors (such as: age, WBC count and cytogenetic risk group), the presence of EMD, number of EMD sites and any specific EMD site were not independently prognostic. Of 165 patients with known favorable cytogenetics EMD was present in only 22 patients (13%). This group appeared to have a worse prognosis, but the numbers are too small for a definitive assessment (figure 1). Conclusions Extramedullary disease is common in newly diagnosed AML with an incidence of almost 24%, but CNS involvement is very rare (0.95%). In contrast to published data, no site of EMD was found to have an independent prognostic impact in multivariate analysis. This large dataset emphasizes the importance of evaluating large number of patients and considering all known risk factors in the multivariate analysis. Disclosures: No relevant conflicts of interest to declare.

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