BIOM-26. SURVIVAL OUTCOMES AND PROGNOSTIC FACTORS IN PRIMARY GLIOBLASTOMA FROM A REAL-WORLD RETROSPECTIVE STUDY

Abstract INTRODUCTION Glioblastoma has limited therapeutic options and is associated with a poor prognosis. Treatment, clinical outcomes, and prognostic factors remain poorly characterised outside of the selected population enrolled in clinical trials. METHODS Demographic, tumour molecular profiles, treatment, and survival data was collated for patients who underwent a biopsy or resection diagnostic of de novo glioblastoma at our centre between July 2011 and December 2015. We used multivariate proportional hazards models to examine the association of potential prognostic markers with survival. RESULTS 490 patients were identified: 60% were male with a median age of 59 years. 60% of patients had surgical debulking, and 40% biopsy only. Subsequently, 56% had standard chemoradiotherapy, 25% non-standard chemo/radio-therapy, and 19% no further treatment; 22% of patients who had adjuvant therapy had surgery at relapse, 37% second-line chemotherapy, and 11% third-line chemotherapy. Median survival was 9.2 months (IQR 7.9-10.3 months), with survival at 12- and 24-months 41% and 13% respectively. In multivariate analysis, longer survival was associated with debulking surgery vs biopsy alone (14.9 vs 8 months) (HR 0.54 [95%CI 0.41-0.70]); subsequent treatment after diagnosis (HR 0.12 [0.08-0.16]) (standard chemoradiotherapy [16.9 months] vs non-standard regimens [9.2 months] vs none [2.0 months]); tumour MGMT promotor methylation (HR 0.71 [0.58-0.87]); and younger age (hazard ratio vs age< 50: 1.70 [1.26-2.30] for ages 50-59; 3.53 [2.65-4.70] for ages 60-69; 4.82 [3.54-6.56] for ages 70+). IDH mutation was associated with longer survival (HR 0.64 [0.66-0.97] in univariate but not multivariate analysis. CONCLUSION Median survival for patients with glioblastoma is less than a year. Younger age, debulking surgery, treatment with chemoradiotherapy, and MGMT promotor methylation are independently associated with longer survival.

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Prognostic Factors Influencing Survival in Solitary Plasmacytoma: A SEER Database Analysis.

Blood ◽

10.1182/blood.v112.11.1670.1670 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1670-1670

Author(s):

Paul Mehan ◽

Giridharan Ramsingh ◽

Jingqin Luo ◽

Daniel Morgansztern ◽

Ravi Vij

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Solitary Plasmacytoma ◽

Seer Database ◽

Disease Specific Survival ◽

Factors Influencing ◽

Younger Age ◽

Disease Specific

Abstract Solitary plasmacytoma (PCM) is a focal, neoplastic, plasma cell disorder without evidence of systemic disease. While PCM is a clinically distinct entity, survival can be limited by progression to multiple myeloma. Prior studies have attempted to identify factors influencing survival in PCM but have been limited by small patient cohorts. This study identified 1472 patients with PCM using the SEER database between 1988 and 2004. The median age of the patients was 64 years (range 12–97), 65.4% male, 34.6% female, 83% Caucasians, 10.7% African Americans and 6.3% other races. 63.8% had medullary PCM and 36.2% extramedullary PCM. 84% of medullary PCM occurred in axial skeleton and the rest in appendicular skeleton. Extramedullary PCM most frequently occurred in the head and neck region (51.4%) followed by skin/subcutaneous tissue (16.2%), GI tract 6% and other sites (26.4%). 55.2% were treated with radiation therapy alone, 29.5% with radiation therapy and surgery and 15.3% with surgery alone. 558 died during this period and the mean overall survival was 6.83 years (range, 0–16.9). The cause of death was multiple myeloma in 49.6%, other cancers 20.9% and cardiovascular diseases 12.9%. In all patients, survival probability at one year was 87.6% (95% CI, 85–89%), at five years was 58.9% (95% CI, 56–62%), and at 10 years was 40.0% (95% CI, 36–44%). The five year overall survival in the ≤40yo cohort was 83.5% as compared to 76.7% and 44.8% in the 40–60yo and >60yo groups, respectively (p<0.0001). The five year disease specific survival probability in the ≤40yo cohort was 94.5% as compared to 86.0% and 66.2% in the 40–60yo group and >60yo group, respectively (p<0.0001) (figure 1)). Overall survival in the extramedullary PCM was 65.9% at five years as compared to 54.6% in the medullary PCM (p<0.0001) and the disease specific survival in the extramedullary PCM was 86.2% compared to 70.1% in the medullary PCM (p<0.0001) (figure 1). Multivariate analysis of disease specific survival revealed that younger age, male gender, extramedullary type, and race other than African American or Caucasian were favorable prognostic factors (Table 1). Younger age, extramedullary site, treatment with XRT + surgery, and race other than African Americans were associated with improved overall survival by multivariate analysis (Table 1). To our knowledge, this is the largest published review of survival in PCM. This study identifies several prognostic risk factors influencing survival in PCM. These risk factors can be used to identify patients at high risk for progression to multiple myeloma. Those at highest risk could be considered for future trials comparing adjuvant systemic therapy compared to local therapy alone. Table 1. Multivariate Analysis of Prognostic Factors Disease Specific Survival Overall Survival Variable Category HR 95% CI P HR 95%CI P Abbreviations: HR, Hazard Ratio; Q, Confidence Inverval Sex Female --- -- --- -- --- --- Male 0.74 0.58~ 0.94 0.01 0.95 0.80~1.13 0.57 Age <40yo --- --- --- --- --- --- 40–60yo 2.68 115~ 6.2 0.02 1.74 1.04~2.91 0.03 >60yo 6.94 3.06~ 15.73 <0.01 5.55 3.40~9.06 <0.01 Race Black --- --- --- --- --- --- White 0.74 0.52~ 1.06 0.1 0.72 0.56~0.92 0.01 Others 0.31 0.13~ 0.75 <0.01 0.48 0.29~0.79 <0.01 Primary Site Extramedullary --- --- --- --- --- --- Medullary 2.35 1.74~.3.18 <0.01 1.37 1.13~1.65 <0.01 Treatment Surgery Only --- --- --- --- --- --- XRT Only 0.90 0.62~ 1.31 0.59 0.82 0.64~1.04 0.10 XRT + Surgery 0.84 0.55~1.26 0.39 0.68 0.52~0.89 <0.01 Period 1988–1993 --- --- --- --- --- --- 1994–1999 0.96 0.72~1.30 0.8 0.96 0.78~1.19 0.74 2000–2004 0.94 0.68~1.30 0.7 0.94 0.75~1.18 0.6 Figure 1: Figure 1:.

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Impact of surgery and chemotherapy on survival in patients with advanced cholangiocarcinoma: A multivariate analysis in a cohort of 242 consecutive patients

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4133 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4133-4133

Author(s):

C. Dreyer ◽

C. Le Tourneau ◽

S. Faivre ◽

V. Paradis ◽

Q. Zhan ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Lymph Node ◽

Median Survival ◽

Tumor Size ◽

Positive Impact ◽

Univariate Analysis ◽

Lymph Node Involvement ◽

Node Involvement ◽

The Impact

4133 Background: Cholangiocarcinoma remains an orphan disease for which prospective studies are missing to evaluate the impact of systemic chemotherapy on survival. Methods: Univariate and multivariate analysis of parameters that might impact survival were analyzed in a cohort of 242 consecutive patients with cholangiocarcinoma treated in a single institution between 2000 and 2004. Variables were WHO performance status (PS), age, symptoms, tumor size, extent of the disease, lymph node involvement, site of metastasis, tumor markers, pathology, and type of treatment including surgery, chemotherapy and radiotherapy. Results: Statistically significant prognostic factors of survival in univariate analysis are displayed in the table : In multivariate analysis, PS, tumor size and surgery were independent prognostic factors. Subgroup analysis demonstrated that in patients with advanced diseases (lymph node involvement, peritoneal carcinomatosis and/or distant metastasis), patients who had no surgery benefited of chemotherapy (median survival 13.1 versus 7.4 months in patients with/without chemotherapy, p = 0.006). Moreover, survival was further improved when patients could benefit of chemotherapy following total and/or partial resection (median survival 22.9 versus 13.0 months in patients with/without chemotherapy, p = 0.03). Conclusions: This study strongly suggests the positive impact on survival of multimodality approaches including surgery and chemotherapy in patients with advanced cholangiocarcinoma. [Table: see text] No significant financial relationships to disclose.

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A retrospective analysis of 5-fluorouracil plus cisplatin as first-line chemotherapy in patients with metastatic or recurrent esophageal squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.204 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 204-204

Author(s):

Shuji Hiramoto ◽

Ken Kato ◽

Hirokazu Shoji ◽

Natsuko T. Okita ◽

Atsuo Takashima ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Prognostic Factor ◽

Esophageal Squamous Cell Carcinoma ◽

Serum Albumin ◽

Survival Time ◽

First Line ◽

Metastatic Site ◽

Line Chemotherapy

204 Background: Patients with metastatic or recurrent esophageal squamous cell carcinoma (ESCC) have a poor prognosis. For decades, 5-fluorouracil /Cisplatin (FP) have been mostly used for these patients as first line chemotherapy. But there were few reports which reveal the reality containing the efficacy of FP regimen for ESCC. We conduct this retrospective study to reveal the efficacy and prognostic factors of the patients treated with FP as first line chemotherapy for ESCC. Methods: Patients with metastatic or recurrent ESCC after esophagectomy were enrolled. FP comprised of CDDP at a dose of 80mg/m2 on day1, and 5-FU at a dose of 800mg/m2given by continuous on days 1-5 every 4 weeks. Cox-proportional hazard model was used for multivariate analysis to evaluate prognostic factors. Results: Between April 2001 and March 2012 in the National Cancer Center Hospital, data of 187 patients were collected by medical records. Characteristics of 187 patients were as follows; the median age (range) 62 (34-84); (male/female) 163/24; (performance status: 0/1/2) 69/110/8; (metastatic/recurrent) 116/71; median number of metastasis 1(range1-4); median cycles of FP 2(range1-10). Overall response rate was 31.6% (95%CI: 25.0-38.7%). Median progression free and overall survival time was 4.9 month and 10.5 month, respectively. In multivariate analysis, serum CRP (≥2 vs <2 mg/dl) (HR=2.61, p<0.001), serum albumin (<3.5 vs >3.5 mg/dl) (HR=1.85, p=0.001) at the time of diagnosis and number of metastatic site (≥2 vs <2) (HR=1.563, p=0.01) were remaining independent prognostic factor for survival. Survival time of the patients who had no these poor prognostic factors was 17.9 month, while survival time who had all poor prognostic factors was only 4.0 month. Conclusions: Number of metastatic site, CRP, and serum albumin are independent prognostic factor on metastatic or recurrent ESCC patients treated with FP. Information from this analysis can be used to aid clinical decision-making and help individual patient risk stratification.

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Clinico-Biological Characteristics and Prognosis of Non-M3 Acute Myeloid Leukemia with High Percentage of Myeloperoxisase Positive Blasts. Single Center Experience.

Blood ◽

10.1182/blood.v108.11.4462.4462 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4462-4462

Author(s):

Pau Montesinos ◽

Lorenzo Algarra ◽

Jaime Sanz ◽

Mari Luz Perez ◽

Leonor Senent ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Myeloid Leukemia ◽

De Novo ◽

Disease Free Survival ◽

Favourable Outcome ◽

Biological Characteristics ◽

Prognostic Impact ◽

Acute Myeloid

Abstract Introduction: It has been suggested that acute myeloid leukemia (AML) showing mature phenotype is associated with favourable outcome. In a study recently published by JALSG, myeloperoxidase (MPO) positivity in over 50% of blasts had favourable prognostic impact, independent from karyotype, on achieving complete remission (CR), overall survival (OS) and disease free survival (DFS). No other studies have established the independent prognostic value of MPO expression. Objectives: Analyze the clinico-biological characteristics of AML with high percentage of MPO+ blasts and its impact on CR, OS and DFS. Material and methods: Between 1986 and 2005, 418 adult patients (median 53 years, range 15–80) were diagnosed with de novo non-APL AML and evaluated for percentage of MPO+ blasts. All patients received intensive chemotherapy. Diagnosis was made by optic microscopy of bone marrow (BM) aspirates stained with May-Grumwald giemsa, MPO, butyrate esterase and or non specific esterase. Cytogenetic and immunophenotype analysis was evaluated in 66% and in 76% of the cases respectively. Results: 118 patients (28%) showed a percentage of MPO+ blasts >75%. AML with MPO+ blasts >75% was associated with M1-M2-M4 subtypes, leucocytes >50×109/L, blasts in BM >70% and HLA-DR negativity (p<0.01). It was also significantly associated with favourable karyotype (11% vs 3% favourable, 52% vs 48% intermediate and 3% vs 15% unfavourable). Patients with AML and MPO+ blasts >75% obtained higher CR rate (71% vs 55%), due to less resistant disease (9% vs 22%, p<0.01). In multivariate analysis favourable karyotype, leukocytes <50×109/L and age <60 were favourable prognostic factors for CR. Median OS and DFS was higher in patients with AML and MPO+ blasts >75% (15 vs 7 months, p<0.001, y 41 vs 12 months, p<0.001, respectively). ). In multivariate analysis, favourable karyotype, leukocytes <50×109/L, age <60 years and MPO+ >50% were favourable prognostic factors for OS; and age <60 and MPO+ >75% were the only independent factors for DFS. Median DFS was higher in patients with AML and MPO+ blasts >75% in the intermediate cytogenetic risk group (59 vs 13 months, p=0.015), age <60 (109 vs 15 months, p=0.003), age >60 (13 vs 7 months, p=0.03), autologous stem cell transplantation (100 vs 9 months, p=0.04) and chemotherapy alone (16 vs 8 months, p=0.003). Conclusion: In our series, patients with AML and MPO+ blasts >75% show less chemoresistant disease and a longer remission duration, the latter independently from the karyotype. This biological characteristic could be useful in designing therapeutic strategies in patients that lack other prognostic markers.

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Single Center Experience of Prognostic Factors and Survival Outcomes Among Veterans with MDS: A Retrospective Analysis

Blood ◽

10.1182/blood.v116.21.4970.4970 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4970-4970

Author(s):

Premal D Lulla ◽

Sarvari Venkata Yellapragada ◽

Zahida Yasin ◽

Carlos E. Arce-Lara

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Growth Factors ◽

Alcohol Use ◽

Iron Overload ◽

Median Survival ◽

Performance Status ◽

Age At Diagnosis ◽

Ecog Performance Status ◽

Transfusion Dependency

Abstract Abstract 4970 Background: While the epidemiologic and demographic characteristics of veterans with MDS have been established (Komrokji et. al, 2009), there is no data on prognostic factors. Several factors including age (Kim SH et. al, 2010), sex (Nosslinger et al 2010), ferritin (Armand et. al 2007), MCV (Wang et. al 2010), use of growth factors (Jaderstan et. al 2008), and co-morbidities (Sperr et. al 2010) independent of the established WHO prognostic scoring system (WPSS) (Malcovati et. al 2007) have been shown to impact survival in MDS. The purpose of this study is to highlight major survival determinants among veterans with an emphasis on transfusion dependency and ferritin. Materials and Methods: Charts of 88 unselected patients (87 males) with a pathological diagnosis of MDS from January 2000 to December 2008 at the Michael E. Debakey VA Medical Center in Houston, Texas were included. The following data was collected at diagnosis: demographics, smoking, alcohol use, initial ECOG performance status, hematological data, cytogenetics, HIV and hepatitis status. Transfusion dependency was defined as needing more than 1 unit of packed red cells each month for 4 consecutive months at anytime after diagnosis. 50 patients had 4 or more ferritin readings spread over a minimum of 4 months, to compute a meaningful mean increase in ferritin per year (MIF). Administration of growth factors, treatment with Azacytidine, Decitabine or Lenalidomide was analyzed as categorical data (intervention or no intervention). Univariate survival analysis was performed using GraphPad Prism 5.0, and Kaplan-Meier curves were computed. Multivariate analysis on significant variables was performed using the Cox model on MedCalc Statistics Software (version 11.3). Results: Demographic factors: The median age at diagnosis was 73 (53-91) with a median OS of 520 days (13-2234). 9 patients (10.2%) progressed to AML at a median time to progression of 159 days (74-614), all with IPSS scores > 1 at diagnosis. Distribution [N (Median OS)] among WHO sub-groups were as follows: RA: 22(659), RARS: 10(1020), RCMD: 39(638), RAEB-1: 5(228), RAEB-2: 9(170), 5q-: 3(521). Age, race, tobacco, alcohol use, hepatitis, HIV status were not significant prognostic variables. Performance status (ECOG) > 2 (p=0.012), and blood group O were the only significant variables on univariate analysis (p=0.029). Hematologic factors: Initial Hb < 8 g/dl, IPSS(Greenberg et. al, 1997) scores > 1.0, transfusion dependency, cytogenetic abnormalities, MIF > 200 per year, MCV < 100 and use of erythropoetin were significant variables in predicting OS on univariable analysis. On multivariate analysis, IPSS scores > 1.0 (p=0.01), transfusion dependency (p=0.0029), ECOG performance status > 2 (p=0.0421) and MIF > 200 (p=0.0294) were independent significant prognostic factors. In the sub-group of MDS without excess blasts (Cermak et. al, 2009), transfusion dependency and MIF > 200 per year were highly significant variables (p<0.0001). Use of Azacitidine (8), decitabine (8) or lenalidomide (4) did not impact survival (p=0.63), although only 14 patients overall received one or more of these treatments. Conclusion: Veteran's with MDS pose a unique population, being predominantly male, older age at diagnosis and with potentially poorer performance status. Based on the above results, these patients had a poorer median survival (1.42 years) than expected from established data (2.1 years, Komrokji et. al 2009). The established prognostic factors, the IPSS scores and transfusion dependency expectedly were independent predictors of OS. Iron overload is rapidly becoming a leading problem in the management of MDS. This is most evident in the transfusion dependent MDS patient without excess blasts with better prognosis and longer median survival, for iron overload to manifest its deleterious effects. MIF values > 200 were intended to represent populations at higher risk for developing iron overload. Interestingly, MIF was independent of transfusion dependency in predicting OS. This highlights the need for prospective studies to establish the role of ferritin and its rise over time to identify populations at risk for iron overload and mortality thereof. The clinical question of benefit from chelation therapy in these patients remains. Disclosures: No relevant conflicts of interest to declare.

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Addition of Lomustine to Idarubicin and Cytarabine Improves the Outcome of Elderly Patients With De Novo Acute Myeloid Leukemia: A Report From the GOELAMS

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.4648 ◽

2010 ◽

Vol 28 (18) ◽

pp. 3028-3034 ◽

Cited By ~ 24

Author(s):

Arnaud Pigneux ◽

Jean-Luc Harousseau ◽

Francis Witz ◽

Mathieu Sauvezie ◽

Marie-Christine Bene ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Elderly Patients ◽

Induction Therapy ◽

Myeloid Leukemia ◽

De Novo ◽

Group I ◽

Acute Myeloid

Purpose No significant improvement in treatment outcome has been seen in elderly patients with acute myeloid leukemia (AML) over the past 20 years. This retrospective analysis investigated the prognostic factors for complete remission (CR) and survival in older patients with AML. Patients and Methods The study involved 847 patients older than 60 years enrolled onto three trials carried out in France between 1995 and 2005. Induction therapy consisted of idarubicin (8 mg/m2, days 1 through 5) and cytarabine (100 mg/m2, days 1 through 7; group I, 339 patients) or the same drugs plus lomustine (200 mg/m2 orally on day 1; group II, 508 patients). Consolidation therapy consisted of anthracycline and cytarabine courses at lower doses, preceded or not by a first course of intermediate-dose cytarabine. Results The rate of CR was significantly higher in patients in group II compared with group I (68% v 58%; P = .002). The rate of toxic death was similar in the two groups. In multivariate analysis, two prognostic factors were linked to CR: nonadverse cytogenetic (P < .003) and addition of lomustine to induction chemotherapy (P = .002). Median overall survival was significantly improved in patients treated with lomustine (median and SE, 12.7 ± 2.2 months v 8.7 ± 2.7 months; P = .004). In multivariate analysis, five prognostic factors positively affected overall survival: addition of lomustine (P = .002), age ≤ 69 years (P < .001), Eastern Cooperative Oncology Group performance status lower than 2 (P = .002), French-American-British subgroup 1/2 (P = .02), and nonadverse cytogenetic (P < .001). Conclusion Lomustine improves the rate of CR and survival in elderly patients with de novo AML when added to standard induction therapy.

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Presence of TP53 Mutation and Monosomal Karyotype Predict the Outcome of Patients with Acute Myeloid Leukemia in Non-Remission at Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-116469 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2168-2168

Author(s):

Yuho Najima ◽

Daichi Sadato ◽

Yuka Harada ◽

Chizuko Hirama ◽

Keisuke Oboki ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Myeloid Leukemia ◽

Tp53 Mutation ◽

De Novo ◽

Conditioning Regimen ◽

Gene Mutations ◽

De Novo Aml ◽

Monosomal Karyotype ◽

Acute Myeloid

Abstract Background Although the outcome after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) for the patients with acute myeloid leukemia (AML) in complete remission has been improved, the prognosis of patients with active disease is still dismal, generally with 20 - 30% of overall survival (OS) at 2 years. Prognostic value of gene mutations detected by the next generation sequencing (NGS) for this extremely poor group remains to be evaluated. Methods A total of 120 patients with AML not in hematological remission who received the first allo-HSCT at our institute between April 2005 and December 2017 were enrolled. For each patient, genomic DNA was extracted from the frozen bone marrow sample harboring leukemic blasts which was preserved at the nearest available date before the initiation of conditioning regimen. Sequencing was performed using TruSight Myeloid Sequencing Panel® on the MiniSeq system (Illumina). Gene variants were detected by in-house analysis pipeline. Charts were retrospectively reviewed on survival, relapse, and non-relapse mortality (NRM). The Kaplan-Meier method was used to assess OS using the log-rank test. Univariate and multivariate analysis were performed to identify potential prognostic factors. The Cox proportional hazards method was used for the multivariate analysis to assess OS. Gray's test and the Fine-Gray test were used to assess the cumulative incidence of relapse (CIR). Competing risks were relapse and NRM. Results Median follow-up of survivors was 1345 days (235 - 4888 days). Median age at transplant was 51 (range 21 - 71). Grafts were from bone marrow (n = 67, 55.8%), peripheral blood (n=42, 35.0%) and cord blood (n=11, 9.2%). Refined disease risk index (Blood. 2014;123:3664-71) scored high (n=61, 51.3%) and very high (n=58, 48.7%). OS at 2 years of the whole cohort was 27.3% (95% confidence interval [CI], 19.4% - 35.7%). There was no significant difference in OS between patients in primary induction failure and in relapse (OS at 2 years: 26.5% [n=50] vs 28.7% [n=70], p= 0.293). NGS analysis revealed TP53 loss-of-function mutation in 23 (19.2%) patients. Among all detected gene mutations, TP53 mutation was the most powerful predictor of poor OS after allo-HSCT (OS at 2 years: 13.5% vs 30.5% for TP53+ [n=23] vs TP53- [n=97], p= 0.0184). Consistent with previous reports, monosomal karyotype (MK, J Clin Ocnol 2010:26;4791-7) was significantly associated with positive TP53 mutation (13.3% of non-MK vs 37.9% of MK, p=0.006). Of note, all the patients (n=11) positive for both prognostic factors died within 1 year after allo-HSCT, whereas OS of the patients without either factor (n=78) was 33.6% at 2 years. Multivariate analysis on OS revealed MK, TP53 mutation, de novo AML (no prior history of MDS), ECOG performance status score 2 or more, C reactive protein 1.0 mg/dL or more, peripheral blood blast frequency of 1% or more at the initiation of conditioning regimen were independent prognostic factors for poor OS. Among them, to determine the prognostic factors critical for deciding the indication of allo-HSCT, we chose pre-transplant factors which were available around one months before transplant. From this point of view, multivariate analysis revealed independent prognostic factors for poor OS after allo-HSCT including MK (Hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.30 - 3.25, p=0.00217), TP53 mutation (HR 1.72; 95% CI 1.04 - 2.86, p=0.035), and de novo AML (HR 1.67; 95% CI 1.04 - 2.86, p=0.036). Because the HR of these three factors were comparable, a score of 1 was assigned to each factor. OS at 2 years was 49.7%, 26.5% and 13.1% for patients with low (score 0, n=23), intermediate (score 1, n=63) and high (score 2 or 3, n=34) risk, respectively (p<0.001, Figure 1A). CIR was significantly lower in low risk group compared to intermediate and high risk groups (9.0%, 49.7% and 48.0% at 2 years, p=0.0128, Figure 1B), whereas NRM was comparable (41.3%, 32.5% and 41.7% at 2 years, p =0.515). Conclusions NGS-analysis revealed the importance of TP53 mutation on transplant outcome of AML in non-remission. The combined score with the information on MK, de novo AML, and TP53 mutation stratified the patients into three groups, including low risk with 50% survival rate, and high risk with shorter survival after allo-HSCT for whom the other strategy might be optimal. Our results would require further validation in larger cohorts. Disclosures Harada: Celgene: Research Funding.

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DNMT3Awt NPM1-Mutation Defines a Subgroup of MDS with Special Favorable Outcomes Towards Decitabine Therapy

Blood ◽

10.1182/blood-2019-124008 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1724-1724

Author(s):

Lingyun Wu ◽

Xiao Li ◽

Feng Xu ◽

He Qi ◽

Zheng Zhang ◽

...

Keyword(s):

Median Survival ◽

De Novo ◽

Conflicts Of Interest ◽

Statistical Significance ◽

Complete Response ◽

Subsequent Treatment ◽

Induction Treatment ◽

Wild Type ◽

Npm1 Mutation ◽

Randomized Controlled Studies

Hypomethylating agents (HMA) (including decitabine and azacitidine) are considered standard of care for higher risk myelodysplastic syndrome (MDS). Clinical data showed only about 30% cases achieved complete response (CR) by decitabine. Mutations in the nucleophosmin-1 (NPM1) gene is one of the most common somatic mutations identified in de novo acute myeloid leukemia (AML) and have also been found in 1% to 5% of MDS patients although with different mutation locus (L287fs) when compared to that in AML (W288fs). Till now, the response and survival of NPM1-mutated MDS patients treated with HMA remains unknown. Here, we retrospectively analyzed higher risk MDSs who accepted decitabine therapy in our center. From December 2009 to July 2018, a total of 194 patients received decitabine induction treatment by 20mg/m2 intravenously for 5 consecutive days every 4-6 weeks. The median therapy course was four. Among them, twelve patients (6.2%) harbored NPM1/L287fs mutation. The median decitabine therapy cycle for the 12 NPM1 mutated patients was also four. To our interest, patients harboring NPM1 mutations achieved a relatively higher CR rate (6 of 12 cases, 50%) when compared to that of patients without NPM1 mutations (59 of 182 cases, 32.4%) , although without statistical significance (p = 0.304). Moreover, when the most common co-mutated genes DNMT3A (6 of 12 cases, 50%) (Figure 1a) was ruled out, patients harboring NPM1 mutation (DNMT3A wild type) achieved a CR rate of 83.3% (five of six), which is significantly higher than that of patients without NPM1 mutation (p = 0.018) (Figure 1b). Of note, when paired sequencing were analyzed, six patients who achieved CR by decitabine showed loss of mutated NPM1; One patients who achieved hematological improvement (HI) showed decreased variant allele frequency (VAF) of NPM1 mutation; Whereas two patients with no response (NR) showed unchanged NPM1 mutation (Figure 1d). Notably, a prolonged relapse-free survival (PFS) was observed in CR patients with NPM1 mutation and DNMT3A wild type (NPM1mut DNMT3Awt) even without any subsequent therapies after receiving 4-5 cycles of decitabine (Figure 1c). The median RFS of CR patients with NPM1mut DNMT3Awt was 66 months, which is significantly longer than that in patients without NPM1mutation (13.5M, p = 0.006) (Figure 1e). A remarkably prolonged median survival was also shown in patients harboring NPM1mut DNMT3Awt (median survival of 80M), which is significantly longer than that of patients without NPM1 mutation (18M) (p = 0.012) (Figure 1f). Interestingly, except with DNMT3A and PTPRD co-mutations, the response and survival of patients harboring NPM1 mutations treated with decitabine were favorable even when co-mutated with IDH2, NRAS, FLT3. In conclusion, NPM1 mutation with DNMT3A wild type defines a specific subgroup of MDS with a good response and prolonged survival by decitabine therapy, even when they were with some prognosis-poor co-mutations and without subsequent treatment. Enlarged sample of randomized controlled studies are needed to confirm our preliminary findings. Figure 1 Disclosures No relevant conflicts of interest to declare.

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Multivariate Evaluation of the Prognostic and Therapeutic Relevance of Cytogenetics in a Merged European-American Cohort of 3860 Patients with MDS.

Blood ◽

10.1182/blood.v110.11.247.247 ◽

2007 ◽

Vol 110 (11) ◽

pp. 247-247 ◽

Cited By ~ 4

Author(s):

Detlef Haase ◽

Elihu H. Estey ◽

Christian Steidl ◽

Ulrich Germing ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Supportive Care ◽

Median Survival ◽

Survival Data ◽

De Novo ◽

Normal Karyotype ◽

Epigenetic Therapy ◽

Chemotherapy Response ◽

Trisomy 8 ◽

Therapy Regimen ◽

Secondary Mds

Abstract This study investigated the influence of cytogenetic findings on survival in MDS, after accounting for other known prognostic parameters and type of treatment. We identified 3210 patients with a known therapy regimen from our large database, including 3860 patients with MDS and secondary AML following MDS. This data pool was collected in the framework of a cooperative project merging data from the German-Austrian MDS study group (55% of pts.) and the MD Anderson Cancer Centre (MDA), Houston, USA (45% of pts.). Median age of all study patients was 65.9 years, the female-male ratio 1:1.53. After accounting for age, sex, % marrow blasts, de novo vs. primary MDS, treatment (supportive care, AML-type, and epigenetic therapy) and site of treatment(Germany/Austria vs.MDA) we looked at the effect of cytogenetic subgroups on survival. Survival data was available for 95.8% of all pts. The distribution of main cytogenetic categories was as follows: normal (1.727, 45%), 5q- (208, 5%), 5q- +1 abnormality (73, 2%), −7/7q- not complex (222, 6%), +8 not complex (203, 5%), complex with −5/−7 (627, 17%), other complex (195, 5%), 20q- not complex (69, 2%), and other not complex (475, 13%). Chemotherapy (c) was applied in 32.9% while 67.1% were treated with supportive care (sc) or epigenetic therapy. The cytogenetic prognosis according to IPSS-criteria was favourable in 1704 (53.1%) and unfavourable in 839 (26.13%) of the 3210 study patients. Multivariate analysis revealed the following non-cytogenetic parameters as unfavourable: age >60, male sex, blasts >5%, secondary MDS, AML-like chemotherapy, MDA as site (due to overrepresentation of high risk MDS). After accounting for these variables the following relative Hazard ratios (HR of 1.0 for normal karyotype) were calculated allowing a relative ranking of cytogentic findings: 5q-: 0.93, 5q- +1: 1.06, other not complex: 1.11, 20q-: 1.31, +8: 1.65, complex without −5/−7: 1.76 −7/7q-: 2.09, complex with −5/−7: 3.88. The effect of cytogenetics in pts. with either supportive care (sc) or chemotherapy (c) measured as relative HR (see above) were: 20q- (sc: 1.25, c: 1.51), 5q- (sc: 0.93, c: 0.73), other not complex (sc: 1.07, c: 1.04), −7/7q- (sc: 2.10, c: 2.09), +8 (sc: 2.05, c:1.54), complex without −5/−7 (sc: 2.23, c: 1.75), complex with −5/−7 (sc: 4.78, c: 3.77) showing that cytogenetics remains it’s prognostic relevance independent from the therapy applied. In Kaplan-Meier-analyses median survival in pts. showing favourable karyotypes was 37.9 months with supportive treatment as compared to 26.4 months with chemotherapy (p<0.01). We observed no therapy-related survival differences with regard to patients of the unfavourable cytogenetic subgroup. The occurrence of complex abnormalities (n=670) was associated with an identical median survival comparing the therapy groups (c: 7.0, sc: 7.1 months). We also investigated groups with distinct abnormalities (5q-, −7/7q-, +8, 20q-) and found significant differences in survival between the therapy groups: Patients with 5q- and 20q- benefited from supportive care while −7/7q- was related with a better survival when chemotherapy was applied. Patients with trisomy 8 showed no differences in survival. Regarding these data, chemotherapy response, expressed by survival, is closely associated with cytogenetics. Complex abnormalities always show a dramatically reduced outcome, independent from the therapeutic strategy.

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Outcome Of MDS and AML With MDS-Related Changes: Treatment Versus Prognostic Factors

Blood ◽

10.1182/blood.v122.21.5223.5223 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5223-5223

Author(s):

Nadja Jaekel ◽

Susann Schulze ◽

Cora Graneist ◽

Rainer Krahl ◽

Wolfram Poenisch ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Survival Time ◽

Median Survival ◽

Median Survival Time ◽

Conflicts Of Interest ◽

Negative Impact ◽

Allogeneic Hct ◽

Comorbidity Burden ◽

The Impact

Abstract The significance of host- and disease-related prognostic factors on outcome in patients (pts) with MDS and AML with MDS-related changes (sAML) depends on the treatment given. The impact of therapy opposed to prognostic variables on the heterogeneity of MDS and sAML was investigated. Patients and methods From January, 2004-August, 2012, 367 pts (MDS, n=208; sAML, n=159) consecutively treated (median age 63y) at the University of Leipzig were included. Patients (84%) with marrow blasts >10% received induction chemotherapy (CT; 59%) or azacitidine (AZA; 25%) (after its approval in the EU in January, 2009) with the intention of performing a subsequent allogeneic hematopoietic cell transplantation (HCT) in pts <70y. Up-front HCT was scheduled if blasts were <10% (n=56). Cytogenetics were categorized according to Schanz et al, JCO 2012 for MDS and the WHO classification for sAML. As confounders in the estimation of therapy, host- and disease-related features were investigated in a multistep process. 38% of pts had >2 comorbidities with no difference between MDS and sAML. The sAML group (median blasts 40%) included 69 and 81 pts with previous MDS and MDS-related cytogenetic abnormality respectively. Cytogenetics were poor and very poor in 34% of MDS. Outcome at two years are presented. Results Median interval between diagnosis of MDS and therapy was 3.6 months. Median survival time for sAML was 15 vs 72 months for MDS (p<0.0005). Overall, age was higher (median 68y) and blasts lower (median 13%) in the AZA group compared to CT (62y and 27%) (p<0.0005). Cytogenetics and the comorbidity burden (CB) were comparable. OS with AZA was similar to up-front HCT (68%) and superior to CT (48%) (p=0.01). OS was 50% if HCT was performed after CT (136 pt) compared to CT alone (p=0.01). In the 20% of pts >70y, AZA was given to 52% and CT to 48%. OS was 55% and best with AZA (p=0.01). Median survival times were 30 for AZA/MDS, 27 for AZA/AML, 15 for CT/AML, and 5 months for CT/MDS. Of the 110 pts <70y with MDS, AZA was given to 50 (45%) and CT to 60 (55%). The IPSS, cytogenetics, CB, BM blasts (10% vs 11.5%) were similar in both groups. With a median age of 63y, the AZA/MDS group was older than the CT/MDS group (median age 60y) (p=0.005). OS for both groups was 68%. NRM (16%) and RI (38% vs 34%) were alike. For the 114 pts <70y with sAML (median age 62%; median blasts 44%) treated with CT, OS was 40% and inferior to MDS (AZA/MDS, p=0.007; CT/MDS, p=0.01) due to higher RI (57%) (p=0.008). Overall, 218 (78%) pts <70y received HCT (after a median of 3 AZA cycles for AZA/MDS). Ferritin, cytogentics, CB, type of donor, and blasts at HCT (median 4%) were comparable in the transplant groups (AZA/MDS, CT/MDS, HCT up-front, CT/sAML). Irrespective of prior therapy (p=0.6), interval between therapy and HCT, and blasts <5 vs >5-<10%, outcome in the MDS groups (OS, 60%, NRM 29%, RI, 32%) was similar. In multivariate analysis, >2 comorbidities and very poor cytogenetics were associated with an inferior OS (p=0.001)and a higher RI (p=0.003). With a median survival time of 11 months for sAML and a RI of 49%, outcome after HCT for sAML was inferior to MDS (p=0.005). In multivariate analysis, blasts <5%, >2 comorbidities were associated with a poor outcome. For MDS/CT and sAML/CT, a complex karyotype (38%) tended to decrease OS (p=0.06) and increase RI (p=0.01) after HCT. Conclusions Treatment was able to reduce the significance of most negative host- and disease-specific prognostic factors on outcome in MDS. AZA is superior to CT in elderly patients and equal to CT in younger patients with MDS and seems to have no negative impact on outcome after HCT. Despite the improvement achieved with allogeneic HCT, AML with MDS-related changes remains a distinct clinic-pathologic entity associated with a worse outcome. Genetics rather than marrow blasts are an important determinant of prognosis after treatment including allogeneic HCT. Disclosures: No relevant conflicts of interest to declare.

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