The Effect of FLT3 and NPM1 Mutation Status on Outcomes of Transplanted Vs. Non-Transplant Treated Elderly Patients with Normal Karyotype AML: A Retrospective Multicenter Study

7052 Background: High treatment-related mortality and low response rates often discourage elderly patients with acute myeloid leukemia from receiving treatment. Previous data demonstrate that only patients lacking expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leukemic blasts are sensitive to temozolomide. Protracted exposure to low doses of temozolomide can significantly inhibit AGAT enzymatic activity. Methods: Phase II clinical trial of tailored temozolomide therapy to high-risk AML patients according to AGAT methylation promoter status. Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200 mg/m2 orally x 7 days. Patients demonstrating lack of AGAT promoter methylation (unmethylated) received protracted doses of temozolomide (100 mg/m2 orally x 14 days) followed by conventional doses of temozolomide. Patients who achieved CR were given up to 5 consolidation treatments. Results: Fifteen patients have completed treatment to date. The median age was 78 (68–83) and nine were male. De novo AML was diagnosed in eight patients and five patients had s-AML. Nine patients had a normal karyotype and three patients had a complex karyotype. Two patients had only a NPM1 mutation and one had NPM1mut/FLT3-ITD. In 13 patients, the AGAT promoter was found to be unmethylated. AGAT protein was present in 5/11 patients. All patients had an intact mismatch repair pathway. Thirteen patients had HCT-CI scores of 0–2. Six patients (6/13) achieved a complete remission (CR) after 1 cycle of therapy (1/2 for patients with methylated and 5/11 for patients with unmethylated AGAT promoter). Nonhematologic toxicities were minimal. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. Three patients remain in CR with a median duration of 22 weeks (14–36 weeks). Seven patients have died from disease progression, while two patients died of neutropenic sepsis (early deaths). With a median follow-up of 38 weeks (10–48), the median overall survival for the entire population is 12 weeks (3.5 - 38) weeks (responders 26.5 weeks). Conclusions: These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status. [Table: see text]

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Effect of adding taxane to platin-5-fluorouracil combination on survival in elderly patients with advanced gastric cancer: A retrospective-multicenter study.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e15572 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e15572-e15572

Author(s):

Meral Gunaldi ◽

Fatih Kose ◽

Nebi Serkan Demirci ◽

Seyda Gunduz ◽

Nuriye Özdemir ◽

...

Keyword(s):

Gastric Cancer ◽

Elderly Patients ◽

Advanced Gastric Cancer ◽

Multicenter Study ◽

Retrospective Multicenter Study

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Microarray Analysis Detects Unique Expression Pattern for NPM1-Mutated AML with Normal Karyotype and Reveals Pathobiological Insights.

Blood ◽

10.1182/blood.v110.11.2382.2382 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2382-2382

Author(s):

Torsten Haferlach ◽

Claudia Haferlach ◽

Alexander Kohlmann ◽

Lothar Wieczorek ◽

Martin Dugas ◽

...

Keyword(s):

Gene Expression ◽

Melting Curve ◽

Normal Karyotype ◽

Support Vector ◽

Melting Curve Analysis ◽

Study Cohort ◽

Data Set ◽

Npm1 Mutation ◽

Mutation Status ◽

Mutational Status

Abstract Recent data indicate that mutations in exon 12 of the nucleophosmin (NPM1) gene characterize a distinct subgroup of adult and pediatric acute myeloid leukemia (AML). AML carrying NPM1 mutations account for about one-third of all adult AML, exhibit distinctive biological and clinical features and show a strong association to AML with normal karyotype (55% mutated). However, the role of NPM1 in leukemogenesis still remains elusive. Here we present data on a cohort of n=66 AML cases with normal karyotype analyzed by high-density whole genome expression microarrays (Affymetrix HG-U133 Plus 2.0). In parallel melting curve analysis was used to assess NPM1 mutational status: 41 cases were characterized as mutated (NPM1+) and 25 cases were unmutated (NPM1−). We first investigated the gene signature that discriminated NPM1+ from NPM1− cases. Genes that were significantly overexpressed comparing NPM1+ against NPM1– cases included a strong homeobox genes signature (HOXA1, HOXA5, HOXA7, HOXA9, HOXA10, HOXA11, HOXB2, HOXB4, HOXB5, HOXB6, HOXB7, MEIS1, and PBX3). A functional analysis (Gene Ontology) revealed a clear association of the group of overexpressed genes with the cell components nucleosome, chromatin, and the nuclear envelope-endoplasmatic reticulum network as well as involvement in the biological processes of nucleosome and chromatin assembly, establishment of protein transport and localization, and Notch signaling pathway. In contrast, the cellular processes completely differed when genes were investigated that were significantly underexpressed in NPM1+ cases compared to NPM1− cases. This group of genes encoded membrane-related proteins (gap junction, intercellular junction, signalosome complex) and proteins involved in cellular morphogenesis and cell communication. The differences in gene expression signatures between NPM1+ and NPM1− cases permit a robust classification approach by gene expression profiling. Support Vector Machine analysis resulted in >92% prediction accuracy of NPM1 mutation status (10-fold cross-validation). The sensitivity was very high for the positive detection of NPM1+ cases (>97%). Using a 100-fold re-sampling approach and splitting the complete data set into a training set (n=44) and testing set (n=22) the following genes were most frequently selected as top discriminatory genes: HOXA5, HOXB4, HOXB5, HOXB6, MEIS1, PBX3, FGFR1, ADAM17, PRICKLE1, and TMPO. Interestingly, the classification was less accurate when also FLT3 internal tandem duplication mutation status was taken into account. The study cohort (n=66) then was distributed as follows: 19 NPM1+/FLT3+, 22 NPM1+/FLT3−, 4 NPM1−/FLT3+, and 21 NPM1−/FLT3− negative cases. Only 14 of 22 (64%) NPM1+/FLT3– cases were correctly predicted, with miscalls falling both into the group of NPM1+/FLT3+ and NPM1−/FLT3− cases. In conclusion, NPM1 mutations are the most frequent mutations in adult AML to date and their central prognostic role is increasingly recognized. Given the fact that they are nearly mutually exclusive with major recurrent genetic abnormalities and that they can be characterized by a distinctive gene expression program these data especially for of NPM1+/FLT3− AML with better outcome may support to classify this as a separate biological subgroup of AML with normal karyotype.

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Karyotype Plus NPM1 Mutation Status Defines a Group of Elderly Patients with AML (≥60 Years) Who Benefit From Intensive Post-Induction Consolidation Therapy

Blood ◽

10.1182/blood.v118.21.2504.2504 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2504-2504

Author(s):

Wolfgang R. Sperr ◽

Otto Zach ◽

Iris Poell ◽

Michael Kundi ◽

Susanne Herndlhofer ◽

...

Keyword(s):

Elderly Patients ◽

Induction Chemotherapy ◽

Induction Therapy ◽

Hematologic Toxicity ◽

Wild Type ◽

Npm1 Mutation ◽

Mutation Status ◽

Predictive Variables ◽

Monosomal Karyotype

Abstract Abstract 2504 Whereas treatment strategies for AML patients (pts) aged <60 years are well established, therapy in the elderly deserves special consideration. In the present study, we analysed survival and risk factors predicting outcome in 192 consecutive patients (pts) with de novo AML aged ≥60 years (median age: 70.5 years, range 60–89 years). Pts were treated at a single center (Medical University of Vienna) between November 1994 and January 2011, and received conventional induction chemotherapy with DAV (daunorubicin, 45 mg/m2/day, days 1–3; etoposide, 100 mg/m2/day, days 1–5; ARA-C, 2 × 100 mg/m2/day, days 1–7; between 1994 and 2008). Pts achieving a complete hematologic remission (CR) were scheduled to receive a full consolidation program with up to 4 cycles of IDAC (ARA-C, 2 × 1 g/m2/day i.v. on days 1, 3, and 5). Of the 192 pts, 115 (60%) achieved a CR following induction therapy, 57 pts (30%) did not achieve a CR, and 20 pts (10%) died within 40 days after start of induction therapy. Among several parameter including the leukocyte count, hemoglobin, platelet count, LDH, and fibrinogen, only the karyotype according the the Breems-Score was an independent predictor for achieving CR in our multivariate analyses. CR rates in pts with core binding factor (CBF) AML, cytogenetically normal (CN) AML, non-monosomal karyotype (Mkneg) AML, and monosomal karyotype (Mkpos) AML, were 100% (8/8), 66% (57/87), 56% (33/59), and 44% (11/25), respectively (p<0.05). Of the 115 pts in CR, 106 (92%) received up to 4 cycles of IDAC (4 cycles, n=53 pts [50%]; 3 cycles, n=20 pts [19%]; 2 cycles, n=20 [19%]; and 1 cycle, n=13 [12%]). Treatment was well tolerated without grade 3 or 4 neurotoxicity. The most frequent non hematologic toxicity was febrile neutropenia requiring antibiotics (1st consolidation: 50.5%; 2nd consolidation: 58.4%, 3rd consolidation: 55.6%, 4th consolidation: 51.0%). A remarkable finding was that the median time of absolute neutropenia in all IDAC cylces (8–9 days/consolidation) was relatively short when compared to induction chemotherapy or other consolidation regimens. Only two patients died during consolidation with IDAC (cardiac failure, n=1, severe sepsis, n=1). The median overall survival (OS) for all pts was 9.7 months, and for pts achieving a CR, the OS amounted to 24.2 months. The most important predictive variables for continuous complete remission (CCR) were the karyotype and the presence of an NPM1 mutation determined by PCR and melting point analysis. As assessed by uni- and multivariate analysis, both parameters were found to be independent predictive variables (p<0.05), whereas the other markers examined, i.e. FLT3 ITD, overexpression of ERG, MN1, or BAALC, as well as the number of induction cycles required to achieve CR, showed no predictive value. The median CCR and CCR after 5 years were 17.9 and 31.3%, respectively in pts with CN/Mkneg-NPM1 mutated AML, and 11.3 months and 25% for pts with CBF AML (p<0.001; see figure). In pts with CN/Mkneg and wild type NPM1 AML and Mkpos AML, the median CCR rates were 10.8 and 6.0 months, respectively. Together, our data show that elderly patients with CN/Mkneg-NPM1 mutated AML or CBF AML can achieve long term CCR when treated with intensive chemotherapy and up to 4 consolidation cycles of IDAC, whereas pts with CN/Mkneg-NPM1 wild type AML and Mkpos AML did not achieve long term CCR despite intensive consolidation. These results are in favour of individualized chemotherapy in elderly pts with AML and suggest that patient-selection in advanced age should not only be based on patient-related factors and the karyotype but also on the NPM1 mutation status. Disclosures: No relevant conflicts of interest to declare.

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NPM1 but not FLT3-ITD mutations predict early blast cell clearance and CR rate in patients with normal karyotype AML (NK-AML) or high-risk myelodysplastic syndrome (MDS)

Blood ◽

10.1182/blood-2008-09-172668 ◽

2009 ◽

Vol 113 (21) ◽

pp. 5250-5253 ◽

Cited By ~ 42

Author(s):

Friederike Schneider ◽

Eva Hoster ◽

Michael Unterhalt ◽

Stephanie Schneider ◽

Annika Dufour ◽

...

Keyword(s):

Normal Karyotype ◽

Genetic Alterations ◽

Blast Cell ◽

Npm1 Mutation ◽

Mutation Status ◽

Cell Clearance ◽

Blast Cells ◽

Favorable Clinical Outcome ◽

Induction Cycle

Abstract Mutations in the NPM1 gene represent the most frequent genetic alterations in patients with acute myeloid leukemia (AML) and are associated with a favorable outcome. In 690 normal karyotype (NK) AML patients the complete remission rates (CRs) and the percentage of patients with adequate in vivo blast cell reduction 1 week after the end of the first induction cycle were significantly higher in NPM1+ (75% and 80%, respectively) than in NPM1− (57% and 57%, respectively) patients, but were unaffected by the FLT3-ITD status. Multivariate analyses revealed the presence of a NPM1 mutation as an independent positive prognostic factor for the achievement of an adequate day-16 blast clearance and a CR. In conclusion, NPM1+ blast cells show a high in vivo sensitivity toward induction chemotherapy irrespective of the FLT3-ITD mutation status. These findings provide insight into the pathophysiology and help to understand the favorable clinical outcome of patients with NPM1+ AML.

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