Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1419-1422 ◽  
Author(s):  
Giovanni Cazzaniga ◽  
Maria Grazia Dell'Oro ◽  
Cristina Mecucci ◽  
Emanuela Giarin ◽  
Riccardo Masetti ◽  
...  
Keyword(s):  
Residual Disease ◽  
Normal Karyotype ◽  
Myelogenous Leukemia ◽  
Potential Candidate ◽  
Npm1 Mutation ◽  
Reading Frame ◽  
Targeted Treatments ◽  
Acute Myelogenous ◽  
Childhood Aml ◽  
French American British

AbstractNucleophosmin (NPM) is a nucleocytoplasmic shuttling protein involved in leukemia-associated chromosomal translocations, and it regulates the alternate reading frame (ARF)-p53 tumorsuppressor pathway. Recently, it has been demonstrated that mutations of the NPM1 gene alter the protein at its C-terminal, causing its cytoplasmic localization. Cytoplasmic NPM was detected in 35% of adult patients with primary non-French-American-British (FAB) classification M3 acute myeloid leukemia (AML), associated mainly with normal karyotype. We evaluated the prevalence of the NPM1 gene mutation in non-M3 childhood AML patients enrolled in the ongoing Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP-AML02) protocol in Italy. NPM1 mutations were found in 7 (6.5%) of 107 successfully analyzed patients. NPM1- mutated patients carried a normal karyotype (7/26, 27.1%) and were older in age. Thus, the NPM1 mutation is a frequent abnormality in AML patients without known genetic marker; the mutation may represent a new target to monitor minimal residual disease in AML and a potential candidate for alternative and targeted treatments. (Blood. 2005;106:1419-1422)

Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype

2005 ◽  
Vol 352 (3) ◽  
pp. 254-266 ◽  
Author(s):  
Brunangelo Falini ◽  
Cristina Mecucci ◽  
Enrico Tiacci ◽  
Myriam Alcalay ◽  
Roberto Rosati ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Normal Karyotype ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous

Experience With 2-Chlorodeoxyadenosine in Previously Untreated Children With Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic Diseases

2001 ◽  
Vol 19 (11) ◽  
pp. 2804-2811 ◽  
Author(s):  
R. A. Krance ◽  
C. A. Hurwitz ◽  
D. R. Head ◽  
S. C. Raimondi ◽  
F. G. Behm ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Myelogenous Leukemia ◽  
Remission Induction ◽  
Allogeneic Bone ◽  
Event Free Survival ◽  
Free Survival ◽  
Secondary Aml ◽  
Acute Myelogenous ◽  
French American British

PURPOSE: To develop more effective chemotherapy regimens for childhood acute myelogenous leukemia (AML). PATIENTS AND METHODS: Between June 1991 and December 1996, we administered the nucleoside analog 2-chlorodeoxyadenosine (2-CDA) to 73 children with primary AML and 20 children with secondary AML or myelodysplastic syndrome (MDS). Patients received one or two 5-day courses of 2-CDA (8.9 mg/m2/d) given by continuous infusion. All patients then received one to three courses of daunomycin, cytarabine, and etoposide (DAV) remission induction therapy. RESULTS: Seventy-two patients with primary AML were assessable for response. Their rate of complete remission (CR) was 24% after one course of 2-CDA, 40% after two courses of 2-CDA, and 78% after DAV therapy. Of the 57 patients who entered CR, 11 subsequently underwent allogeneic bone marrow transplantation (BMT), and 40 underwent autologous BMT. Twenty-nine patients remain in continuous CR after BMT. Two patients remain in CR after chemotherapy only. The 5-year event-free survival (EFS) estimate was 40% (SE = 0.080%). Patients with French-American-British (FAB) M5 AML had a higher rate of CR after treatment with 2-CDA (45% after one course and 70.6% after two courses) than did others (P = .002). In contrast, no patient with FAB M7 AML (n = 10) entered CR after treatment with 2-CDA. Similarly, no patient with primary MDS (n = 6) responded to 2-CDA. Seven patients with secondary AML or MDS (n = 14) had a partial response to one course of 2-CDA. CONCLUSION: This agent was well tolerated, and its toxicity was acceptable. Future trials should examine the effectiveness of 2-CDA given in combination with other agents effective against AML.

Evaluation of Minimal Residual Disease Based on NPM1 Mutations in AML with Intermediate Risk Cytogenetics: A Prospective Study of 36 Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2847-2847
Author(s):  
Aline Renneville ◽  
Florence Pasquier ◽  
Selim Corm ◽  
Nathalie Philippe ◽  
Charikleia Kelaidi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Genomic Dna ◽  
Residual Disease ◽  
Normal Karyotype ◽  
Intermediate Risk ◽  
Npm1 Mutation ◽  
Log Reduction ◽  
Minimal Residual

Abstract Mutations in exon 12 of the nucleophosmin (NPM1) gene occur in approximately 50% of adult acute myeloid leukemia (AML) with normal karyotype. More than 40 mutant variants have been identified. Most of these mutations consist of a 4-bp insertion, which can be used as a target for minimal residual disease (MRD) monitoring. We previously checked the stability of NPM1 mutations at relapse in 21 NPM1-mutated patients at initial diagnosis. In this prospective study, we evaluated MRD by real-time quantitative PCR (RQ-PCR) in 36 NPM1-mutated AML patients corresponding to 33 adult and 3 pediatric cases, treated according to the French ALFA9801 or ALFA9802 and ELAM02 protocols, respectively. Out of these patients, 31/34 (91%) had normal karyotype, 13/33 (39%) had a high initial white blood cell count, and 10/36 (28%) were FLT3-Intern Tandem Duplication (FLT3-ITD) positive. 28 (78%) patients carry NPM mutation A, 3 (8%) mutation B and 5 (14%) other rare variants. RQ-PCR assays using a mutation-specific primer were performed on cDNA for mutation A and B and on genomic DNA for other NPM1 mutants. In our experiments, the maximal reproductible sensitivity of NPM1-based MRD detection is about 10−4 on genomic DNA and 10−5 to 10−6 on cDNA. The median follow-up was 260 days [40–791]. 2 to 9 follow-up samples from bone marrow and/or peripheral blood were analysed per patient. No correlation was found between leukocytosis at diagnosis and initial expression ratio of NPM1 mutation. The study of MRD log reduction after induction therapy shows that molecular responses are very heterogeneous (from 4.10−2 to more than 1.10−5), but 50% of patients reach at least a 4 log reduction in NPM1 levels. Patients with FLT3-ITD tend to have lower log reduction after induction than patients without FLT3-ITD, although not statistically significant (P=0.07). The analysis of NPM1-MRD in bone marrow and in peripheral blood at the same follow-up time-points shows that NPM1 levels can be until 1 log higher in bone marrow. This indicates that the evaluation of NPM1-MRD in bone marrow is more informative than in peripheral blood. We found all relapses had NPM1-MRD levels comparable to those observed at diagnosis. Among the 5 patients who relapsed so far, 2 were predictable by increasing MRD levels 1 to 4 months before hematological relapse. In 29 out of 36 cases, we could monitor MRD by both NPM1 mutation and WT1 gene expression. The comparison of the MRD profiles obtained by these two approaches reveals some discordant results, which can be, at least in part, explained by difference in the sensitivity of the RQ-PCR techniques, since the sensitivity of WT1 expression as MRD target is generally not higher than 10−3. In conclusion, NPM1 mutations are very specific and sensitive markers for MRD monitoring in AML. Further studies are required to determine if NPM1-MRD provides an independent prognostic factor and may be useful for therapeutic stratification in AML patients with intermediate risk cytogenetics.

Mutation in the Nucleophosmin Gene (NPM1) Is a Stable Marker for Minimal Residual Disease Monitoring in Acute Myeloid Leukemia Patients with Increased Sensitivity and Specificity Compared to Expression of the Wilms Tumor (WT1) Gene.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1602-1602
Author(s):  
Thomas Kristensen ◽  
Birgitte Strange Preiss ◽  
Lone Friis ◽  
Michael B. Møller
Keyword(s):  
Gene Expression ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Wilms Tumor ◽  
Normal Karyotype ◽  
Leukemia Cells ◽  
Mutational Load ◽  
Wt1 Gene ◽  
Npm1 Mutation ◽  
Minimal Residual

Abstract Abstract 1602 Poster Board I-628 Mutation in exon 12 of the nucleophosmin (NPM1) gene occurs in approximately 60% of acute myeloid leukemia (AML) patients with normal karyotype. To date, molecular minimal residual disease (MRD) monitoring in this patient group has primarily been based on expression of the Wilms tumor gene (WT1), although expression of WT1 in non-leukemia cells limits the specificity of this marker. Mutation in the NPM1 gene is potentially a superior MRD marker compared to WT1 gene expression by being specific to the malignant clone. The use of NPM1 mutation as a MRD marker would furthermore be in line with the widespread use of leukemia cell specific fusion-genes as MRD markers in AML patients with balanced translocations. In the present study, we therefore evaluated NPM1 mutation as a MRD marker with respect to stability, sensitivity and specificity in direct comparison to WT1 gene expression. A total of 13 relapsed AML patients with normal karyotype that were positive for mutation in NPM1 and WT1 gene expression at the time of diagnosis were included in the study. The NPM1 mutational load and WT1 gene expression was analyzed by real-time qPCR in up to 22 peripheral blood mononuclear cell samples per patient from the time of primary diagnosis to latest follow-up to compare the kinetics of the two markers during periods of morphological remission and relapse events. The 13 patients experienced a total of 18 morphological relapses which were all accompanied by high levels of NPM1 mutation, along with high WT1 mRNA levels, thus demonstrating complete stability of NPM1 mutation during relapse in the present material. During periods of complete morphological remission, the NPM1 mutational load was below detection limit (< 1/1000 cells) in all samples. In contrast, WT1 gene expression was detectable in 70% of these samples, thus demonstrating the limited specificity of this marker. This background WT1 expression in non-leukemia cells reached levels of up to 1% of the levels detected at the time of diagnosis thus limiting the de facto MRD marker sensitivity of WT1. All samples with detectable levels of NPM1 mutation after a period of complete molecular remission were followed by a morphological relapse within weeks. The present study therefore shows that mutation in NPM1 is a stable and more sensitive and specific, and therefore superior, molecular MRD marker than WT1. Disclosures No relevant conflicts of interest to declare.

A Phase II Expansion Study Of Vorinostat In Combination With Idarubicin and Cytarabine For Patients With Acute Myelogenous Leukemia (AML) With FLT3 Molecular Alterations

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2684-2684 ◽  
Author(s):  
Koichi Takahashi ◽  
Elias Jabbour ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Response Rate ◽  
De Novo ◽  
Phase Ii Study ◽  
High Response Rate ◽  
Myelogenous Leukemia ◽  
Abnormal Karyotype ◽  
Npm1 Mutation ◽  
Acute Myelogenous

Abstract Background The combination of vorinostat, idarubicin and cytarabine (IA+vorinostat) is associated with high response rate in patients with newly diagnosed acute myelogenous leukemia (AML) or higher-risk myelodysplastic syndromes (MDS) (JCO 2012;30:2204). In that study, presence of FLT3-ITD was associated with 100% overall response rate (ORR) in 11 patients. To confirm the efficacy of this combination, we extended the phase II study to treat 2 additional cohorts: one for patients with newly diagnosed (untreated cohort) and the other with relapsed and refractory (R/R cohort) AML or higher-risk MDS with FLT3 alteration (both ITD and D835 mutation). Methods Patients with the above diagnosis, ages 15 to 65 years, with appropriate organ function (measured cardiac ejection fraction ≥ 50%, serum creatinine ≤ 2 mg/dl, total bilirubin ≤ 2 mg/dl, and GPT/GOT ≤ 2.5 x upper limit of normal) whose eastern cooperative group (ECOG) defined performance status ≤ 2 were eligible for the study. Study treatment comprised of vorinostat 500 mg orally three times a day (days 1 to 3), idarubicin 12 mg/m2 intravenously (IV) daily x 3 days (days 4 to 6), and cytarabine 1.5 g/m2 IV as a continuous infusion daily x 3 - 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy with lower dose combination and up to 12 months of maintenance therapy with single-agent vorinostat. Result Untreated cohort included 26 patients, whereas 13 patients were treated in R/R cohort (total 39 patients). Thirty six patients had de novo AML, 1 had de novo MDS and 2 had therapy-related AML. For the R/R patients, the median number of prior therapies was 3 (range: 1-6). The median age of the entire study group was 49 (range: 19-64) and 17 (44%) were male. Among the patients whose cytogenetic result were available, 20 (51%) patients had normal and 15 (39%) had abnormal karyotype. By Medical Research Council (MRC) criteria, 30 (77%) patients had intermediate risk and 9 (23%) had poor risk karyotype. Thirty three (85%) patients had FLT3-ITD only, 4 (10%) had both FLT3-ITD and D835 mutation, and 2 (5%) had D835 mutation only. Seventeen (44%) patients had NPM1 mutation. In untreated cohort (N = 26), CR and CRp were documented in 21 (80%) and 2 (8%) patients, respectively (ORR = 88%). In R/R cohort (N = 13), overall response (OR) was observed in 4 (30%) patients (CR in 2 [15%] and CRp in 2[15%]). Of those 4 patients who had OR in R/R cohort, 2 patients were refractory to other high-dose cytarabine-based regimen. The median duration of CR or CRp was 9.2 months (range: 0.1-48.4) in untreated cohort and was 2.9 months (range: 1.6-4.7) in R/R cohort. Twelve (46%) patients in the untreated cohort were bridged to stem cell transplant (SCT) while they were in 1st CR. None of the patients in R/R cohort were bridged to SCT. No difference in response was observed in 1) younger (Age < 60) vs. older patients, 2) normal vs. abnormal karyotype, 3) intermediate vs. poor risk cytogenetics by MRC criteria, 4) presence of RAS mutation, 5) presence of NPM1 mutation, or 6) de novo vs. therapy-related disease. The median overall survival (OS) was 21.7 months (95% CI: 8.1-35.3) in the untreated cohort and was 4.9 months (95% CI: 0.1-10.4) in the R/R cohort. Early treatment related mortality (defined by the death within 4 weeks of the induction) was documented in 1 (4%) patient in the untreated cohort and 2 (15%) patients in the R/R cohort. Toxicity profiles were similar to that reported in the original phase II study (JCO 2012;30:2204). Discussion Vorinostat in combination with IA provides high response rate and durable remission in previously untreateed AML or higher risk MDS patients with FLT3 alteration but is less effective in patients with R/R disease. Phase III randomized study of IA+/- vorinostat in previously untreated AML patients is ongoing (SWOG S1203). Disclosures: Off Label Use: vorinostat in MDS and AML. Cortes:Ambit: Research Funding; Astellas: Research Funding; Argo: Research Funding; Novartis: Research Funding.

scholarly journals The myth of the second remission of acute leukemia in the adult

Blood ◽  
2013 ◽  
Vol 121 (7) ◽  
pp. 1077-1082 ◽  
Author(s):  
Stephen J. Forman ◽  
Jacob M. Rowe
Keyword(s):  
Acute Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Transplantation ◽  
Myelogenous Leukemia ◽  
Curative Therapy ◽  
Successful Transplantation ◽  
Acute Myelogenous ◽  
First Remission ◽  
First Relapse

Abstract Although the majority of adult patients with both acute lymphoblastic leukemia and acute myelogenous leukemia achieve remission with upfront chemotherapy, many patients still suffer relapse. Often, the strategy is proposed of treating patients with relapsed leukemia into a second remission (CR2) and then proceeding to allogeneic transplantation as the definitive curative approach. However, the long-term outcomes of such a strategy are poor: the 5-year overall survival from first relapse for patients with acute leukemia is only approximately 10%. This Perspective highlights the fact that most patients do not achieve CR2 and therefore never really have an opportunity for a potential curative therapy. Although patients who undergo transplantation after relapse may be cured, those who do not achieve CR2 are rarely candidates for transplantation; therefore, the overall outcome for patients who relapse is dismal. There is therefore an urgent need not only for more effective upfront therapy to prevent relapse, but also for the development of therapies that can serve as effective bridging treatments between relapse and transplantation. We suggest that more optimal use of minimal residual disease detection during first remission may also improve the chances for successful transplantation therapy via earlier reinduction therapy, allowing transplantation before overt relapse.

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