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Dive into the research topics where Daniela Pietra is active.

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Featured researches published by Daniela Pietra.


The New England Journal of Medicine | 2013

Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms

Thorsten Klampfl; Heinz Gisslinger; Ashot S. Harutyunyan; Harini Nivarthi; Elisa Rumi; Jelena D. Milosevic; Nicole C.C. Them; Tiina Berg; Bettina Gisslinger; Daniela Pietra; Doris Chen; Gregory I. Vladimer; Klaudia Bagienski; Chiara Milanesi; Ilaria Casetti; Emanuela Sant'Antonio; Ferretti; Chiara Elena; Fiorella Schischlik; Ciara Cleary; Six M; Martin Schalling; Andreas Schönegger; Christoph Bock; Luca Malcovati; Cristiana Pascutto; Giulio Superti-Furga; Mario Cazzola; Robert Kralovics

BACKGROUND Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients. METHODS We performed whole-exome sequencing to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Resequencing of CALR, encoding calreticulin, was then performed in cohorts of patients with myeloid neoplasms. RESULTS Somatic insertions or deletions in exon 9 of CALR were detected in all patients who underwent whole-exome sequencing. Resequencing in 1107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. In essential thrombocythemia and primary myelofibrosis, CALR mutations and JAK2 and MPL mutations were mutually exclusive. Among patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 or MPL, CALR mutations were detected in 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis. A total of 36 types of insertions or deletions were identified that all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2. CONCLUSIONS Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F mutation. (Funded by the MPN Research Foundation and Associazione Italiana per la Ricerca sul Cancro.).


Leukemia | 2013

Mutations and prognosis in primary myelofibrosis

Alessandro M. Vannucchi; Terra L. Lasho; Paola Guglielmelli; Flavia Biamonte; Animesh Pardanani; Arturo Pereira; Christy Finke; Joannah Score; Naseema Gangat; Carmela Mannarelli; Rhett P. Ketterling; Giada Rotunno; Ryan A. Knudson; Maria Chiara Susini; Rebecca R. Laborde; Ambra Spolverini; Alessandro Pancrazzi; Lisa Pieri; Rossella Manfredini; Enrico Tagliafico; Roberta Zini; Amy V. Jones; Katerina Zoi; Andreas Reiter; Andrew S Duncombe; Daniela Pietra; Elisa Rumi; Francisco Cervantes; Giovanni Barosi; M Cazzola

Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; P<0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P=0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations. Mutational profiling for ASXL1, EZH2, SRSF2 and IDH identifies PMF patients who are at risk for premature death or leukemic transformation.


Blood | 2014

JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes

Elisa Rumi; Daniela Pietra; Virginia Valeria Ferretti; Thorsten Klampfl; Ashot S. Harutyunyan; Jelena D. Milosevic; Nicole C.C. Them; Tiina Berg; Chiara Elena; Ilaria Casetti; Chiara Milanesi; Emanuela Sant’Antonio; Marta Bellini; Elena Fugazza; Maria C. Renna; Emanuela Boveri; Cesare Astori; Cristiana Pascutto; Robert Kralovics; Mario Cazzola

Patients with essential thrombocythemia may carry JAK2 (V617F), an MPL substitution, or a calreticulin gene (CALR) mutation. We studied biologic and clinical features of essential thrombocythemia according to JAK2 or CALR mutation status and in relation to those of polycythemia vera. The mutant allele burden was lower in JAK2-mutated than in CALR-mutated essential thrombocythemia. Patients with JAK2 (V617F) were older, had a higher hemoglobin level and white blood cell count, and lower platelet count and serum erythropoietin than those with CALR mutation. Hematologic parameters of patients with JAK2-mutated essential thrombocythemia or polycythemia vera were related to the mutant allele burden. While no polycythemic transformation was observed in CALR-mutated patients, the cumulative risk was 29% at 15 years in those with JAK2-mutated essential thrombocythemia. There was no significant difference in myelofibrotic transformation between the 2 subtypes of essential thrombocythemia. Patients with JAK2-mutated essential thrombocythemia and those with polycythemia vera had a similar risk of thrombosis, which was twice that of patients with the CALR mutation. These observations are consistent with the notion that JAK2-mutated essential thrombocythemia and polycythemia vera represent different phenotypes of a single myeloproliferative neoplasm, whereas CALR-mutated essential thrombocythemia is a distinct disease entity.


Leukemia | 2010

A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications

Francesco Passamonti; Elisa Rumi; Daniela Pietra; Chiara Elena; Emanuela Boveri; Luca Arcaini; E Roncoroni; Cesare Astori; Michele Merli; Sabrina Boggi; Cristiana Pascutto; Mario Lazzarino; Mario Cazzola

We studied the relationship between JAK2 (V617F) mutant allele burden and clinical phenotype, disease progression and survival in patients with polycythemia vera (PV). The percentage of granulocyte mutant alleles was evaluated using a quantitative real-time polymerase chain reaction-based allelic discrimination assay. Of the 338 patients enrolled in this prospective study, 320 (94.7%) carried the JAK2 (V617F) mutation. Direct relationships were found between mutant allele burden and hemoglobin concentration (P=0.001), white blood cell count (P=0.001), spleen size (P=0.001) and age-adjusted bone marrow cellularity (P=0.002), while an inverse relationship was found with platelet count (P<0.001). During the study period, eight patients progressed to post-PV myelofibrosis (MF) (all carrying >50% mutant alleles), while 10 patients developed acute myeloid leukemia (AML). The mutant allele burden was significantly related to the risk of developing myelofibrosis (P=0.029) and retained its significant effect also in multivariable analysis (P=0.03). By contrast, the risk of developing AML as well as that of thrombosis was not significantly related to mutant allele burden. Leukocytosis did not affect thrombosis, MF, leukemia or survival. In conclusion, a JAK2 (V617F) allele burden >50% represents a risk factor for progression to MF in PV.


Haematologica | 2008

Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients

Francesco Passamonti; Elisa Rumi; Luca Arcaini; Emanuela Boveri; Chiara Elena; Daniela Pietra; Sabrina Boggi; Cesare Astori; Paolo Bernasconi; Marzia Varettoni; Ercole Brusamolino; Cristiana Pascutto; Mario Lazzarino

The findings from this study on a large series of patients treated according to current clinical practice provide reassurance that essential thrombocythemia is an indolent disorder and affected patients have a long survival. Background Essential thrombocythemia is a chronic myeloproliferative disorder; patients with this disorder have a propensity to develop thrombosis, myelofibrosis, and leukemia. Design and Methods We studied 605 patients with essential thrombocythemia (follow-up 4596 person-years) with the aim of defining prognostic factors for thrombosis, myelofibrosis, and leukemia during follow-up. Results Sixty-six patients (11%) developed thrombosis with a 10-year risk of 14%. Age >60 years (p<0.001) and a history of thrombosis (p=0.03) were independent risk factors for thrombosis. Progression to myelofibrosis occurred in 17 patients (2.8%) with a 10-year risk of 3.9%. Anemia at diagnosis of essential thrombocythemia was significantly correlated (p<0.001) with progression to myelofibrosis. Leukemia occurred in 14 patients (2.3%) at a median time of 11 years after the diagnosis of essential thrombocythemia; the risk was 2.6% at 10 years. Age >60 years (p=0.02) was significantly correlated with the development of leukemia. Cytotoxic treatment did not imply a higher risk of leukemia. At the time of the analysis, 64 of the 605 patients (10.6%) had died. The 10-year probability of survival was 88%, with a median survival of 22.3 years. Age >60 years (p<0.001) and history of thrombosis (p=0.001) were independent risk factors for survival. Conclusions The findings from this study on a large series of patients treated according to current clinical practice provide reassurance that essential thrombocythemia is an indolent disorder and affected patients have a long survival. The main risk is thrombosis, while myelofibrosis and leukemia are rare and late complications.


Blood | 2014

Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis

Elisa Rumi; Daniela Pietra; Cristiana Pascutto; Paola Guglielmelli; Alejandra Martínez-Trillos; Ilaria Casetti; Dolors Colomer; Lisa Pieri; Marta Pratcorona; Giada Rotunno; Emanuela Sant’Antonio; Marta Bellini; Chiara Cavalloni; Carmela Mannarelli; Chiara Milanesi; Emanuela Boveri; Virginia Valeria Ferretti; Cesare Astori; Vittorio Rosti; Francisco Cervantes; Giovanni Barosi; Alessandro M. Vannucchi; Mario Cazzola

We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.


Journal of Clinical Oncology | 2009

Clinical Relevance of Bone Marrow Fibrosis and CD34-Positive Cell Clusters in Primary Myelodysplastic Syndromes

Matteo G. Della Porta; Luca Malcovati; Emanuela Boveri; Erica Travaglino; Daniela Pietra; Cristiana Pascutto; Francesco Passamonti; Rosangela Invernizzi; Alessandro Castello; Umberto Magrini; Mario Lazzarino; Mario Cazzola

PURPOSE We studied bone marrow (BM) histologic abnormalities in myelodysplastic syndromes (MDS) classified according to WHO criteria to determine their clinical correlates and prognostic value. PATIENTS AND METHODS Three hundred one consecutive patients were retrospectively evaluated for BM fibrosis and CD34 immunoreactivity. Marrow fibrosis was assessed following the European consensus guidelines. RESULTS Moderate to severe BM fibrosis was detected in 17% of cases and was associated with multilineage dysplasia (P = .001), high transfusion requirement (P < .001), and poor-risk cytogenetics (P = .007). CD34+ cell clusters were found in 23% of patients and were associated with WHO categories with excess of blasts (P < .001) and poor-risk cytogenetics (P = .001). In multivariable analysis, BM fibrosis and presence of CD34+ cell clusters had independent negative impact on overall survival (P < .001 and P = .019, respectively) and leukemia-free survival (P < .001 and P = .004, respectively). A hierarchical clustering analysis identified three subsets of patients with distinct clinical features. One cluster consisted mainly of patients with BM fibrosis, multilineage dysplasia, and high transfusion requirement; these individuals had lower overall survival and leukemia-free survival (P = .001 and P < .001, respectively). Within patients stratified according to International Prognostic Scoring System and WHO classification-based Prognostic Scoring System categories, BM fibrosis involved a shift to a one-step more advanced risk group. CONCLUSION BM fibrosis identifies a distinct subgroup of MDS with multilineage dysplasia, high transfusion requirement, and poor prognosis and represents an independent prognostic factor that may be useful in clinical decision making. Furthermore, the presence of CD34+ cell clusters is an independent risk factor for progression to acute leukemia.


Blood | 2011

Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations.

Francesco Passamonti; Chiara Elena; Susanne Schnittger; Radek C. Skoda; Anthony R. Green; François Girodon; Jean-Jacques Kiladjian; Mary Frances McMullin; Marco Ruggeri; Carles Besses; Alessandro M. Vannucchi; Eric Lippert; Heinz Gisslinger; Elisa Rumi; Thomas Lehmann; Christina A. Ortmann; Daniela Pietra; Cristiana Pascutto; Torsten Haferlach; Mario Cazzola

Although approximately 95% of patients with polycythemia vera (PV) harbor the V617F mutation in JAK2 exon 14, several mutations in exon 12 have been described in the remaining patients. We conducted a European collaborative study to define the molecular and clinical features of patients harboring these mutations. Overall, 106 PVs were recruited and 17 different mutations identified. Irrespective of the mutation, two-thirds of patients had isolated erythrocytosis, whereas the remaining subjects had erythrocytosis plus leukocytosis and/or thrombocytosis. Compared with JAK2 (V617F)-positive PV patients, those with exon 12 mutations had significantly higher hemoglobin level and lower platelet and leukocyte counts at diagnosis but similar incidences of thrombosis, myelofibrosis, leukemia, and death. In a multivariable analysis, age more than 60 years and prior thrombosis predicted thrombosis. These findings suggest that, despite the phenotypical difference, the outcome of JAK2 exon 12 mutations-positive PV is similar to that of JAK2 (V617F)-positive PV.


Leukemia | 2014

The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients

Paola Guglielmelli; Terra L. Lasho; Giada Rotunno; Joannah Score; Carmela Mannarelli; Alessandro Pancrazzi; Flavia Biamonte; Animesh Pardanani; Katerina Zoi; Andreas Reiter; Andrew S Duncombe; Tiziana Fanelli; Daniela Pietra; Elisa Rumi; Christy Finke; Naseema Gangat; Rhett P. Ketterling; Ryan A. Knudson; Curt A. Hanson; Alberto Bosi; Arturo Pereira; Rossella Manfredini; Francisco Cervantes; Giovanni Barosi; Marie Cazzola; Nicholas C.P. Cross; Alessandro M. Vannucchi; Ayalew Tefferi

We recently defined a high-molecular risk category (HMR) in primary myelofibrosis (PMF), based on the presence of at least one of the five ‘prognostically detrimental’ mutated genes (ASXL1, EZH2, SRSF2 and IDH1/2). Herein, we evaluate the additional prognostic value of the ‘number’ of mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo Clinic (n=260). In the European cohort, 167 (31%) patients were HMR: 127 (23.6%) had one and 40 (7.4%) had two or more mutated genes. The presence of two or more mutations predicted the worst survival: median 2.6 years (hazard ratio (HR) 3.8, 95% confidence interval (CI) 2.6–5.7) vs 7.0 years (HR 1.9, 95% CI 1.4–2.6) for one mutation vs 12.3 years for no mutations. The results were validated in the Mayo cohort and prognostic significance in both cohorts was independent of International Prognostic Scoring System (IPSS; HR 2.4, 95% CI 1.6–3.6) and dynamic IPSS (DIPSS)-plus (HR 1.9, 95% CI 1.2–3.1), respectively. Two or more mutations were also associated with shortened leukemia-free survival (HR 6.2, 95% CI 3.5–10.7), also Mayo validated. Calreticulin mutations favorably affected survival, independently of both number of mutations and IPSS/DIPSS-plus. We conclude that the ‘number’ of prognostically detrimental mutations provides added value in the combined molecular and clinical prognostication of PMF.


Blood | 2015

SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts

Luca Malcovati; Mohsen Karimi; Elli Papaemmanuil; Ilaria Ambaglio; Martin Jädersten; Monika Jansson; Chiara Elena; Anna Gallì; Gunilla Walldin; Matteo G. Della Porta; Klas Raaschou-Jensen; Erica Travaglino; Klaus Kallenbach; Daniela Pietra; Viktor Ljungström; Simona Conte; Emanuela Boveri; Rosangela Invernizzi; Richard Rosenquist; Peter J. Campbell; Mario Cazzola; Eva Hellström Lindberg

Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P < .001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ratio [HR], .37; P = .003) and lower cumulative incidence of disease progression (HR = 0.31; P = .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P = .015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome.

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Robert Kralovics

Austrian Academy of Sciences

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