Laboratory of Neuro Oncohematology

Santa Lucia di Serino, Italy

Laboratory of Neuro Oncohematology

Santa Lucia di Serino, Italy
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Breccia M.,University of Rome La Sapienza | Mazzarella L.,Italian National Cancer Institute | Bagnardi V.,Italian National Cancer Institute | Bagnardi V.,University of Milan Bicocca | And 12 more authors.
Blood | Year: 2012

We investigated whether body mass index (BMI) correlates with distinct outcomes in newly diagnosed acute promyelocytic leukemia (APL). The study population included 144 patients with newly diagnosed and genetically confirmed APL consecutively treated at a single institution. All patients received All-trans retinoic acid and idarubicin according to the GIMEMA protocols AIDA-0493 and AIDA-2000. Outcome estimates according to the BMI were carried out together with multivariable analysis for the risk of relapse and differentiation syndrome. Fifty-four (37.5%) were under/normal weight (BMI < 25), whereas 90 (62.5%) patients were overweight/obese (BMI ≥ 25). An increased BMI was associated with older age (P < .0001) and male sex (P = .02). BMI was the most powerful predictor of differentiation syndrome in multivariable analysis (odds ratio = 7.24; 95% CI, 1.50-34; P = .014). After a median follow-up of 6 years, the estimated cumulative incidence of relapse at 5 years was 31.6% (95% CI, 22.7%-43.8%) in overweight/obese and 11.2% (95% CI, 5.3%-23.8%) in underweight/normal weight patients (P = .029). Multivariable analysis showed that BMI was an independent predictor of relapse (hazard ratio = 2.45, 95% CI, 1.00-5.99, in overweight/obese vs under/normal weight patients, P = .049). An increased BMI at diagnosis is associated with a higher risk of developing differentiation syndrome and disease relapse in APL patients treated with AIDA protocols. © 2012 by The American Society of Hematology.

Ramadan S.M.,Cairo University | Ramadan S.M.,University of Rome Tor Vergata | Fouad T.M.,Cairo University | Summa V.,University of Rome Tor Vergata | And 4 more authors.
Haematologica | Year: 2012

Therapy-related acute myeloid leukemia is an unfortunate complication of cancer treatment, particularly for patients with highly curable primary malignancies and favorable life expectancy. The risk of developing therapy-related acute myeloid leukemia also applies to patients with non-malignant conditions, such as autoimmune diseases treated with cytotoxic and/or immunosuppressive agents. There is considerable evidence to suggest that there is an increased occurrence of hematologic malignancies in patients with autoimmune diseases compared to the general population, with a further increase in risk after exposure to cytotoxic therapies. Unfortunately, studies have failed to reveal a clear correlation between leukemia development and exposure to individual agents used for the treatment of autoimmune diseases. Given the dismal outcome of secondary acute myeloid leukemia and the wide range of available agents for treatment of autoimmune diseases, an increased awareness of this risk and further investigation into the pathogenetic mechanisms of acute leukemia in autoimmune disease patients are warranted. This article will review the data available on the development of acute myeloid leukemia in patients with autoimmune diseases. Possible leukemogeneic mechanisms in these patients, as well as evidence supporting the association of their primary immunosuppressive status and their exposure to specific therapies, will also be reviewed. This review also supports the idea that it may be misleading to label leukemias that develop in patients with autoimmune diseases who are exposed to cytotoxic agents as 'therapy-related leukemias'. A better understanding of the molecular defects in autoimmune disease patients who develop acute leukemia will lead to a better understanding of the association between these two diseases entities. © 2012 Ferrata Storti Foundation.

Pelosi A.,Regina Elena Cancer Institute | Careccia S.,Regina Elena Cancer Institute | Lulli V.,Instituto Superiore Of Sanita | Romania P.,Instituto Superiore Of Sanita | And 12 more authors.
Oncogene | Year: 2013

MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression post-transcriptionally, are involved in many complex cellular processes. Several miRNAs are differentially expressed in hematopoietic tissues and play important roles in normal differentiation, but, when aberrantly regulated, contribute to the abnormal proliferation and differentiation of leukemic cells. Recently, we reported that a small subset of miRNAs is differentially expressed in acute promyelocytic leukemia (APL) blasts and is modulated by treatment with all-trans-retinoic acid (ATRA). In particular, PML/RARα-positive blasts from APL patients display lower levels of miRNA let-7c, a member of the let-7 family, than normal promyelocytes and its expression increases after ATRA treatment. In this study, we investigated the effects of let-7c in acute myeloid leukemia (AML) cells. We found that ectopic expression of let-7c promotes granulocytic differentiation of AML cell lines and primary blasts. Moreover, we identified PBX2, a well-known homeodomain protein whose aberrant expression enhances HoxA9-dependent leukemogenesis, as a novel let-7c target that may contribute to the AML phenotype. Together, these studies raise the possibility that perturbation of the let-7c-PBX2 pathway may have a therapeutic value in AML. © 2013 Macmillan Publishers Limited.

Ottone T.,University of Rome Tor Vergata | Ottone T.,Laboratory of Neuro Oncohematology | Zaza S.,University of Rome Tor Vergata | Divona M.,University of Rome Tor Vergata | And 22 more authors.
British Journal of Haematology | Year: 2013

FLT3 internal tandem duplication (ITD) mutations are frequently detected at diagnosis in cytogenetically normal acute myeloid leukaemia (CN-AML) and predict unfavourable outcome. FLT3 ITD is an unstable aberration and may be lost or acquired at relapse. Recent whole genome sequencing studies have suggested that FLT3 ITD+ve AML relapse may evolve from small subclones undetectable at diagnosis by routine polymerase chain reaction (PCR). We developed a patient-specific real-time quantitative-PCR (RQ-PCR) to implement FLT3 ITD detection in six AML patients whose blasts carried wild-type FLT3 at diagnosis and who relapsed with FLT3 ITD by routine PCR. Patient-specific forward primers were designed after cloning and sequencing the FLT3 ITD in each case. The assay allowed retrospective detection of FLT3 ITD in diagnostic samples of 4/6 cases and to establish the kinetics of clonal evolution preceding relapse. After conventional chemotherapy, all patients had early relapse despite having been classified as NPM1+ve/FLT3 ITD-ve at presentation, with shorter remissions being observed in four patients re-classified as FLT3 ITD+ve by the new assay. Notably, FLT3 ITD clone became detectable by conventional PCR in three patients tested during remission after initial treatment. Our data underscore the need of identifying low FLT3 ITD levels, which are probably associated with relapse in otherwise good prognosis CN-AML. © 2013 John Wiley & Sons Ltd.

Breccia M.,University of Rome La Sapienza | Cicconi L.,University of Rome Tor Vergata | Cicconi L.,Laboratory of Neuro Oncohematology | Lo-Coco F.,University of Rome Tor Vergata | Lo-Coco F.,Laboratory of Neuro Oncohematology
Current Opinion in Hematology | Year: 2014

Purpose of review Arsenic trioxide (ATO) has been shown to be the most effective single agent in acute promyelocytic leukaemia (APL) and has been approved for the treatment of relapsed patients both in the US and Europe. The role of ATO in front-line therapy of APL is under investigation. Recent findings Pilot studies using ATO with or without all-trans retinoic acid (ATRA) have been carried out in newly diagnosed APL patients with the aim to reduce the short and long-term toxic effects of chemotherapy and to improve clinical outcome. Especially in patients with non-high-risk APL, the ATRA + ATO approach allowed significant increase in event-free survival and overall survival rates compared to standard ATRA and chemotherapy. This has been demonstrated by pilot studies and, more recently, by a randomized comparative multi-centre study conducted in Italy and Germany. Summary The ATO + ATRA strategy for APL may provide the first paradigm of acute leukaemia curability by targeted agents and without chemotherapy. However, longer follow-up of available studies and independent confirmation of the Italian-German findings are awaited to firmly establish this paradigm. Finally, extension of this approach to other patient categories such as high-risk, elderly and children will need to be explored in the near future. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Breccia M.,University of Rome La Sapienza | Minotti C.,University of Rome La Sapienza | Latagliata R.,University of Rome La Sapienza | Loglisci G.,University of Rome La Sapienza | And 4 more authors.
Leukemia Research | Year: 2013

Despite the impressive results obtained with standard chemotherapy, approximately 20% of acute promyelocytic leukemia (APL) patients undergo disease relapse thereby requiring salvage therapy. Few data is available on long-term prognosis in relation to time to complete remission (CR): we reviewed 142 patients treated with AIDA protocols and we found that 42 out of 142 (29.6%) patients achieved CR after 35 days (median time, 42 days). No significant differences in presenting features, including FAB subtype, type of PML/RARA transcript and relapse risk at presentation between the two patient groups achieving CR > or <35 days were revealed, except for male sex and older age that were significantly associated with delayed CR. Rate of relapse was 31% in patients with delayed CR compared to 17% in the group of patients who achieved CR < 35 days (p=0.001), with a 5-year CIR of 29.6% compared to 12% (p=0.03). APL patients with delayed CR should be more closely monitored during follow-up for early identification of relapse and prompt administration of pre-emptive salvage therapy. © 2012 Elsevier Ltd.

Breccia M.,University of Rome La Sapienza | Coco F.L.,University of Rome Tor Vergata | Coco F.L.,Laboratory of Neuro Oncohematology
Thrombosis Research | Year: 2014

Acute promyelocytic leukemia (APL) has become the most curable form of acute myeloid leukemia after the advent of all-trans retinoic acid (ATRA). However, early deaths (ED) mostly due to the disease-associated coagulopathy remain the major cause of treatment failure. In particular, hemorrhagic events account for 40-65% of ED and several prognostic factors have been identified for such hemorrhagic deaths, including poor performance status, high white blood cell (WBC) count and coagulopathy. Occurrence of thrombosis during treatment with ATRA may be associated with differentiation syndrome (DS) or represent an isolated event. Some prognostic factors have been reported to be associated with thrombosis, including increased WBC or aberrant immunophenotype of leukemic promyelocytes. Aim of this review is to report the incidence, severity, possible pathogenesis and clinical manifestations of thrombo-haemorrhagic deaths in APL. © 2014 Elsevier Ltd. All rights reserved. © 2014 Elsevier Ltd.

Testa U.,Instituto Superiore Of Sanita | Lo-Coco F.,University of Rome Tor Vergata | Lo-Coco F.,Laboratory of Neuro Oncohematology
Annals of Hematology | Year: 2016

All trans retinoic acid (ATRA) has revolutionized the therapy of acute promyelocytic leukemia (APL). Treatment of this leukemia with ATRA in combination with chemotherapy has resulted in complete remission rates >90 % and long-term remission rates above 80 %. Furthermore, the combination of ATRA and arsenic trioxide (ATO) was shown to be safe and effective in frontline treatment and, for patients with low and intermediate risk disease, possibly superior to the standard ATRA and anthracycline-based regimen. However, in spite of this tremendous progress, APL still remains associated with a high incidence of early death due to the frequent occurrence of an abrupt bleeding diathesis. This hemorrhagic syndrome more frequently develops in high-risk APL patients, currently defined as those exhibiting >10 × 109/L WBC at presentation. In addition to high WBC count, other molecular and immunophenotypic features have been associated with high-risk APL. Among them, the expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2 help to identify a subset of patients at higher risk of relapse and often the expression of these markers is associated with high WBC count. At the molecular level, the short PML/RARA isoform and FLT3-internal tandem duplication (ITD) mutations have been associated with increased relapse risk. These observations indicate that extended immunophenotypic and molecular characterization of APL at diagnosis including evaluation of CD2, CD56, and CD34 antigens and of FLT3 mutations may help to better design risk-adapted treatment in this disease. © 2016 Springer-Verlag Berlin Heidelberg

Lo-Coco F.,University of Rome Tor Vergata | Lo-Coco F.,Laboratory of Neuro Oncohematology | Latagliata R.,University of Rome La Sapienza | Breccia M.,University of Rome La Sapienza
Mediterranean Journal of Hematology and Infectious Diseases | Year: 2013

Unlike other forms of AML, APL is less frequently diagnosed in the elderly and has a relatively favourable outcome. Elderly patients with APL seem at least as responsive to therapy as do younger patients, but rates of response and survival are lower in this age setting owing to a higher incidence of early deaths and deaths in remission when conventional treatment with ATRA and chemotherapy is used. Elderly APL patients are more likely to present with low-risk features compared with younger patients, and this may explain the relative low risk of relapse reported in several clinical studies. Alternative approaches, such as arsenic trioxide and gentuzumab ozogamicin have been tested with success in this setting and could replace in the near future frontline conventional chemotherapy and ATRA.

PubMed | Laboratory of Neuro Oncohematology
Type: | Journal: Journal of hematology & oncology | Year: 2012

MicroRNA have a central role in normal haematopoiesis and are deregulated in acute myeloid leukaemia (AML). The purpose of the study was to investigate by qRT-PCR the expression of miRNAs involved in myeloid differentiation (miR-424, miR-155, miR-223, miR-17-5p) in 48 patients with cytogenetically normal AML well characterized for NPM1 and/or FLT3 mutations. Three types of normalization were used for the data validation.We found that miR-424 was down-modulated in AMLs with NPM1mutA regardless of FLT3 status. On the contrary, miR-155 showed up-regulation in patients with FLT3 internal tandem duplications (ITD) with or without NPM1 mutations. No significant associations were found by analyzing miR-223 and miR-17-5p in relation to FLT3 and NPM1 status.This study supports the view that major genetic subsets of CN-AML are associated with distinct miRNA signatures and suggests that miR-424 and miR-155 deregulation is involved in the pathogenesis of CN-AML with NPM1 and FLT3-ITD mutations, respectively.

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