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Maria Teresa Voso,
Massimo Breccia,
Monia Lunghi,
Antonella Poloni,
Pasquale Niscola,
Carlo Finelli,
Alessia Bari,
Pellegrino Musto,
Renato Zambello, Luana Fianchi,
Giuliana Alimena,
Giuseppe Leone
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ABSTRACT: In patients with myelodysplastic syndromes (MDS), the likelihood of having a sustained response to azacitidine is increased by maximizing treatment duration. This is important as prognosis post-relapse is poor. There is also the concern that early termination of treatment may result in rapid disease progression. We reviewed outcomes in 13 patients who discontinued azacitidine (decitabine in one patient), while still responding to the treatment. Most patients rapidly relapsed; median time to progression was 5.4 months. Reasons for treatment discontinuation included comorbidities, infections and patient choice. These findings illustrate the risk of prematurely terminating azacitidine therapy in MDS. © 2013 John Wiley & Sons A/S.
European Journal Of Haematology 01/2013; · 2.61 Impact Factor
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Massimo Breccia, Luana Fianchi,
Monia Lunghi,
Gianluca Gaidano,
Alessandro Levis,
Carlo Finelli,
Valeria Santini,
Pellegrino Musto,
Giovanna Mansueto,
Esther N Oliva,
Pietro Leoni,
Antonietta Aloe Spiriti,
Stefan Hohaus,
Giuseppe Leone,
Giuliana Alimena,
Maria Teresa Voso
Leukemia & lymphoma 11/2012; · 2.40 Impact Factor
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Luana Fianchi,
Marianna Criscuolo,
Monia Lunghi,
Gianluca Gaidano,
Massimo Breccia,
Alessandro Levis,
Carlo Finelli,
Valeria Santini,
Pellegrino Musto,
Esther N Oliva,
Pietro Leoni,
Antonietta Aloe Spiriti,
Francesco D'Alò,
Stefan Hohaus,
Livio Pagano,
Giuseppe Leone,
Maria Teresa Voso
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ABSTRACT: Therapy-related myeloid neoplasms (t-MN), including myelodysplastic syndromes and acute myeloid leukemia (t-MDS and t-AML) are associated to clinical and biologic unfavorable prognostic features, including high levels of DNA methylation.
We retrospectively evaluated 50 t-MN patients (34 MDS and 16 AML) selected among all patients receiving azacitidine (AZA) at 10 Italian Hematology Centers. Patients had developed a t-MN at a median of 6.5 years (range 1.7- 29) after treatment of the primary tumor (hematological neoplasm, 27 patients; solid tumor, 23 patients).
The overall response rate was 42% (complete remission: 10 patients, partial remission: 2 and hematological improvement: 8 patients) and was obtained after a median of 3 cycles (range 1-6). Median overall survival (OS) was 21 months (range 1-53.6+) from AZA start. OS was significantly better in patients with less than 20% blasts, in normal karyotype t-AML and when AZA was used as front-line treatment. This was confirmed by the multivariate analysis.
This study reports efficacy of AZA in the largest series of therapy-related MN patients treated with 5-AZA. Our data show that blasts and karyotype maintain their important prognostic role in t-MN also in the azacitidine era.
Journal of Hematology & Oncology 08/2012; 5:44. · 3.99 Impact Factor
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Leukemia & lymphoma 06/2012; · 2.40 Impact Factor
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Patrizia Chiusolo,
Sabrina Giammarco,
Silvia Bellesi,
Elisabetta Metafuni,
Nicola Piccirillo,
Daniela De Ritis,
Sara Marietti,
Sorà Federica,
Luca Laurenti, Luana Fianchi,
Stefan Hohaus,
Leone Giuseppe,
Simona Sica
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ABSTRACT: In the last years, the influence of different genes involved in metabolism of chemotherapeutic agents has been studied. Methotrexate (MTX) is a key compound of chemotherapeutic regimens used in the treatment of acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL) and Burkitt's lymphomas (BL). This study aims to evaluate the role of MTHFR C677T and A1298C polymorphisms and G80A reduced folate carrier gene (RFC1) in a cohort of adult patients with lymphoproliferative malignancies submitted to high-dose MTX followed by leucovorin rescue.
We performed the analysis of these polymorphisms on genomic DNA with RFLP-PCR.
Patients carrying MTHFR A1298C variant showed decreased hepatic and hematological toxicity (P = 0.03). Overall survival (OS) and progression-free survival (PFS) between homozygous wild-type and variant patients for the RFC1 G(80)A were significantly different (P = 0.035 and P = 0.02, respectively). A significant correlation between hematological toxicity and age (P = 0.003) was observed. There was no significant influence of MTHFR C677T genotype on toxicity, OS and PFS.
Leucovorin rescue given after high-dose MTX probably accounts for the lack of influence of C677T polymorphism. To better define a role of RFC1 polymorphism on patients outcome, it would be worthwhile to perform a study on intracellular MTX level and RFC1 substrate binding affinities in different genotypes.
Cancer Chemotherapy and Pharmacology 03/2012; 69(3):691-6. · 2.83 Impact Factor
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ABSTRACT: Infections are a major cause of morbidity and mortality in patients with myelodysplastic syndrome (MDS) due to quantitative and qualitative granulocytic defects. We evaluated the in vitro bactericidal and fungicidal activities of neutrophils isolated from MDS. With comparison to those from healthy individuals, MDS neutrophils following infection showed a significantly reduced killing activity against Escherichia coli at 8 (p=0.002), 24 (p<0.0001), 48 (p=0.0005), and 72 h (p=0.0264), against Lactococcus lactis at 24 (p=0.0002), 48 (p<0.0001), and 72 h (p<0.0001), and more against Candida albicans at 8 (p=0.0003), 24 (p<0.0001), 48 (p<0.0001), and 72 h (p<0.0001). Our data show that MDS neutrophils have an impaired microbicidal function, which might account for the high susceptibility to infections of MDS patients.
Leukemia research 12/2011; 36(3):331-3. · 2.36 Impact Factor
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ABSTRACT: The purpose of this review is to update knowledge on therapy-related myeloid neoplasms (t-MN), taking into account the new 2008 WHO classification, new genome-wide approaches for the definition of susceptibility towards t-MN and the introduction of new more aggressive treatments in cancer patients.
t-MN are an increasing matter in cancer survivors treated with chemoradiotherapy. One of the major concerns in hematologic malignancies is childhood acute lymphoblastic leukemia, in which the leukemogenic role of extended etoposide/teniposide treatment, concomitant intensive antimetabolite and asparaginase, granulocyte colony-stimulating factor (G-CSF) and prophylactic cranial radiotherapy use have been established. In high-risk Hodgkin lymphoma, 3% t-MN have been observed at 10-year follow-up with the escalated bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone (BEACOPP) schedule, versus 0.4% with doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD). In lymphoproliferative diseases the new drugs fludarabine and lenalidomide may increase the risk of second tumors, when associated to other cytotoxic therapies. Among solid tumors, breast cancer is most frequently associated to t-MN. The risk is correlated to higher chemotherapy doses, radiotherapy, use of G-CSF, but also independent from treatment, suggesting a genetic predisposition to both diseases. Radiotherapy plays a role also in female pelvic tumors and in testicular cancer, when associated to cisplatin.
The risk of t-MN is not negligible, although below 2% in most series. This is particularly significant for younger cancer patients and during the first 5 years after the primary malignancies. Efforts should be maximized to identify susceptibility factors to identify patients at risk, in whom more leukemogenic drugs and schedules should be avoided.
Current opinion in oncology 09/2011; 23(6):672-80. · 4.09 Impact Factor
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ABSTRACT: Plasma cell leukemia (PCL) is a highly aggressive plasma cell disease characterized by a poor prognosis and a low response rate to conventional therapy. Herein, we describe a 69-year-old patient with primary PCL, developing testicular disease while in complete hematological remission, following by muscle involvement and peritoneal dissemination.
International journal of hematology 02/2011; 93(2):224-7. · 1.17 Impact Factor
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ABSTRACT: Acute myeloid leukemia (AML) is a clonal disorder of the hematopoietic stem cell, typical of the elderly, with a median age of over 60 years at diagnosis. In AML, older age is one of the strongest independent adverse prognostic factor, associated with decreased complete response rate, worse disease-free and overall survival, with highest rates of treatment related mortality, resistant disease and relapse, compared to younger patients. Outcomes are compromised in older patients not only by increased comorbidities and susceptibility to toxicity from therapy, but it is now recognized that elderly AML has peculiar biologic characteristics with a negative impact on treatment response.In older individuals prolonged exposure to environmental carcinogens may be the basis for similarities to therapy-related myeloid malignancies (t-MN), which result from toxic effects of previous cytotoxic treatments on hematopoietic stem cells. Age is itself a risk factor for t-MN, which are more frequent in elderly patients, where also a shorter latency between treatment of primary tumor and t-MN has been reported. t-MN following chemotherapy with alkylating agents and elderly AML frequently present MDS-related cytogenetic abnormalities, including complex or monosomal karyotype, and a myelodysplastic phase preceding the diagnosis of overt leukemia. Similarly, t-MN and elderly-AML share common molecular abnormalities, such as reduced frequency of NPM1, FLT3 and CEBPA mutations and increased MDR1 expression.Given the unfavorable prognosis of elderly and t-MN and the similar clinical and molecular aspects, this is a promising field for implementation of new treatment protocols including alternative biological drugs.
Mediterranean Journal of Hematology and Infectious Diseases 01/2011; 3(1):e2011052.
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ABSTRACT: Breast cancer is the most frequent cancer among women and the leading cause of death among middle-aged women. Early detection by mammography screening and improvement of therapeutic options have increased breast cancer survival rates, with the consequence that late side effects of cancer treatment become increasingly important. In particular, patients treated with adjuvant chemotherapy regimens, commonly including alkylating agents and anthracyclines, are at increased risk of developing leukemia, further enhanced by the use of radiotherapy. In the last few years also the use of growth factors seems to increase the risk of secondary leukemia. The purpose of this review is to update epidemiology of therapy-related myeloid neoplasms occurring in breast cancer patients.
Mediterranean Journal of Hematology and Infectious Diseases 01/2011; 3(1):e2011069.
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Mariangela Greco,
Francesco D'Alò,
Alessandra Scardocci,
Marianna Criscuolo,
Emiliano Fabiani,
Francesco Guidi,
Annalisa Di Ruscio,
Giuseppe Migliara,
Livio Pagano, Luana Fianchi,
Patrizia Chiusolo,
Stefan Hohaus,
Giuseppe Leone,
Maria Teresa Voso
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ABSTRACT: DNA methylation is one of the major epigenetic changes in human cancers, leading to silencing of tumor suppressor genes, with a pathogenetic role in tumor development and progression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Methylation of key promoter regions, induced by cytotoxic therapy together with complex genetic changes, is important in the biology of therapy-related myeloid neoplasms (t-MN). We were interested in the characterization of the methylation pattern of AML and MDS de novo and therapy-related. We studied 385 patients (179 females, 206 males), of a median age of 66 years (range 16-98 years). There were 105 MDS, 208 de novo AML and 72 t-MN (45 MDS and 27 AML). Using a methylation-specific PCR, we studied the promoter methylation status of E-cadherin (CDH1), TSP1 and DAP-Kinase 1. These genes have been shown to be involved in the malignant transformation, interfering with angiogenesis, interaction with micro-environment, apoptosis and xenobiotic detoxification. We found no associations between promoter hypermethylation and gender or age at the time of initial diagnosis. In patients with MDS, there were no associations between hypermethylation and clinical characteristics, including IPSS score, WHO classification and cytogenetics. DAPK1 was more frequently methylated in t-MDS/AML when compared to de novo MDS and AML (39% vs 15.3% and 24.4%, p=0.0001), while methylation of CDH1 was similar in t-MDS/AML and AML (51% and 53.4%), but less frequent in de novo MDS (29%) (p=0.003). In the t-MDS/AML group, we found that the methylation pattern appeared to be related to the primary tumor, with DAPK1 more frequently methylated in patients with a previous lymphoproliferative disease (75% vs 32%, p=0.006). On the other hand, methylation of CDH1 was associated to radiotherapy for the primary malignancy (84.5% vs 38%, p=0.003). TSP1 hypermethylation was rare and not characteristic of t-MDS/AML. In 177 patients studied for concurrent methylation of several promoters, t-MN and AML de novo were significantly more frequently hypermethylated in 2 or more promoter regions than de novo MDS (20% vs 12.4%, p<0.001). Chemotherapy and individual genetic predisposition have a role in t-MDS/AML development, the identification of specific epigenetic modifications may explain complexity and genomic instability of these diseases and give the basis for targeted-therapy. The significant association with previous malignancy subtypes may underlie a likely susceptibility to methylation of specific targets and a role for constitutional epimutations as predisposing factors for the development of therapy-related myeloid neoplasm.
Blood Cells Molecules and Diseases 10/2010; 45(3):181-5. · 2.35 Impact Factor
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ABSTRACT: Invasive fungal infections are significant causes of morbidity and mortality in patients with hematological malignancies. Patients with acute myeloid leukemia and those who have undergone allogeneic hematopoietic stem cell transplantation are at especially high risk. Various fungal agents are responsible for this complication, but Aspergillus spp. and Candida spp. are the most frequently isolated micro-organisms; less commonly, infections could be caused by Zygomycetes or other rare molds or yeasts. Several new systemically-administered antifungal agents have been approved for clinical use since 2001; these agents include liposomal amphotericin B, voriconazole, caspofungin, and posaconazole, and they represent a major advance in antifungal therapy and have improved the prognosis of patients with hematological malignancies. This review focuses on therapeutic aspects of the management of fungal infections in hematological patients.
Blood reviews 03/2010; 24(2):51-61. · 7.19 Impact Factor
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ABSTRACT: Therapy-related myeloid neoplasms (t-MN) include acute myeloid leukemias and myelodysplastic syndromes arising in patients who have been treated with chemotherapy, radiation therapy, immunosuppressive agents or after documented exposure to environmental carcinogen. t-MN are defined according to the primary treatment and the corresponding genetic and molecular lesions. Chromosome(s) 7 and/or 5 monosomies or deletions are typical of alkylating agent-induced AML, while balanced translocations involving chromosome bands 11q23 and 21q22 are associated to preceeding therapy with DNA-topoisomerase II inhibitors. Antimetabolites, and in particular the immunosuppressive agents azathioprine and fludarabine, have also been recently associated to t-MN. Leukemias developing after benzene exposure are similar to t-MN and are characterized by chromosomal aberrations, which have been also observed among otherwise healthy benzene-exposed workers. Individual predisposing factors, including polymorphisms of detoxification and DNA-repair enzymes have been identified. Two genetic variants in key metabolizing enzymes, myeloperoxidase and NAD(P)H:quinone oxidoreductase, have been shown to influence susceptibility to benzene hematotoxicity. Combination of polymorphisms impairing detoxification and DNA repair may significantly increase therapy-related myeloid neoplasm risk. Among hematological malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased t-MN risk, particularly when receiving MOPP-based and escalated-BEACOPP regimens, and when alkylators are combined to radiotherapy. Patients with lymphoma are at highest risk if total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation. The addition of granulocyte-colony stimulating factor (G-CSF) and radiotherapy plays a significant role in t-MN following treatment of childhood acute lymphoblastic leukemia. In solid tumors, treatment for breast cancer and germ-cell tumors has been associated with a 1-5% lifetime risk of t-MN.
Chemico-biological interactions 12/2009; 184(1-2):39-45. · 2.46 Impact Factor
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Maria Teresa Voso,
Francesco D'Alò,
Mariangela Greco,
Emiliano Fabiani,
Marianna Criscuolo,
Giuseppe Migliara,
Livio Pagano, Luana Fianchi,
Francesco Guidi,
Stefan Hohaus,
Giuseppe Leone
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ABSTRACT: Therapy-related Myelodysplastic Syndromes/Acute Myeloid Leukemias (t-MDS/AML) are one of the most compelling long term adverse events occurring in cancer survivors treated with chemo-radiotherapy regimes. Beside several well-described genetic lesions, a growing amount of data suggests that abnormalities in DNA methylation profile contribute to multistep secondary leukemogenesis. Two distinct alterations of normal DNA methylation patterns may occur in cancer: a global hypomethylation resulting in chromosomal instability and loss of genetic integrity, and promoter specific DNA hypermethylation which leads to silencing of tumor suppressor genes. Cytotoxic drugs and radiation have been shown to affect tissue DNA methylation profile. Radiation is able to induce a stable DNA hypomethylation in both target and bystander tissues. Gene promoter methylation is a common finding in t-MDS/AML and has been associated to a shorter latency period from the treatment of the primary tumor. Among the studied genes, p15 methylation correlated to monosomy/deletion of chromosome 7q, suggesting that it could be a relevant event in alkylating agent-induced leukemogenesis. We found frequent methylation of DAPK in the t-MDS/AML group, especially in patients with a previous lymphoproliferative disease. In patients studied for concurrent methylation of several promoters, t-MDS/AML were significantly more frequently hypermethylated in 2 or more promoter regions than de novo MDS or AML suggesting that promoter hypermethylation of genes involved in cell cycle control, apoptosis and DNA repair pathways is a frequent finding in t-MDS/AML and may contribute to secondary leukemogenesis. However, how the epigenetic machinery is disrupted after chemo/radiotherapy and during secondary carcinogenesis is still unknown, warranting further studies.
Chemico-biological interactions 10/2009; 184(1-2):46-9. · 2.46 Impact Factor
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Livio Pagano,
Morena Caira,
Anna Candoni,
Massimo Offidani,
Bruno Martino,
Giorgina Specchia,
Domenico Pastore,
Marta Stanzani,
Chiara Cattaneo,
Rosa Fanci, [......],
Alessandro Bonini,
Adriana Vacca,
Anna Chierichini,
Lorella Melillo,
Chiara de Waure, Luana Fianchi,
Marta Riva,
Giuseppe Leone,
Franco Aversa,
Annamaria Nosari
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ABSTRACT: The aim of this study was to evaluate prognostic factors, treatments and outcome of invasive aspergillosis in patients with acute myeloid leukemia based on data collected in a registry.
The registry, which was activated in 2004 and closed in 2007, collected data on patients with acute myeloid leukemia, admitted to 21 hematologic divisions in tertiary care centers or university hospitals in Italy, who developed proven or probable invasive aspergillosis.
One hundred and forty cases of invasive aspergillosis were collected, with most cases occurring during the period of post-induction aplasia, the highest risk phase in acute myeloid leukemia. The mortality rate attributable to invasive aspergillosis was 27%, confirming previous reports of a downward trend in this rate. Univariate and multivariate analyses revealed that the stage of acute myeloid leukemia and the duration of, and recovery from, neutropenia were independent prognostic factors. We analyzed outcomes after treatment with the three most frequently used drugs (liposomal amphotericin B, caspofungin, voriconazole). No differences emerged in survival at day 120 or in the overall response rate which was 71%, ranging from 61% with caspofungin to 84% with voriconazole.
Our series confirms the downward trend in mortality rates reported in previous series, with all new drugs providing similar survival and response rates. Recovery from neutropenia and disease stage are crucial prognostic factors. Efficacious antifungal drugs bridge the period of maximum risk due to poor hematologic and immunological reconstitution.
Haematologica 10/2009; 95(4):644-50. · 6.42 Impact Factor
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ABSTRACT: Zygomycosis is an invasive infection that can occur particularly in patients with haematological malignancy. The causative fungi are members of the order Mucorales, and individual species within this group require a high level of laboratory skill to be identified. Zygomycosis can present as rhinocerebral, pulmonary, or disseminated disease, with a rapid clinical course. The optimal management of these cases requires early diagnosis, aggressive antifungal therapy and, when possible, surgical debridement. Founded on clinical experience, but without the benefit of comparative studies, liposomal amphotericin B has become the therapeutic agent of choice. Posaconazole is an orally administered triazole with a demonstrated in vitro and in vivo activity against most Zygomycetes that is comparable to that of amphotericin B. Studies on salvage therapy with posaconazole have yielded promising results, and successful case reports are also available. As an adjuvant approach, iron chelation with deferasirox has shown promising results, although clinical experience is still limited.
British Journal of Haematology 06/2009; 146(6):597-606. · 4.94 Impact Factor
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ABSTRACT: To identify risk factors for mortality in patients suffering from hematological malignancies with concurrent bacteremia caused by Escherichia coli. Particular attention was focused on defining the impact of extended-spectrum-beta-lactamase (ESBL) production and fluoroquinolone resistance by the bacterial isolates on mortality.
A retrospective eight-year cohort study design was employed. The outcome measured was death within 30 days of the first positive blood culture. Survivor and non-survivor subgroups were compared to identify predictors of mortality.
A total of 62 episodes of bacteremia caused by E. coli were analyzed. The overall incidences of ESBL production and fluoroquinolone resistance were 41.9% and 62.9%, respectively. The overall 30-day mortality rate was 20.9% (13/62). In a multivariate analysis, significant predictors of mortality were inadequate initial antimicrobial therapy (OR=14.96, 95% CI 1.95-114.51; P=0.009), infection caused by ESBL-producing isolates (OR=8.84, 95% CI 1.48-52.91; P=0.01), and prolonged neutropenia (OR=8.10, 95% CI 1.29-50.57; P=0.02).
Sound knowledge of the local distribution of pathogens and their susceptibility patterns and prompt initiation of effective antimicrobial treatment are essential in patients suffering from hematological malignancies with BSIs caused by E. coli.
The Journal of infection 05/2009; 58(4):299-307. · 4.13 Impact Factor
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Mario Tumbarello,
Teresa Spanu,
Morena Caira,
Enrico M Trecarichi,
Luca Laurenti,
Eva Montuori, Luana Fianchi,
Fiammetta Leone,
Giovanni Fadda,
Roberto Cauda,
Livio Pagano
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ABSTRACT: We conducted a retrospective cohort study to identify risk factors for mortality in a large cohort of hematologic patients with bacteremia. From 2000 through 2005, bacteremia was diagnosed in 217 patients with hematologic malignancies. The infections were caused only by Gram-positive organisms in 57.1% (124/217) cases and only by Gram-negative bacteria in 37.8% (82/217); the remaining 5.1% (11/217) were polymicrobial. The overall 30-day mortality rate was 20.3% (44/217). In multivariate analysis, significant predictors of mortality were prolonged neutropenia (P < 0.001), acute renal failure (P = 0.002), nosocomial bacteremia (P = 0.009), age >55 years (P = 0.007), and monomicrobial bacteremia due to antibiotic-resistant Gram-negative bacteria (P = 0.009). Reducing fatal outcomes associated with bacteremia in patients with hematologic malignancies is a challenge, and the emergence of resistance to the antimicrobials widely used in this setting is of great concern. Future infection trends must be carefully monitored and treatment guidelines adjusted accordingly.
Diagnostic microbiology and infectious disease 04/2009; 64(3):320-6. · 2.45 Impact Factor
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ABSTRACT: Burkitt's lymphoma is a highly aggressive mature B-cell neoplasm consisting of endemic, sporadic, and immunodeficiency-associated variants, sharing many morphologic and immunophenotypic features. It is characterized by a high proliferation rate and propensity for extranodal sites such as gastrointestinal tract and reproductive organs. Brief-duration, high-intensity chemotherapy regimens including aggressive central nervous system prophylaxis have had remarkable success in the treatment of this disease in the sporadic form, with very high complete remission rate and overall survival in adults. Although Burkitt's lymphoma is extremely chemosensitive, biologically targeted therapies should be developed, because current treatment options are suboptimal for patients with poor prognostic features or with relapsed disease.
Mediterranean Journal of Hematology and Infectious Diseases 01/2009; 1(2):e2009030.
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Haematologica 12/2008; 93(11):1611-6. · 6.42 Impact Factor
