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  • 1
    In: HemaSphere, Ovid Technologies (Wolters Kluwer Health), Vol. 4, No. 5 ( 2020-09-23), p. e483-
    Type of Medium: Online Resource
    ISSN: 2572-9241
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 2
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 966, No. 1 ( 2002-06), p. 187-192
    Abstract: A bstract : Several lines of experimental evidence suggest that sex hormones may influence the development and activity of chronic graft‐versus‐host disease (cGVHD), which frequently occurs in patients undergoing allogeneic bone marrow transplantation (ABMT). Following ABMT, young women are commonly treated with hormone replacement therapy (HRT) because of irreversible gonadal failure. It seemed therefore worthwhile to investigate the effects of this therapy on the activity of cGVHD. Premenopausal women treated with ABMT for hematological malignancies between January 1997 and December 2000 were evaluated for cGVHD activity. They were divided into two groups, depending on whether or not they were treated with HRT. Seventy‐one women qualified for the present study: 39 received HRT (treated group), while 32 did not (controls). In both groups of patients, cGVHD activity score was comparable before the start of HRT. No differences were observed in cGVHD activity score between the HRT group and controls after 3, 6, 12, and 24 months from the start of HRT. Furthermore, HRT did not induce any increase in the cGVHD activity score in the treated group of patients at any time from the start of HRT. According to present data, HRT did not appear to influence the activity of cGVHD in young women who underwent ABMT for hematological malignancies. Therefore, we can safely propose this therapy for women with gonadal failure after ABMT.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2002
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  • 3
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 5603-5603
    Abstract: BACKGROUND AND AIMS In patients with myelodysplastic syndromes (MDS) several validated prognostic scores, such as IPSS and R-IPSS, are available to assess the risk of AML progression and predict overall survival (OS) as well as leukemia-free survival (LFS). A number of molecular aberrations can be identified in MDS. However, differently from AML, none of the current prognostic indexes takes into account molecular profile at diagnosis. WT1 expression has often been evaluated in acute leukemias and MDS. High WT1 expression levels on bone marrow at diagnosis have been reported to identify MDS patients who are at high risk of progression to AML. BAALC (Brain And Acute Leukemia Cytoplasmic) hyper-expression has been associated with a poor prognosis in AML patients, whereas its prognostic value in MDS is not yet clearly defined. The aim of our study was to determine if combined assessment of WT1 and BAALC expression levels at diagnosis could be predictive of leukemic evolution. MATERIALS AND METHODS We selected 86 patients with available WT1 and BAALC expression levels on BM samples at diagnosis. According to IPSS score, 22 patient were considered low-risk, 27 intermediate-1 and 28 intermediate-2 or high risk. Patients underwent different treatment schedules including supportive care, erythropoietin, hypomethylating and immunomodulating agents, according to their risk group. Median follow-up was 36 months (range 4 -121 months). Leukemia-free survival (LFS) was calculated from the diagnosis until last follow-up or documented leukemic progression as defined in literature. LFS was estimated using the Kaplan–Meier method. All Real-Time PCR were performed on DNA Engine 2 (Opticon®, MJ Research®). WT1 copy number/Abl copy number 1000x104 was used as cut-off value for high WT1 expression, a level of 1000x104 BAALC copy number/Abl copy number was set as cut-off for BAALC hyper-expression. RESULTS After a median time of 32 months, 43 patients died. The main cause of death was leukemic evolution (accounting for 31/43 deaths, 72%), other causes were cardiovascular events and infections (data not shown). The risk of death by any cause was significantly affected by leukemic evolution, diagnosis according to WHO classification and molecular expression profile at diagnosis. Multivariate analysis showed that leukemic evolution was an independent predictor of death (p 〈 0.001). Twenty-nine leukemic evolutions were observed. Median LFS was 34 months. The probability of leukemic evolution was significantly affected by karyotype, IPSS and R-IPSS scores, diagnosis according to WHO classification, and molecular profile at diagnosis. According to our data WT1 and BAALC combined expression levels further enhanced prognostic stratification. In IPSS Int-1, Int-2/high and in R-IPSS high risk groups, low levels of expression resulted in significantly lower probability of leukemic progression, whereas high levels predicted poor outcome. Furthermore, in patients assigned to IPSS unfavorable prognostic groups, low levels of WT1 and BAALC seemed to predict a significantly longer LFS. In the univariate analysis LFS duration was significantly affected by WT1 and BAALC expression levels (fig. 1), IPSS and R-IPSS scores, karyotype and WHO classification at diagnosis. A multivariate Cox Regression model showed that LFS duration was significantly influenced only by molecular profile at diagnosis and R-IPSS risk group (p 〈 0.001 and p 〈 0.01, respectively). Median OS was 32 months. In univariate analysis OS was significantly influenced by diagnosis according to WHO classification, karyotype, R-IPSS score, leukemic evolution and molecular profile expression at diagnosis. The multivariate model disclosed molecular expression profile, R-IPSS score and leukemic evolution as independent predictor of OS (p 〈 0.02, 〈 0.03 and 〈 0.01, respectively). CONCLUSIONS In MDS patients combined WT1 and BAALC expression levels on bone marrow samples at diagnosis is a reliable predictor of risk of AML progression, LFS and OS. This can improve risk stratification especially in intermediate and high risk groups and may lead to a risk tailored therapy. Figure 1: LFS according to molecular profile Figure 1:. LFS according to molecular profile Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 4
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 83, No. 11 ( 2004-11), p. 696-703
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2004
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  • 5
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 88, No. 9 ( 2009-9), p. 855-861
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2009
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 14 ( 2017-05-10), p. 1591-1597
    Abstract: Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non-del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second-line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 7
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 52, No. 10 ( 2011-10), p. 1942-1948
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2011
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  • 8
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1702-1702
    Abstract: Abstract 1702 Background: Prognostic assessment has a crucial role in clinical evaluation of patients (pts) affected by myelodysplastic syndrome (MDS). Recently a Revised International Prognostic Scoring System (IPSS-R) has been developed (Greenberg et al, 2012) to improve the standard IPSS (Greenberg et al, 1997): it identifies five different prognostic categories mainly based on stratification of cytogenetic risk. Another prognostic score proposed in clinical practice is WPSS, based on transfusion dependency and WHO morphologic classification (Malcovati et al, 2005) subsequently modified (rWPSS) introducing level of hemoglobin in lieu of the previous not well defined variable of transfusion dependency (Malcovati et al, 2011). Aims: Aim of our study was to evaluate in a cohort of MDS pts enrolled in the Multiregional Italian MDS Registry the prognostic value of IPSS-R respect to IPSS and compare it with both WPSS and rWPSS. Materials and methods: Among the 1918 MDS pts enrolled in the Multiregional Italian MDS Registry from 1999 to 2012 we excluded all the cases already included in the IWG-PM database that generated the IPSS-R. We thus obtained a cohort of 646 pts with complete follow up. We evaluated the prognostic power of IPSS-R respect to IPSS, WPSS and rWPSS respectively by Harrell's C statistics, analyzing as endpoints overall survival (OS), leukemic evolution (LE) and progression free survival (PFS). For LE we considered leukemic evolution as an event, while all the other causes of death were competing events. For PFS we consider either leukemic evolution or death for any causes as an event. Results: Median age of MDS patients was 75 years (interquartile range: 69–80 years). 378 (59%) out of 646 pts were males. WHO classification was as follows: 33% RCMD, 10% RAEB-1, 9% RAEB-2, 6% CMML, 2% MDS-U, the remaining 40% were RARS, RA, isolated 5q deletion. Median follow up of censored pts was 17 months. According to IPSS score, 47% of pts were low risk, 39% Int-1, 10% Int-2 and 4% high risk. WPSS stratification was as follows: 31% were very low (VL) risk, 37% low (L), 19% intermediate (I), 11% high (H) and 2% very high (VH). By applying rWPSS stratification we obtained 30% VL, 35% L, 17% I, 15% H and 3% VH risk pts. IPSS-R risk stratification was as follows: 20% VL, 46% L, 20% I, 9% H and 5% VH risk pts. OS was analyzed according to the different scores by Kaplan-Meyer method. All prognostic systems allowed the identification of survival curves with significant differences among the different categories of risk stratification. IPSS-R application defined OS curves which better defined patients prognostic categories as shown in fig 1. In fact Harrel's C statistics demonstrated a better predictive value of the IPSS-R respect to IPSS, but also respect to WPSS and rWPSS (C=0,73; 0,63; 0,65; 0,64 respectively). Similar results have been obtained also considering time to LE (fig 2). Harrel's C statistics for LE was 0,84; 0,76; 0,78; 0,77 respectively in IPSS-R, IPSS, WPSS, rWPSS risk stratification groups. Moreover, we analyzed PFS outcomes (fig 3). Also in this case, IPSS-R showed the greatest prognostic power: Harrel's C statistics was 0,76; 0,67; 0,66; 0,69 respectively in IPSS-R, IPSS, WPSS, rWPSS risk stratification groups. Conclusions: In our hands, IPSS-R score demonstrated a better prognostic power respect to previously published prognostic systems (IPSS, WPSS, rWPSS). The cohort of MDS patients we employed to validate the new prognostic scoring system has a short follow up (17 months), due to the exclusion of cases already used to establish the IPSS-R system, and the majority of these are lower risk ones. We can conclude that a careful classification based on cytogenetic examination improve the prognostic power of the score. Thus, IPSS-R is confirmed to be a refined tool, easily applicable in real life and empowered respect to the currently used scores to define MDS patient prognosis. Disclosures: Saglio: Bristol-Myers Squibb: Consultancy, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 9
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2678-2678
    Abstract: Background The majority of myelodysplastic syndrome (MDS), primary myelofibrosis (MPN) and aplastic anemia (AA) patients during the course of the disease develops a symptomatic anemia requiring transfusions of packed red blood cells (PRBC), each of them containing approximately 200 mg of elementary iron. Because of the fact that human beings are unable to actively eliminate iron from the body, secondary emosiderosis yet becomes evident when body iron content is above 7-14 grams, an amount easily reached after receiving as few as 15-30 PRCB units.From a pathophysiologic point of view, long-term transfusion therapy is certainly the most important cause of iron overload (IOL) in these patients; nevertheless, others mechanism account for this phenomenon, and in particular the role of the ineffective erythropoiesis.Deferasirox (DSX) is the principal option currently available for iron chelation therapy in the management of IOL due to transfusion dependent anemia. DSX is also a potent NF-kB inhibitor, and this effect may explain in part the phenomenon of hematological improvements reported in different clinical trials and in case reports. Materials and Methods We analyzed 21 patients,16 male and 5 female, with transfusion dependent anemia and with a transfusional history of almost 10 packed PRBC, treated with DSX from 1 February 2013 to 1 February 2014. Median age was 80 years (65-88). 20 patients (95%) have almost a comorbidity, 7 of them (30%) have more than 3 comorbidities. Heart disease was the most common comorbidity. At baseline median creatinine clearance was 76 ml/min; in 12 patients was 〈 60ml/min but 〉 40 ml/min, according to NCCN Guidelines. All patients (16 MDS, 3 MPN, 1 AA, 1 hemolytic anemia) were evaluated for IOL by serum ferritin (SF), while only 7 with RM T2*.Median SF at baseline was 1750 μg/L and median PRBC was 32.The starting dose of DSX was 10 mg/kg/day; the dosage should be adjusted up to 20–30 mg/kg/daily according to the transfusional regimen, SF and IOL, if tolerated. Objectives To observe safety, tolerability, and efficacy of iron chelation therapy with DSX in older patients with transfusion dependent anemia. Results The SF decreased of 50% and 66% after 3 and 6 months respectively. The SF was normalized (SF 〈 500 μg/L) in 5 patients (24%) after six months. The IOL occurred also in patients with a short transfusional history, inferior to 10 packed red blood cells, and SF 〈 1000 μg/L. That was more evident in MDS patients especially in RARS. The median dose tolerated of DSX was 20 mg/kg/daily.The drug related adverse events (AE) was evaluated by the Common Terminology Criteria for Adverse Events (CTCAE versione 4.02). The severe adverse events (SAE) occurred in 10%.The most Common AE were diarrhea, nausea, upper abdominal pain, serum creatinine increase and rash. Hematologic response according to IWG criteria 2006 with DSX were observed in 17% of patients and was more frequent in MPN than MDS, independently from IOL. Conclusion DSX has shown high efficacy in a variety of iron overloaded patients with different anemias. Appropriate patient selection and regular clinical multidisciplinary evaluation of comorbidity and concomitant therapy remains a critical components of successful ther­apy, combined with carefull monitoring for both adverse effects and clinical efficacy, in order to derive the most benefit from a carefully imple­mented chelation strategy.In our cohort improvement of erythropoiesis was marginal. This might be due to the very small patient group analyzed. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 10
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2927-2927
    Abstract: Abstract 2927 Background: Immunological changes have a primary role in the initiation and progression of myelodysplastic syndromes (MDS). Cytokine levels, such as IL-7 and IFN-gamma, are associated with lower-risk disease. Treatment with lenalidomide has proven efficacy in red blood cell (RBC) transfusion-dependent lower-risk MDS patients with del(5q). Lenalidomide exerts anti-angiogenic, anti-proliferative, and pro-erythropoietic effects; in particular, it has been shown that lenalidomide inhibits the proliferation and function of T regulatory cells (Tregs). Finally, MDS patients undergoing lenalidomide treatment experience erythroid responses and suppression of the del(5q) clone. Aims: In a multicenter Italian phase II trial to evaluate safety and efficacy of lenalidomide in primary MDS patients with del(5q) and Low- or Int-1 risk IPSS, we investigated changes in the transcription of cytokines and their receptors during treatment. Methods: The starting dose of lenalidomide was 10 mg p.o once daily on a continuous daily schedule for a maximum of 12 months. Bone marrow (BM) aspirates were obtained on study entry and every 12 weeks. Assays were performed using TaqMan® Low Density Array Fluidic card (TaqMan® Human Array, Applied Biosystems, Foster City, CA, USA) based on Applied Biosystems PRISM® 7900HT comparative ddCT method, according to the manufacturer's instructions. Target gene expression levels were measured in triplicate and normalized against the expression of the 18S housekeeping gene from a BM pool of normal, healthy subjects at all timepoints. Median relative gene expression values in MDS patients were compared to healthy subjects, set as a value of 1. Results: We report data obtained at baseline and after 12 weeks. Informed consent was obtained in all patients. Twenty-seven patients (5 M, 22 F) were evaluated at baseline and after 12 weeks. Mean age was 72 ± 9 years. Mean Hb level was 8.5 ± 0.9 g/dL and 16 patients were RBC transfusion -dependent (requiring at least 4 RBC transfusions in the preceding 2 months). Seven patients had additional cytogenetic abnormalities. Twenty-one patients (80%) experienced erythroid responses by week 12. Significant variations in gene expression of cytokines and receptors were observed during treatment. Genes significantly regulated during lenalidomide treatment (P 〈 0.05) are shown in the Table. In particular, FAS, IL-7 and FOXP3 gene were generally under-expressed at baseline and significantly increased after 12 weeks. Accordingly, IL7R was over-expressed in all patients at baseline and its expression was significantly reduced during treatment. Furthermore, IFN-gamma expression increased during therapy. Summary: The protein encoded by FAS gene is a member of the TNF-receptor superfamily and its interaction with its ligand leads to apoptosis. Interleukin (IL)-7 is an essential cytokine that promotes the proliferation and survival of B- and T-lymphocyte progenitors. The IL7R gene on chromosome 5 (5p13) codifies for the IL7 receptor, which blocks apoptosis during differentiation and activation of T lymphocytes. It functions, in part, through the induction of the expression of the antiapoptotic protein Bcl-2. The protein encoded by the FOXP3 gene is a member of transcriptional regulators. Defects in this gene are the cause of X-linked autoimmunity-immunodeficiency syndrome. The results of the present study indicate that lenalidomide may act through immunological changes. Further detailed analyses in these patients may provide new insights into the pathogenesis of MDS with del(5q) and the long-term effects of lenalidomide treatment on immunological changes in BM cells. Disclosures: Oliva: Celgene: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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