Publications by authors named "Antonella Geromin"

29 Publications

  • Page 1 of 1

Risk Factors and Outcome of Infection after Hematopoietic Stem Cell Transplantation.

J Clin Med 2020 Nov 16;9(11). Epub 2020 Nov 16.

Clinica Ematologica ed Unità di Terapie Cellulari, Azienda Sanitaria Universitaria Friuli Centrale, Piazzale S. Maria della Misericordia 10, 33100 Udine, Italy.

Patients who undergo hematopoietic stem cell transplants (HSCT) are at major risk of (CD) infection (CDI), the most common cause of nosocomial diarrhea. We conducted a retrospective study, which enrolled 481 patients who underwent autologous (220) or allogeneic HSCT (261) in a 5-year period, with the aim of identifying the incidence, risk factors and outcome of CDI between the start of conditioning and 100 days after HSCT. The overall cumulative incidence of CDI based upon clinical evidence was 5.4% (95% CI, 3.7% to 7.8%), without any significant difference between the two types of procedures. The median time between HSCT and CDI diagnosis was 12 days. Out of 26 patients, 19 (73%) with clinical and symptomatic evidence of CDI were positive also for enzymatic or molecular detection of toxigenic CD; in particular, in 5 out of 26 patients (19%) CD binary toxin was also detected. CDI diagnoses significantly increased in the period 2018-2019, since the introduction in the microbiology lab unit of the two-step diagnostic test based on GDH immunoenzymatic detection and toxin B/binary toxin/027 ribotype detection by real-time PCR. Via multivariate analysis, abdominal surgery within 10 years before HSCT ( = 0.002), antibiotic therapy within two months before HSCT ( = 0.000), HCV infection ( = 0.023) and occurrence of bacterial or fungal infections up to 100 days after HSCT ( = 0.003) were significantly associated with a higher risk of CDI development. The 26 patients were treated with first-line vancomycin (24) or fidaxomicine (2) and only 2 patients needed a second-line treatment, due to the persistence of stool positivity. No significant relationship was identified between CDI and the development of acute graft versus host disease (GVHD) after allogeneic HSCT. At a median follow-up of 25 months (range 1-65), the cumulative incidence of transplant related mortality (TRM) was 16.6% (95% CI 11.7% to 22.4%) and the 3-year overall survival (OS) was 67.0% (95% CI 61.9% to 71.6%). The development of CDI had no significant impact on TRM and OS, which were significantly impaired in the multivariate analysis by gastrointestinal and urogenital comorbidities, severe GVHD, previous infections or hospitalization within two months before HSCT, active disease at transplant and occurrence of infections after HSCT. We conclude that 20% of all episodes of diarrhea occurring up to 100 days after HSCT were related to toxigenic CD infection. Patients with a history of previous abdominal surgery or HCV infection, or those who had received broad spectrum parenteral antibacterial therapy were at major risk for CDI development. CDIs were successfully treated with vancomycin or fidaxomicin after auto-HSCT as well as after allo-HSCT.
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http://dx.doi.org/10.3390/jcm9113673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696044PMC
November 2020

ABCG2 and CD200 define patients at high risk of relapse in ELN favorable subgroup of AML.

Eur J Haematol 2017 Sep 20;99(3):269-274. Epub 2017 Jul 20.

Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata, Udine, Italy.

Objective: Overexpression of ABCG2 and CD200 has been independently associated with poor outcome in acute myeloid leukemia (AML). However, no data are available on the role of these two factors in patients with core-binding factor (CBF)-positive or FLT3-negative/NPM1-mutated cytogenetically normal (CN) AML.

Methods: We analyzed 65 adult AML patients with CBF+ (n=16) or FLT3-/NPM1+ CN (n=49), evaluating clinical and biological factors associated with complete remission attainment, leukemia-free survival (LFS) and overall survival (OS).

Results: ABCG2 was expressed in 36 (55%) cases, and CD200 was positive in 33 (51%) cases, six at high levels. Both ABCG2 and CD200 positivity have a negative impact on relapse risk: 3-year LFS was 51% vs 82% in ABCG2+ cases (RR 3.3), 49% vs 82% in CD200+ patients (RR=4.4), and 25% in CD200- high cases (RR=17.1). ABCG2 and CD200 affected also OS with 3-year OS of 39% in ABCG2+ (compared to 71% in ABCG2-; RR=2.6) and CD200+ (compared to 68% in CD200-; RR=2.5) patients.

Conclusions: Our data confirm a negative impact of ABCG2 and CD200 overexpression also in AML patients considered at favorable risk according to ELN cytogenetic/molecular classification.
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http://dx.doi.org/10.1111/ejh.12915DOI Listing
September 2017

High CD200 expression is associated with poor prognosis in cytogenetically normal acute myeloid leukemia, even in FlT3-ITD-/NPM1+ patients.

Leuk Res 2017 07 4;58:31-38. Epub 2017 Apr 4.

Division of Hematology and Bone Marrow Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy. Electronic address:

Overexpression of CD200, a trans-membrane protein belonging to the immunoglobulin superfamily, has been associated with poor prognosis in patients with acute myeloid leukemia (AML). As few data are available in the subset of cytogenetically-normal (CN) AML, we retrospectively evaluated the correlations between CD200 expression and response to therapy in a series of 139 adults with CN-AML. CD200 was expressed in 67/139 (48%) cases; 18 of them (28%) expressed CD200 at high intensity. No differences in CD200 expression rate were observed according to age, WBC count, type of leukemia, FLT3 or NMP1 mutation, and CD56 expression. A higher incidence of CD200 expression was observed in CD34+ cases (P<0.0001) and in BCL2+ patients (P=0.04). Complete remission (CR) was evaluable achieved in 98 patients (70%): 56/71 (79%) in CD200- and 47/67 (63%) in CD200+ patients (P=0.03), with a lower CR rate in patients with high CD200 intensity (9/18, 50%). CD200 expression had a negative impact on long-term outcome. CD200 expression, per se, did not impact on disease-free survival (DFS), but cases with high CD200 expression had a lower 3-year DFS compared to CD200-negative and low-expressing ones (0% vs 65% vs 68%, P=0.019). Three-year overall survival (OS) was 51% in CD200- and 27% in CD200+ patients (P=0.01), with a significant difference among cases with low or high CD200 expression (35% vs 0%, P=0.001). CD200 high expression defined a group with very poor DFS and OS also among the 37 FLT3-/NPM1+: 3-year DFS and OS were 88% and 60% in CD200-, 50% and 32% in CD200 low and 0% and 0% in CD200 high patients, respectively (P=0.01 for DFS and P=0.05 for OS). Our data suggest a negative impact of CD200 expression in CN-AML, with a further worsening in high-expressing cases, also in the subset of FLT3-/NPM1+ patients.
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http://dx.doi.org/10.1016/j.leukres.2017.04.001DOI Listing
July 2017

Impact of fludarabine-based induction therapy on outcome of FLT3-/NPM1+ cytogenetically normal acute myeloid leukemia.

Am J Hematol 2017 Apr 13;92(4):E45-E47. Epub 2017 Feb 13.

Division of Hematology and BMT, Department of Experimental and Clinical Medical Sciences, Azienda Sanitaria Universitaria Integrata, Udine, Italy.

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http://dx.doi.org/10.1002/ajh.24651DOI Listing
April 2017

Risk Factors and Outcomes of Infections by Multidrug-Resistant Gram-Negative Bacteria in Patients Undergoing Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2017 Feb 4;23(2):333-339. Epub 2016 Nov 4.

Clinica Ematologica, Dipartimento di Scienze Sperimentali e Cliniche, Università di Udine, Udine, Italy.

The objective of this study was to determine risk factors and outcomes of infections by multidrug-resistant gram-negative (MDR GN) bacteria in 241 recipients of hematopoietic stem cell transplantation (HSCT). The cumulative incidence of infections was 10.5% (95% CI, 12.0% to 25.8%), with 57% of infections occurring during the period of severe neutropenia (neutrophil count < .1 × 10/L). In multivariate analysis, allogeneic transplant and colonization with MDR GN bacteria at admission to the transplant unit were significantly associated with an increased risk of infection. Although we observed neither transplant-related mortality (TRM) nor deaths due to infections by MDR GN bacteria after autologous transplant, in the allogeneic setting a significant difference was reported in terms of overall survival (OS) and TRM between patients who developed infections and those who did not (1-year OS, 39% versus 68%; 1-year TRM, 42% versus 19%). In multivariate analysis, refractory disease and development of grades III to IV graft-versus-host disease (GVHD) were factors that affected both TRM and OS, whereas occurrence of infections by MDR GN pathogens significantly reduced OS. We conclude that eligibility to allogeneic HSCT in MDR GN bacteria carriers should be carefully evaluated together with all other factors that independently influence outcome (disease status, donor, and GVHD risk).
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http://dx.doi.org/10.1016/j.bbmt.2016.11.005DOI Listing
February 2017

ABCG2, Cytogenetics, and Age Predict Relapse after Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in Complete Remission.

Biol Blood Marrow Transplant 2016 09 10;22(9):1621-1626. Epub 2016 May 10.

Division of Hematology and Stem Cell Transplantation, Azienda Ospedaliero-Universitaria di Udine, Udine, Italy.

Recent studies have shown that ABGG2 protein overexpression in acute myeloid leukemia (AML) may be associated with poor response to therapy and increased relapse risk. Few data are available in patients with AML undergoing allogeneic stem cell transplantation (SCT), particularly when in complete remission (CR). We analyzed 105 patients with AML who underwent allogeneic SCT in CR evaluating the role of ABCG2 and other pretransplantation features on subsequent transplantation outcomes. Factors negatively associated with leukemia-free survival (LFS) were unfavorable cytogenetics (3-year LFS 48% versus 80%, P = .0035) and ABCG2 positivity (65% versus 80%, P = .045). Three-year cumulative incidence of relapse (CIR) in the whole population was 20%; a higher incidence of relapse was associated with adverse cytogenetics (41% versus 16%, P = .018), ABCG2 overexpression (29% versus 15%, P = .04), and, marginally, age > 50 years (30% versus 14%, P = .06). We grouped patients according to the combination of these 3 risk factors: no patient relapsed within 3 years from SCT in the group without risk factors, whereas the 3-year CIR was 12% (95% confidence interval [CI], 2% to 25%) in the group with 1 risk factor and 47% (95% CI, 31% to 70%) in patients with 2 or 3 risk factors (P = .00005). In conclusion, allogeneic SCT does not seem to abrogate the negative prognosis associated with ABCG2 overexpression at diagnosis, specifically in terms of a higher relapse risk. ABCG2, age, and cytogenetics can predict AML relapse after SCT in patients who undergo transplantation while in CR.
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http://dx.doi.org/10.1016/j.bbmt.2016.05.002DOI Listing
September 2016

Clinical impact of CD200 expression in patients with acute myeloid leukemia and correlation with other molecular prognostic factors.

Oncotarget 2015 Oct;6(30):30212-21

Division of Hematology and Bone Marrow Transplantation, Azienda Ospedaliero-Universitaria di Udine, Udine, Italy.

CD200, a protein belonging to the immunoglobulin superfamily, has been associated with a poor prognosis in lymphoproliferative disorders and in acute leukemia. We studied the expression of CD200 in a series of 244 patients with diagnosis of acute myeloid leukemia (AML), to evaluate its impact on outcome and its possible association with other known prognostic factors. CD200 was found in 136/244 (56%) patients, in 41 of whom (30%) with high intensity of expression (MFI ≥ 11). CD200 was more frequent in secondary compared to de novo leukemia (p = 0.0006), in CD34 positive cases (p = 0.00001), in Bcl2 overexpressing cases (p = 0.01), in those wild-type Flt3 (p = 0.004) and with favorable or unfavorable compared to intermediate karyotype (p = 0.0003). CD200+ patients have a two-fold lower probability to attain complete remission, both in univariate (p = 0.006) and multivariate (p = 0.04) analysis. The negative impact of CD200 was found also in overall survival (p = 0.02) and was correlated with the intensity of expression of the molecule (p = 0.024). CD200 has an additive negative impact on survival in patients with unfavorable cytogenetic (p = 0.046) and in secondary leukemia (p = 0.05), and is associate with a worsening of outcome in patients with favorable biological markers, such as mutated NPM (p = 0.02), wild-type Flt3 (p = 0.034), negativity of CD34 (p = 0.03) and of CD56 (p = 0.03). In conclusion, CD200 is emerging as both a prognostic factor and a potential target of novel therapeutic approaches for AML, aiming to reverse the "do not eat me" signal of CD200 or to manipulate the suppressive immune microenvironment induced by CD200 binding to its receptor.
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http://dx.doi.org/10.18632/oncotarget.4901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745791PMC
October 2015

ABCG2 overexpression in patients with acute myeloid leukemia: Impact on stem cell transplantation outcome.

Am J Hematol 2015 Sep 22;90(9):784-9. Epub 2015 Jul 22.

Division of Hematology and Bone Marrow Transplantation, Azienda Ospedaliero-Universitaria di Udine, Udine, Italy.

ABGG2 protein overexpression in acute myeloid leukemia (AML) has been associated with poor response to conventional chemotherapy and increased relapse risk. No data are available on the role of allogeneic stem cell transplantation (SCT) in reversing its negative prognostic role. We have reviewed the outcome of 142 patients with high risk AML who underwent allogeneic SCT in complete remission (n = 94) or with active disease (n = 48). Patients with ABCG2 overexpression at AML diagnosis have lower leukemia free survival (LFS) and increased cumulative incidence of relapse (CIR) compared with ABCG2- patients (5-year LFS 50% vs. 65%, P = 0.01; 5-year CIR 46% vs. 27%, P = 0.003). Five-year overall survival was not significantly different between ABCG2+ and ABCG2- patients (39% vs. 51%, P = 0.1). However, if we consider only disease-related deaths, ABCG2 maintains its negative role (64% vs. 78%, P = 0.018). The negative impact of ABCG2 overexpression was higher in patients undergoing SCT in CR compared with patients receiving transplant with active disease. Conditioning regimen did not abrogate the effect of ABCG2 overexpression, as CIR was higher in ABCG2+ patients receiving both myeloablative (44% vs. 22%, P = 0.018) or reduced intensity conditioning (50% vs. 32%, P = 0.03). In conclusion, ABCG2 overexpression at AML diagnosis identifies a subset of patients with poor outcome also after allogeneic SCT, mainly in terms of higher relapse rates. Prospective studies employing conditioning drugs or post-transplant strategies able to target ABCG2 are needed to maximize the curative potential of stem cell transplantation.
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http://dx.doi.org/10.1002/ajh.24084DOI Listing
September 2015

Factors affecting outcome of allogeneic stem cell transplantation as salvage in patients with acute myeloid leukemia primary refractory to intensive induction therapy.

Am J Hematol 2014 Sep 19;89(9):933-4. Epub 2014 Jun 19.

Division of Hematology and Bone Marrow Transplantation, Department of Clinical and Experimental Medical Sciences, AOU Udine, Udine, Italy.

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http://dx.doi.org/10.1002/ajh.23769DOI Listing
September 2014

Donor compatibility and performance status affect outcome of allogeneic haematopoietic stem cell transplant in patients with relapsed or refractory acute myeloid leukaemia.

Ann Hematol 2012 Dec 15;91(12):1937-43. Epub 2012 Aug 15.

Division of Hematology and Bone Marrow Transplantation & Department of Experimental and Clinical Medical Sciences, Azienda Ospedaliero-Universitaria di Udine, P.zzale S. M. Misericordia, 15, 33100 Udine, Italy.

We retrospectively analysed 78 patients with relapsed (n = 38), primary refractory (n = 34) or untreated (n = 6) acute myeloid leukaemia (AML) who underwent allogeneic HSCT at our Institution between 2002 and 2011, to verify outcome and to identify factors that can affect long-term outcome. Myeloablative conditioning regimens were used in 48 patients (24 siblings, 24 matched unrelated donor (MUD)), while 30 patients (18 siblings, 12 MUD) received reduced-intensity conditioning. Acute graft versus host disease (GVHD) developed in 37 (47 %) patients, while chronic GVHD occurred in 19 of the 65 evaluable patients (29 %). With a median follow-up time of 5 years, 13 of 78 patients (17 %) are alive and in complete remission (CR), while 64 have died. Cause of death was disease recurrence in 37 patients (58 %), infection in ten patients (16 %) and GVHD in six (9 %). One-year non-relapse mortality was 35 %. In multivariate analysis, performance status ≥80 % WHO and a full-matched donor were associated with a better outcome: these two variables allowed for risk stratification, identifying three groups with significantly different survival after transplant (P = 0.0001). Considering post-transplant variables, only CR at recovery and development of cGVHD were correlated with a longer survival. Our data confirm the capacity of allogeneic transplant to prolong survival in a significant proportion of extremely high-risk AML patients.
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http://dx.doi.org/10.1007/s00277-012-1551-xDOI Listing
December 2012

Prognostic significance of delayed thrombocytopenia after allogeneic stem cell transplant.

Am J Hematol 2011 Sep 9;86(9):790-2. Epub 2011 Aug 9.

Clinica Ematologica, Centro Trapianti e Terapie Cellulari Carlo Melzi, DISM, Azienda Ospedaliero Universitaria S. M. Misericordia, 33100 Udine, Italy.

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http://dx.doi.org/10.1002/ajh.22086DOI Listing
September 2011

Concomitant ABCG2 overexpression and FLT3-ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse.

Cancer 2011 May 29;117(10):2156-62. Epub 2010 Nov 29.

Division of Hematology and Bone Marrow Transplantation, Department of Medical and Morphological Researches, AOU Udine, Udine, Italy.

Background: ABCG2 protein overexpression and FLT3 internal tandem duplication (ITD) correlate with higher relapse rate and shorter disease-free survival (DFS) in acute myeloid leukemia (AML), but no data are available on the possible effect of concomitant presence of these 2 factors.

Methods: The authors analyzed the outcome of 166 cases of adult AML patients who were homogeneously treated with a fludarabine-based induction therapy.

Results: ABCG2 overexpression and FLT3-ITD were detected in 83 (50%) and 47 (28%) patients, respectively. A significant correlation was found between ABCG2 positivity and FLT3 mutation, with 33 (40%) ITD in 83 ABCG2-positive patients compared with 14 (17%) ITD in 83 ABCG2-negative patients (P = .002). Complete remission (CR) after induction therapy was achieved in 95 (57%) patients. Neither ABCG2 overexpression nor FLT3-ITD had any impact on achievement of CR. Relapse occurred in 42 of 95 (44%) patients at a median time of 28 months. Time to relapse was shortened in patients overexpressing ABCG2 (P = .0004). DFS was not affected by FLT3-ITD alone, but FLT3 mutation significantly worsened long-term outcome of ABCG2-positive patients. DFS at 1 and 3 years in patients with overexpression of both ABCG2 and FLT3-ITD was only 36% and 28%, respectively; in ABCG2-positive/FLT3-negative patients, DFS at 1 and 3 years was 65% and 48%, respectively; and in ABCG2-negative cases (regardless of FLT3 status), DFS at 1 and 3 years was greater than 85% and 75%.

Conclusions: Concomitant overexpression of ABCG2 and FLT3-ITD is relatively frequent and identifies a subgroup of AML patients with a significantly worse prognosis. The possible interactions between these 2 prognostic factors need to be defined.
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http://dx.doi.org/10.1002/cncr.25753DOI Listing
May 2011

Fludarabine-based induction therapy does not overcome the negative effect of ABCG2 (BCRP) over-expression in adult acute myeloid leukemia patients.

Leuk Res 2010 Jul 31;34(7):942-5. Epub 2010 Jan 31.

Clinica Ematologica e Centro Trapianti e Terapie Cellulari C. Melzi, Azienda Ospedaliero-Universitaria di Udine, Dipartimento di Ricerche Mediche e Morfologiche, Università di Udine, Udine, Italy.

Over-expression of multidrug resistance (MDR) proteins PGP and BCRP has a negative prognostic impact in acute myeloid leukemia (AML) patients. Inclusion of fludarabine in induction chemotherapy increases remission rate in PGP over-expressing cases. We investigated the role of BCRP in 138 adult AML patients receiving induction therapy with fludarabine. None of the MDR-related proteins influenced complete remission attainment. Conversely, high levels of BCRP significantly affected disease-free survival, as higher relapse rates (48.5% vs 28.5%) and earlier relapse occurred in BCRP+ patients. Also overall survival was affected by BCRP positivity, and survival significantly worsened in case of concomitant PGP and BCRP over-expression.
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http://dx.doi.org/10.1016/j.leukres.2010.01.008DOI Listing
July 2010

The use of G-CSF during first line chemotherapy adversely affects the yield of PBSC mobilization in non-Hodgkin's lymphoma patients.

Adv Clin Path 2002 Jan;6(1):11-6

Chair and Division of Hematology, Bone Marrow Transplant Unit, Department of Medical and Morphological Research, University Hospital, Udine, Italy.

Regardless the mobilization procedure used there is a great variability from patient to patient in the yield of CD34 collections for autologous transplantation. We analyzed retrospectively our non-Hodgkin's lymphoma survey of 60 patients harvested with G-CSF alone after a unique first line chemotherapy; 67% of patients harvested a sufficient number of CD34+ cells during the first attempt of mobilization. The charachteristics of leukaphereses procedures were the same for all the patients. Sex, age, months from the end of chemo- or radio-therapy did not have a significance in influencing mobilization capability, while requirement of G-CSF during chemotherapy was statistically different from failures to successes: 16/20 (80%) of patients failing to reach the target of 2x10(6)/kg CD34+ cells had required G-CSF support during previous chemotherapy versus 18/40 (45%) in the successful group (p 0,005). Our observation supports the hypotesis that individual biological charachteristics of each patient are the most important factors in affecting mobilization capability, deserving further investigation: mobilization schedules tailored on a given patient would minimize the rate of failures, avoiding a second attempt of collection that implies additional economic expenses and negative consequences on the maintenance of dose intensity.
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January 2002

Case-control study of multidrug resistance phenotype and response to induction treatment including or not fludarabine in newly diagnosed acute myeloid leukaemia patients.

Br J Haematol 2007 Jan;136(1):87-95

Chair of Haematology, Unit of Blood Diseases and Cell Therapies, University of Brescia, Brescia, Italy.

One hundred and six patients aged /= 6) vs. 75% among the MDR-Pgp-negative (neg(ve)) ones (MFI < 6) (P = 0.16). Conversely, in the controls, the CR rate was 44% among the MDR-Pgp-pos(ve) patients vs. 67% among the MDR-Pgp-neg(ve) ones (P = 0.02). The 4-year disease-free survival (DFS) and overall survival (OS) of MDR-Pgp-pos(ve) cases were significantly longer than those of MDR-Pgp-pos(ve) controls (DFS, 28.1% vs. 6.5%, P = 0.004; OS, 33.5% vs. 9.6%, P = 0.01). This difference was not found among the MDR-Pgp-neg(ve) patients. By univariate (P = 0.007) and multivariate (P = 0.007) analysis, the MDR-Pgp-pos(ve) phenotype was negatively correlated with CR and it emerged as the most important independent negative prognostic factor, after cytogenetics. Our study confirms the prognostic impact of the MDR phenotype in AML and strongly suggests fludarabine-based induction treatments as a promising strategy for MDR-Pgp-pos(ve) AML patients. In this setting of patients, large prospective randomised studies should be planned.
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http://dx.doi.org/10.1111/j.1365-2141.2006.06390.xDOI Listing
January 2007

Effect on survival of the development of late-onset non-infectious pulmonary complications after stem cell transplantation.

Haematologica 2006 Sep;91(9):1268-72

Division of Haematology, Transplantation Unit and Cellular Therapies Carlo Melzi, Department of Clinical and Morphological Research, University Hospital of Udine.

We evaluated the incidence, risk factors, and clinical outcome of late-onset non-infectious pulmonary complications (LONIPC) in 599 patients who underwent hematopoietic allogeneic stem cell transplantation (HSCT). The 2-year cumulative incidence of LONIPC was 10% among the 438 patients surviving more than 3 months after HSCT. Transplants from an unrelated donor and occurrence of extensive chronic graft-versus-host disease were the variables significantly associated with the development of LONIPC. The 5-year overall survival was significantly worse among patients with LONIPC than among those without (34% vs 65%, p=0.009). Causes of death were respiratory failure and infections. The relapse rate was similar in the two groups.
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September 2006

The prognostic value of P-glycoprotein (ABCB) and breast cancer resistance protein (ABCG2) in adults with de novo acute myeloid leukemia with normal karyotype.

Haematologica 2006 Jun 16;91(6):825-8. Epub 2006 May 16.

Division of Hematology and Bone Marrow Transplantation, Udine University Hospital, Udine, Italy.

Multidrug resistance is a major cause of treatment failure in acute myeloid leukemia (AML). P-glycoprotein (PGP) over-expression has an unfavorable prognostic significance, while the role of breast cancer resistance protein (BCRP) is less clear, especially in AML patients with a normal karyotype. We studied 73 consecutive AML patients with a normal karyotype. BCRP was over-expressed in 24 patients (33%) and was significantly co-expressed with PGP (13/24 vs 11/49, p=0.006) and with CD56. Only PGP, along with age and CD34, affected the achievement of complete remission (p=0.02), while BCRP-positive cases showed an increased risk of relapse (p=0.005) and a shorter disease-free survival (p=0.027). BCRP over-expression did not influence the achievement of remission, but significantly affected the duration of complete remissions. BCRP may, therefore, be regarded as a prognostic factor in patients with normal karyotype AML, for the design of risk-adapted post-remission therapy.
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June 2006

The development of autoantibodies after allogeneic stem cell transplantation is related with chronic graft-vs-host disease and immune recovery.

Exp Hematol 2006 Mar;34(3):389-96

Division of Haematology and Blood and Bone Marrow Transplantation Unit "Carlo Melzi," Department of Clinical and Morphological Research, Udine, Italy.

Objective: Chronic graft-vs-host disease (GVHD) has certain similarities with autoimmune diseases and is associated with the development of various autoantibodies in some patients. In this study, we analyzed the occurrence of autoantibodies in 63 patients surviving longer than 3 months after an allogeneic haematopoietic stem cell transplantation (HSCT), with the aim of detecting a possible association between occurrence of autoantibodies and development of chronic GVHD and immune recovery after HSCT.

Patients And Methods: The patients were screened every 3 months for the occurrence of the following autoantibodies: anti-nuclear (ANA), anti-mitochondrial (AMA), anti-smooth muscle (ASMA), anti-cardiolipin (ACLA), anti-liver-kidney microsomal (LKM), anti-DNA, anti-neutrophil cytoplasmatic (ANCA), and anti-thyroid antibodies. Peripheral blood immunophenotyping with anti-CD3, CD4, CD8, CD19, CD20, CD16, and CD56 antibodies was evaluated at the same intervals.

Results: Autoantibodies were not found in 18 patients (29%), at least in one screening in 29 patients (46%), and in all screenings in 16 patients (25%). ANA were found in 41 patients (65%), AMA in 4 (6%), ASMA in 4 (6%), ANCA in 7 (11%), ACLA in 1 (2%), anti-thyroid antibodies in 3 (5%), and anti-DNA in 2 (3%). More than one antibody occurred in 16/63 (25%) positive patients. ANA was significantly more frequent in patients with chronic GVHD and, among these, in those with the extensive form. The nucleolar pattern of immunofluorescence of ANA but not its titer was correlated with the extension of chronic GVHD. Patients who developed autoantibodies had higher CD20(+) cell blood counts than negative patients in the third month (p=0.006), ninth month (p=0.061), and twelfth month (p=0.043).

Conclusion: We conclude that patients with chronic GVHD, particularly those with an extensive involvement, were likely to develop autoantibodies and have a faster B-cell recovery, suggesting a role of B cells in the pathogenesis of chronic GVHD.
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http://dx.doi.org/10.1016/j.exphem.2005.12.011DOI Listing
March 2006

Sclerodermatous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: incidence, predictors and outcome.

Haematologica 2006 Feb;91(2):258-61

Division of Haematology, Dept. of Clinical and Morphological Research, University of Udine.

Scleroderma may be one of the most severe forms of chronic graft-versus-host disease (GVHD). We retrospectively evaluated its incidence, predictor variables and outcome in 133 patients who survived at least 4 months after allogeneic hematopoietic stem cell transplantation. The 5-year cumulative incidence was 15.5% in patients with chronic GVHD. The generalized form had a progressive course despite immunosuppressive therapy. Eosinophilia, autoimmune markers, and previous skin involvement by chronic GVHD with disorders of pigmentation were significantly associated with an increased probability of developing scleroderma.
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February 2006

Autologous stem cell transplantation for systemic lupus erythematosus.

Lupus 2004 ;13(3):168-76

Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.

Systemic lupus erythematosus (SLE) is responsive to treatment with immunosuppressives and steroids, but often pursues a relapsing or refractory course resulting in increasing incapacity and reduced survival. Autologous stem cell transplantation (ASCT) following immunoablative chemotherapy is a newer therapy for autoimmune disease of potential use in severe SLE. A retrospective registry survey was carried out by the European Blood and Marrow Transplant and European League Against Rheumatism (EBMT/EULAR) registry. Data was collected from 53 patients with SLE treated by ASCT in 23 centres. Disease duration before ASCT was 59 (2-155) months (median, range), 44 (83%) were female, and median age was 29 (9-52) years. At the time of ASCT a median of seven American College of Rheumatology (ACR) diagnostic criteria for SLE were present (range 2-10) and 33 (62%) had nephritis. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony stimulating factor in 93% of cases. Ex vivo CD34 stem cell selection was performed in 42% of patients. Conditioning regimens employed cyclophosphamide in 84%, anti-thymocyte globulin in 76% and lymphoid irradiation in 22%. The mean duration of follow-up after ASCT was 26 (0-78) months. Remission of disease activity (SLEDAI < 3) was seen in 33/50 (66%; 95%CI 52-80) evaluable patients by six months, of which 10/31 (32%; 95%CI 15-50) subsequently relapsed after six (3-40) months. Relapse was associated with negative anti-double stranded DNA (anti-dsDNA) antibodies before ASCT (P = 0.007). There were 12 deaths after 1.5 (0-48) months, of which seven (12%; 95%CI 3-21) were related to the procedure. Mortality was associated with a longer disease course before ASCT (P = 0.036). In conclusion, this registry study demonstrates the efficacy of ASCT for remission induction of refractory SLE, although mortality appeared high. The safety of this procedure is likely to be improved by patient selection and choice of conditioning regimen. The return of disease activity in one-third of patients might be reduced by long-term immunosuppressive therapy post-ASCT.
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http://dx.doi.org/10.1191/0961203304lu525oaDOI Listing
July 2004

Antibody binding capacity for evaluation of MDR-related proteins in acute promyelocytic leukemia: Onset versus relapse expression.

Cytometry B Clin Cytom 2004 May;59(1):40-5

Department of Medical and Morphological Research, Division of Hematology, University Hospital, Udine, Italy.

Background: Multidrug resistance (MDR) remains a major obstacle for successful treatment in cancer, in particular in acute leukemia. In acute promyelocytic leukemia (APL), the high sensitivity to anthracyclines appears to be attributable to the low frequency of MDR proteins overexpression at onset even if 30% of patients still relapse and become resistant to therapy. In attempt to explain different blast cell sensitivity, we studied the expression of PGP, MRP1, MRP2, and LRP in 45 cases of APL, comparing onset of disease with relapse.

Methods: PGP, LRP, and MRP on bone marrow or peripheral blood blast cells were evaluated by flow cytometry using the MRK-16, LRP-56, MRP-m6, and MRP2 antibodies and results expressed by the mean fluorescence index (MFI). The antibody binding capacity (ABC) for each MDR protein was also calculated.

Results: At diagnosis, only 2 of 45 patients overexpressed PGP and 1 overexpressed LRP. PGP and LRP overexpressing cases significantly grew up during disease progression and at second relapse mean PGP MFI and mean LRP MFI were significantly higher than at onset (P = 0.001 and P = 0.008, respectively). By analyzing ABC, the same trend was more evident because a significant increment of PGP and LRP was observed at second (P = 0.002 and P = 0.002, respectively), but even at first relapse (P = 0.018 and P = 0.002, respectively). No changes were demonstrated in MRP1 and MRP2 expression in any phase of disease considered.

Conclusions: Our data confirm the low expression at diagnosis of proteins related to development of drug resistance in APL. The evidence of a relative easy induction of PGP and LRP, but not of MRP, can be useful in choosing drugs to employ for consolidation or rescue therapy.
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http://dx.doi.org/10.1002/cyto.b.20006DOI Listing
May 2004

Clinical characteristics, prognostic factors and multidrug-resistance related protein expression in 36 adult patients with acute promyelocytic leukemia.

Eur J Haematol 2003 Jul;71(1):1-8

Division of Hematology and Bone Marrow Transplantation, Department of Medical and Morphological Researches, University Hospital, Udine, Italy.

Unlabelled: We report on a single-center experience about the characteristics and outcome of 36 acute promyelocytic leukemia (APL) patients observed at our Department of Hematology between 1990 and 2002. The expression, of multidrug-resistance (MDR) associated proteins (PGP, LRP, MRP1) was also analyzed. There were 12 males and 24 females (median age 37 yr), 89% (32 of 36) with classic morphology, and 11% (four of 36) with a microgranular variant. Risk class (according to GIMEMA/PETHEMA): 25% (nine of 36) high risk (HR), 53% (nineteen of 36) intermediate risk (IR), 22% (eight of 36) low risk (LR). PGP, LRP, and MRP1 expression at onset and at first relapse was low. CD33 antigen expression was high in all cases. The patients were treated according to GIMEMA protocols (LAP0389 and AIDA) including ATRA in induction in 75% (27 of 36) of cases and 94% (34 of 36) achieved a complete remission (CR) after induction therapy while 6% (two of 36) died early (DDI) of hemorrhage.

Outcome: 71% (24 of 34) of evaluable patients remain in CR at a median follow-up of 57 months (range 4-158 months) while 29% (10 of 34) relapsed at a median time of 12 months (range 8-43 months) and, of them, eight of 10 died early. The majority of patients that relapsed were in high-risk group. The overall survival (OS) of the whole population at 32 months was 66% and the DFS at 42 months was 62%. A statistically significant difference in terms of DFS was observed between HR and IR/LR patients (P = 0.04 by log-rank). DFS was not affected by age, sex, Hb levels, karyotype, and BCR isoform. At conclusion, our data confirm that despite the high rate of success with ATRA plus chemotherapy as induction (more than 90% of CR), about 30% of APL patients have a relapse (without a long-lasting second remission) and underline the importance of patient stratification in distinct risk groups at diagnosis in order to better adapt the type and intensity of treatment (risk-adapted therapy). Taking into account the high expression of CD33 and the low expression of MDR proteins in APL, new and investigational approaches like gemtuzumab-ozogamicin, with or without ATRA and other new drugs, should be strongly considered expecially in HR APL.
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http://dx.doi.org/10.1034/j.1600-0609.2003.00084.xDOI Listing
July 2003

CD56 and PGP expression in acute myeloid leukemia: impact on clinical outcome.

Haematologica 2002 Nov;87(11):1135-40

Department of Hematology, University of Siena, Italy.

Background And Objectives: Overexpression of P-glycoprotein (PGP), a multidrug-related (MDR) protein, is one of the most important factors responsible for reduced drug sensitivity in acute myeloid leukemia (AML). Recently, we demonstrated that the presence of CD56 antigen, an isoform of the neural adhesion molecule, in AML cells is a negative independent prognostic factor for the achievement of complete remission (CR) and correlates with shorter survival. Since in our previous report we observed a more frequent PGP expression in CD56+ patients, we hypothesized that the reduced response to chemotherapy in this group of patients was due to increased PGP-mediated drug efflux. To confirm this hypothesis in this study PGP and CD56 expression on AML cells was correlated with other clinical and biological features and treatment response.

Design And Methods: Immunophenotypic analysis, including evaluation of CD56 and PGP expression, was performed using multiparameter flow cytometry on fresh and/or cryopreserved blast cells, obtained after informed consent, from bone marrow and/or peripheral blood of 143 consecutive newly diagnosed AML cases at the time of diagnosis. Samples expressing CD56 in at least 15% or more cells were considered as positive (CD56+). PGP expression was expressed as a mean fluorescence index (MFI) i.e. as the ratio of sample mean fluorescence channel and the isotypic control mean fluorescence channel.

Results: Overall results showed that 67/143 cases were PGP-/CD56-, 23/143 were PGP+ /CD56+, 40/143 were PGP+/CD56- and the remaining 13/143 were PGP-/CD56+. CD56+ and PGP+ on AML cells significantly reduced the CR rate (83% in the PGP-/CD56- group vs 60% in the PGP-/CD56+ group, 46% in the PGP+/CD56- group and 58% in the PGP+/CD56+ group, p = 0.002). In addition we observed a significantly higher proportion of total failures in patients expressing PGP or CD56 compared to in the group not expressing either (73% vs 27%, respectively; p = 0.0001). CD56 and PGP overexpression influenced the overall survival: in fact, the median survival of CD56+ and PGP+ patients ranged from 10 to 23 months, while the actuarial survival of CD56-/PGP- patients at 5 years is 52% (p = 0.023).

Interpretation And Conclusions: Our data underline the independent negative prognostic role of PGP and CD56 expression in acute myeloid leukemia. Since the mechanism by which CD56 reduces drug sensitivity is still unknown, further investigations are required.
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November 2002

Activity of all-trans-retinoic acid in a case of central nervous system extramedullary relapse of acute promyelocytic leukemia.

Eur J Haematol 2002 May;68(5):310-3

Division of Hematology, Department of Bone Marrow Transplantation, Udine University Hospital, P. le S. Maria della Misericordia, I-13300 Udine, Italy.

We describe a patient with an acute promyelocytic leukemia (APL) previously treated with two courses of cytarabin, idarubicin and all-trans retinoic acid (ATRA), who presented a medullary and meningeal relapse after 8 months of complete remission. A diagnosis of central nervous system (CNS) involvement was based on the appearance of APL blasts in the cerebrospinal fluid (CSF); magnetic resonance (MR) imaging was negative. The neurological symptoms were not evident at the time of recognition of the medullary recurrence, but appeared a few days later, when the patient had already received a reinduction treatment. When the CSF was first examined, showing atypical promyelocytes, there was no excess of blasts on bone-marrow examination. The patient was treated with ATRA and intrathecal administrations of cytoxic drugs, achieving a complete long-lasting CNS remission. The appearance of mature myeloid cells in the CSF during this treatment suggested a possible differentiating effect of ATRA towards extramedullary relapse.
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http://dx.doi.org/10.1034/j.1600-0609.2002.01660.xDOI Listing
May 2002

Autologous stem cell transplantation for Hodgkin's lymphoma: results and prognostic factors in 51 high-risk patients.

Adv Clin Path 2002 Apr;6(2):77-85

Division of Haematology, Bone Marrow Transplant Unit, Department of Medical and Morphological Research, University Hospital, Udine, Italy.

Autologous stem cell transplantation (ASCT) is largely employed in primary resistant or recurrent Hodgkin's Lymphoma (HL), while its role early in the course of the disease is still controversial. Our purpose was to analyse the results of 51 high-risk HL patients autografted at our Institution and the role of possible prognostic risk factors for the outcome. Twelve (23.5%) patients were in complete remission at transplant and were transplanted as having an high risk disease; 20 (39.5%) patients were in partial response and 19 (37.0%) were transplanted as primary induction failure. At a median time of 38 (6-111) months from ASCT, 36 (70.5%) patients are alive in complete remission, 8 (15.5%) patients are alive with disease and 7 (14.0%) died for progression. Thirty out of 32 (94.0%) patients transplanted with responsive disease (either complete or partial response) are alive without disease. Six out of 19 (32.0%) patients transplanted with resistant disease are alive in complete remission. The overall survival of the entire population is 77.0% at 60 (14-151) months from diagnosis. Disease free survival of the 22 patients that achieved a complete remission after ASCT (16 in partial response and 6 with resistant disease) is 100%. In our experience, more than 90% of patients transplanted with responsive but high risk disease, seem achieving and maintaining a durable complete remission, and more than 30.0% of patients submitted to ASCT with refractory disease can be potentially rescued by transplant.
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April 2002

P-glycoprotein, lung resistance-related protein and multidrug resistance-associated protein in de novo adult acute lymphoblastic leukaemia.

Br J Haematol 2002 Mar;116(3):519-27

Division of Haematology, Department of Medical and Morphological Research, University Hospital, Udine, Italy.

P-glycoprotein (P-gp), lung resistance-related protein (LRP) and multidrug resistance-associated protein (MRP) expression, and blast cell intracellular daunorubicin accumulation (IDA) were evaluated in 95 previously untreated cases of adult acute lymphoblastic leukaemia (ALL) using flow cytometry. Forty-five out of 95 (47%) patients were P-gp positive (+), 12/66 (18%) were LRP+ and 11/66 (17%) were MRP+. Eighteen out of 66 (28%) patients showed a simultaneous multidrug resistance (MDR)-related protein expression higher than controls for more than one protein, while 24/66 (36%) cases did not overexpress any protein. Twenty-one out of 24 (87%) cases overexpressing at least one MDR-related protein had a defect in accumulating daunorubicin into their blast cells, while only 4/24 (16%) cases who did not overexpress any protein had similar features. The complete remission rates were similar in MDR-positive and -negative (-) patients but relapses within 6 months were more frequent in P-gp+ cases, and therefore the disease-free survival duration was shorter in P-gp+ than in P-gp- patients (P = 0.01). The number of MRP+ and/or LRP+ cases was too small to be able to draw any conclusion on their role in affecting or predicting therapy outcome. In conclusion, P-gp overexpression associated with a defect in daunorubicin accumulation is a frequent feature in adult ALL at onset and seems to be related to poorer therapy outcome and, consequently, a shorter disease-free survival. LRP and MRP overexpression seems to be a rare event and no conclusion can be drawn on its prognostic role.
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http://dx.doi.org/10.1046/j.0007-1048.2001.03322.xDOI Listing
March 2002