Publications by authors named "Angela Michelutti"

32 Publications

Cytomegalovirus Prophylaxis versus Pre-emptive Strategy: Different CD4 and CD8 T Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 Jun 5;27(6):518.e1-518.e4. Epub 2021 Mar 5.

Hematology and Transplant Center Unit, Dipartimento di Area Medica (DAME), Udine University Hospital, Udine, Italy.

Reconstitution of T cells after transplantation is a determinant of the long-term success of the procedure, and the correlation with T cell recovery and cytomegalovirus reactivation and disease is well known. We evaluated 110 patients who underwent transplantation: 55 received pre-emptive antiviral treatment, and in the other 55 patients, prophylaxis with letermovir was employed. A progressive statistically significant difference in T cell reconstitution between the 2 groups was observed, starting from day +60 with faster recovery in the pre-emptive group. Moreover, a higher incidence of cytomegalovirus reactivation was observed in prophylactic group after discontinuation of letermovir, and subsequent antiviral treatment has been necessary. Our findings confirm, as previously reported, that cytomegalovirus reactivation is a potent stimulator of T cell function.
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http://dx.doi.org/10.1016/j.jtct.2021.03.003DOI Listing
June 2021

Impact of Concomitant Aberrant CD200 and BCL2 Overexpression on Outcome of Acute Myeloid Leukemia: A Cohort Study from a Single Center

Turk J Haematol 2021 06 18;38(2):119-125. Epub 2021 Feb 18.

University of Udine, Department of Medical Area, Division of Hematology and Stem Cell Transplantation, Udine, Italy

Objective: CD200 and BCL2 overexpression is independently associated with inferior survival in acute myeloid leukemia (AML), and these two factors are frequently co-expressed; however, no data are available on the role of concomitant aberrant CD200 and BCL2 expression on outcome of AML patients. We aimed to elucidate the prognostic role of CD200/BCL2 co-expression and its association with specific leukemia subsets.

Materials And Methods: We analyzed 242 adult AML patients uniformly treated with intensive chemotherapy, evaluating the impact of CD200 and BCL2 expression on complete remission (CR), disease-free survival, and overall survival (OS).

Results: CD200 and BCL2 were expressed in 139 (57.4%) and 137 (56.6%) cases, respectively, with 92 patients (38%) displaying double positivity (DP), 58 (24%) displaying double negativity (DN), and 92 patients expressing only either CD200 (n=47) or BCL2 (n=45). CR was achieved in 71% of cases, being less frequent in DP patients (60%) compared to other groups (76%-81%, p<0.001). In the whole population 3-year OS was 44%, being lower in DP patients (28%) than in patients with single CD200 or BCL2 expression (47%) or DN cases (60%; p=0.004). Other factors associated with worse OS were advanced age, CD34 positivity, secondary AML, and high white blood cell count at diagnosis; combining these 4 factors with CD200/BCL2 DP, we identified 6 groups with significantly different rates of survival (3-year OS ranging from 90% to 0%).

Conclusion: Our data support a synergistic effect of CD200 and BCL2 in AML cells, conferring an enhanced survival capacity in a permissive microenvironment and resulting in worse prognosis.
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http://dx.doi.org/10.4274/tjh.galenos.2021.2020.0728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171206PMC
June 2021

Features, reason for testing, and changes with time of 583 paroxysmal nocturnal hemoglobinuria clones from 529 patients: a multicenter Italian study.

Ann Hematol 2019 May 13;98(5):1083-1093. Epub 2019 Mar 13.

Dipartimento di Medicina, Ematologia e Immunologia Clinica Policlinico Universitario, Padova, Italy.

In this study, we aimed at disclosing the main features of paroxysmal nocturnal hemoglobinuria (PNH) clones, their association with presentation syndromes, and their changes during follow-up. A large-scale, cooperative collection (583 clones from 529 patients) of flow cytometric and clinical data was entered into a national repository. Reason for testing guidelines were provided to the 41 participating laboratories, which followed the 2010 technical recommendations for PNH testing by Borowitz. Subsequently, the 30 second-level laboratories adopted the 2012 guidelines for high-resolution PNH testing, both upon order by the local clinicians and as an independent laboratory initiative in selected cases. Type3 and Type2 PNH clones (total and partial absence of glycosyl-phosphatidyl-inositol-anchor, respectively) were simultaneously present in 54 patients. In these patients, Type3 component was sevenfold larger than Type2 (p < 0.001). Frequency distribution analysis of solitary Type3 clone size (N = 442) evidenced two discrete patterns: small (20% of peripheral neutrophils) and large (> 70%) clones. The first pattern was significantly associated with bone marrow failure and myelodysplastic syndromes, the second one with hemolysis, hemoglobinuria, and thrombosis. Pediatric patients (N = 34) showed significant preponderance of small clones and bone marrow failure. The majority of PNH clones involved neutrophils, monocytes, and erythrocytes. Nevertheless, we found clones made exclusively by white cells (N = 13) or erythrocytes (N = 3). Rare cases showed clonal white cells restricted only to monocytes (6 cases) or neutrophils (3 cases). Retesting over 1-year follow-up in 151 cases showed a marked clone size increase in 4 cases and a decrease in 13, demonstrating that early breaking-down of PNH clones is not a rare event (8.6% of cases). This collaborative nationwide study demonstrates a clear-cut difference in size between Type2 and Type3 clones, emphasizes the existence of just two classes of PNH presentations based on Type3 clone size, depicts an asymmetric cellular composition of PNH clones, and documents the possible occurrence of changes in clone size during the follow-up.
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http://dx.doi.org/10.1007/s00277-019-03644-8DOI Listing
May 2019

ABCG2 overexpression and deoxyadenosine analogue activity in acute myeloid leukemia.

Cancer 2017 12 20;123(24):4934-4935. Epub 2017 Oct 20.

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

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http://dx.doi.org/10.1002/cncr.31037DOI Listing
December 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

BAALC overexpression retains its negative prognostic role across all cytogenetic risk groups in acute myeloid leukemia patients.

Am J Hematol 2013 Oct 23;88(10):848-52. Epub 2013 Jul 23.

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

Overexpression of brain and acute leukemia cytoplasmic (BAALC) gene confers poor prognosis in cytogenetically normal acute myeloid leukemia (AML) patients, while less defined is its role in AML with abnormal karyotype. We evaluated the effect of BAALC overexpression on outcome of 175 adult AML patients with different cytogenetic risks. Karyotype was favorable in 13, intermediate in 117 and unfavorable in 45 patients, respectively. Quantitative BAALC expression was determined by real-time PCR, with cut off value set at 50th percentile. BAALC was overexpressed in 87/175 (50%) patients, without association with cytogenetic status. High BAALC was associated with unmutated NPM (P = 0.006) and CD34 positivity (P < 0.0001). Complete remission (CR) was attained in 111 patients (63%), and was maintained at 5 years in 52 ± 7%. BAALC overexpression had a negative impact on CR achievement (P = 0.04), while did not influence relapse probability. Median survival was 22 months with a 5-years overall survival (OS) of 35%. Factors with a negative impact on OS were older age (P = 0.0001), unfavorable cytogenetic (P = 0.005), ABCG2 overexpression (P = 0.03) and high BAALC levels (P = 0.01). We observed a worse outcome in patients with high BAALC expression through all cytogenetic risk categories: 5-years OS was 100% vs. 71% in patients with favorable cytogenetics (P = 0.05), 55% vs. 40% in cases with intermediate karyotype (P = 0.04) and 34% vs. 23% in unfavorable cytogenetic subgroup (P = 0.02). BAALC overexpression identified AML patients with poor prognosis in all cytogenetic groups. Though relatively rare, BAALC positivity in patients with favorable or unfavorable karyotype significantly worsened survival.
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http://dx.doi.org/10.1002/ajh.23516DOI Listing
October 2013

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

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

Quantitative assessment of WT1 gene expression after allogeneic stem cell transplantation is a useful tool for monitoring minimal residual disease in acute myeloid leukemia.

Eur J Haematol 2009 Jan 17;82(1):61-8. Epub 2008 Sep 17.

Division of Hematology and Bone Marrow Transplantation, Department of Medical and Morphologic Research, University of Udine, Udine, Italy.

Introduction: WT1 overexpression is described in several oncological diseases including acute myeloid leukemia (AML). Quantification of WT1 in bone marrow samples may be useful as a marker of minimal residual disease (MRD) and may predict the relapse of AML after allogeneic hematopoietic stem cell transplant (HSCT).

Methods And Results: The quantitative expression of WT1 was measured in 38 AML patients (16 males and 22 females) at diagnosis, at the time of transplant and after the allogeneic HSCT (at precise time points). All cases showed high WT1 expression levels at diagnosis with a mean of 4189 (SD 3325) and a median of 3495 (range 454-13923) copies WT1/10(4)Abl. At transplant, 25 patients (66%) were in complete cytologic remission (CcR) and 13 (34%) had refractory or relapsed AML. Bone marrow samples from patients transplanted in CcR showed significantly lower WT1 expression levels during HSCT compared with the samples from patients with a relapsed or refractory AML (P = 0.004). After HSCT, a rapid decline in WT1 expression levels was observed in all patients who attained or maintained a condition of CcR. Six of 38 patients (13%) relapsed after HSCT and all of them had an increase in WT1 expression at/or before relapse. Five of these six patients died of leukemia and one was successfully reinduced with donor lymphocyte infusion (DLI) + chemotherapy with a rapid reduction of WT1 levels. Besides, we found a complete concordance between WT1 expression levels and other disease markers (when available).

Conclusions: In our experience, there was a complete concordance between WT1 expression levels (measured by quantitative RT-PCR at precise time points) and status of AML before and after allogeneic HSCT. WT1 may be useful as a non-specific leukemia marker for monitoring MRD and as a predictor of AML clinical relapse. Based on these results, cases with increase of WT1 levels after HSCT and without graft vs. host disease may be candidate to discontinuation of immunosuppression and/or DLI therapy.
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http://dx.doi.org/10.1111/j.1600-0609.2008.01158.xDOI Listing
January 2009

Gemtuzumab-ozogamicin in combination with fludarabine, cytarabine, idarubicin (FLAI-GO) as induction therapy in CD33-positive AML patients younger than 65 years.

Leuk Res 2008 Dec 14;32(12):1800-8. Epub 2008 Jul 14.

Division of Hematology, Bone Marrow Transplantation Unit, Department of Clinical and Morphological Research, University Hospital, Udine, Italy.

Introduction: The addition of gemtuzumab-ozogamicin (GO) to an induction regimen including synergistic drugs, such as intermediate dose of cytarabine (Ara-C), idarubicin and fludarabine (FLAI), could reduce treatment failure in acute myeloid leukemia (AML) patients. Nevertheless, the role and safety of this antibody target-therapy in first-line chemotherapy in patients younger than 65 years has not yet been defined.

Patients And Methods: The primary goal of this prospective phase II pilot study was to evaluate the efficacy and the safety profile of FLAI plus GO as induction regimen. Thirty consecutive AML patients were included. All patients were younger than 65 with a median age of 53 years and CD33 expression exceeded 20% in all cases. The M/F ratio was 16/14 and 21/30 (70%) of patients were poor-risk at diagnosis. The induction regimen (FLAI-GO) included fludarabine (30mg/m(2)) and Ara-C (2g/m(2)) on days 1-5, idarubicin (10mg/m(2)) on days 1, 3, and 5 and GO (3mg/m(2)) on day 6. Hematopoietic stem cell transplant (HSCT) was planned for all high risk AML patients in first complete remission (CR) after consolidation with intermediate doses of Ara-C and idarubicin (IDAC-IDA). Cytogenetic, multidrug-resistance phenotype, FLT3 mutation status, and WT1 quantitative expression analyses were performed at diagnosis in all patients. WT1 expression and cytogenetic (in positive cases) analyses were performed after induction to detect and follow minimal residual disease.

Results: Patients were evaluated for response rate, treatment-related adverse events, overall survival and relapse free survival. After induction with FLAI-GO, CR rate was 90% (26 of 29 evaluable pts); one patient achieved partial remission and two were resistant. There was only one case of death during induction (DDI). After FLAI-GO, the mean value of WT1 dropped from 4200+/-2777 copies/10(4)ABL to 192+/-399 copies/10(4)ABL. The toxicity of FLAI-GO was acceptable; 57% of patients experienced transient and reversible GO infusion-related adverse events (especially fever and chills), but no cases of veno-occlusive disease occurred during CHT or after HSCT. After a median follow-up of 16 months (range 2-25), 24/30 (80%) patients are alive (24/24 in CR). The probability of 1-year OS and RFS was 90 and 85%, respectively. Allogeneic and autologus HSCT was performed in 19 (63%) and 4 (13%) patients, respectively.

Conclusions: These preliminary results suggest that FLAI-GO is an effective and well tolerated induction regimen for CD33 positive AML patients younger than 65 years, with a high complete response rate, favourable safety profile, low DDI. These results encourage the testing of this regimen in a multicenter prospective trial.
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http://dx.doi.org/10.1016/j.leukres.2008.05.011DOI Listing
December 2008

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

The role of MDR-related proteins in the prognosis of adult acute myeloid leukaemia (AML) with normal karyotype.

Hematol Oncol 2007 Mar;25(1):38-43

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

Cytogenetic abnormalities are among the most important factors affecting the outcome of patients with acute myeloid leukaemia (AML), but approximately 40-50% of AML cases display a normal karyotype at diagnosis. Multidrug resistance (MDR) proteins overexpression is associated with worse prognosis in acute leukaemias, but its role in normal karyotype AML is less defined. We analysed the expression of P-glycoprotein (PGP), MDR-related protein (MRP) and lung resistance protein (LRP) in 135 adult patients with normal karyotype AML and its correlation with other biological features of the disease, to evaluate the impact of MDR proteins on response to therapy and on survival. Increased PGP expression was associated with lower rate of complete remission (CR; p = 0.006), similarly to advanced age. Cases overexpressing PGP displayed also a shorter event-free survival (EFS; 4 vs. 10 months, p = 0.035) and the increased expression of at least one MDR protein was associated with a reduced overall survival (OS; p = 0.038). Also age was predictive of worse prognosis. Our data confirm the prognostic role of MDR proteins, in particular of PGP, also in AML patients with normal karyotype at diagnosis. This finding could be used to stratify patients with different prognosis and to design risk-adapted therapeutic strategies.
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http://dx.doi.org/10.1002/hon.806DOI Listing
March 2007

Efficacy of liposomal daunorubicin and cytarabine as reinduction chemotherapy in relapsed acute lymphoblastic leukaemia despite expression of multidrug resistance-related proteins.

Eur J Haematol 2006 Oct 19;77(4):293-9. Epub 2006 Jul 19.

Division of Haematology and Bone Marrow Transplantation, Department of Medical and Morphological Researches (DMMR), University of Udine, Udine, Italy.

The treatment of relapsed adult acute lymphoblastic leukaemia (ALL) is frequently unsuccessful with current chemotherapy regimens, and often there is an overexpression of multidrug resistance (MDR)-related proteins. Liposomal encapsulation makes daunorubicin (DNR) less sensitive to the efflux effect of P-glycoprotein (PGP), and in vitro data indicate that liposomal-encapsulated DNR (Daunoxome-DNX) is more toxic than DNR against ALL cell lines. In this study, we assessed the in vivo and in vitro efficacy and toxicity of DNX plus cytarabine (Ara-C) as reinduction chemotherapy in 25 relapsed ALL patients (pts). The expression of MDR-related proteins (PGP, MRP1 and LRP) was also analysed. Of the 25 pts, 12 were males and 13 females; median age was 32 yr (range 18-58). Six cases were ALL T and 19 ALL B; eight pts were Ph+ (32%), and nine Bcr-Abl+ (36%). The expression of MDR-related proteins, and DNR and DNX retention and induction of apoptosis in leukaemic cells were evaluated in all cases. Seventeen of 25 (68%) pts were at first relapse and eight (32%) at second or subsequent relapse. The DNX was given in a dose of 80 mg/m(2)/d (days 1-3) in 11/25 pts (44%) and in a dose of 100 mg/m(2)/d (days 1-3) in 14/25 pts (66%). In all pts, Ara-C was administered in a dose of 2 g/m(2) (days 1-5). Twenty pts (80%) achieved a complete remission (CR) and two (8%) entered a partial remission (PR) for an overall response (OR) rate of 88% (22/25), with a tolerable toxicity and without significant cardiotoxicity. Before the start of DNX therapy, 18/25 (72%) cases overexpressed at least one MDR-related protein compared with 9/25 (36%) cases with MDR overexpression at diagnosis (P = 0.01). Taking into account the small number of cases, the response rate was not affected by MDR expression and the in vitro results also showed a higher uptake and apoptotic cell death by DNX compared with DNR. Twelve pts subsequently underwent allogeneic bone marrow transplantation (11 unrelated donor BMT, and one sibling BMT). The overall survival was 39% after 12 months. These data show the efficacy (OR rate 88% and CR rate 80%) of DNX plus Ara-C as reinduction therapy in very poor-risk ALL pts and the response rate seems not to be affected by MDR overexpression. Moreover, the high rate of remissions and the good clinical tolerance in heavily pretreated pts suggest a promising role of DNX in ALL chemotherapy regimens.
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http://dx.doi.org/10.1111/j.1600-0609.2006.00708.xDOI Listing
October 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

Epstein-Barr virus reactivation in a patient treated with anti-thymocyte globulin for severe aplastic anemia.

Am J Hematol 2006 May;81(5):355-7

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

Epstein-Barr virus (EBV) infection and reactivation is an increasing complication in immune deficient patients, particularly after allogeneic hematopoietic stem cell transplantation (HSCT). Therapy with anti-thymocyte globulin (ATG) is associated with higher incidence of EBV-related disease in HSCT patients, but this risk is not documented in patients receiving ATG for severe aplastic anemia (SAA). We describe the case of a patient who developed an EBV infection, with the clinical features of an infectious mononucleosis, after immune suppression with cyclosporine and two courses of ATG for SAA.
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http://dx.doi.org/10.1002/ajh.20560DOI Listing
May 2006

Caspofungin as first line therapy of pulmonary invasive fungal infections in 32 immunocompromised patients with hematologic malignancies.

Eur J Haematol 2005 Sep;75(3):227-33

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

Invasive Fungal Infections (IFI) remain a severe and major complication among patients with hematologic diseases, but the recent availability of new antifungal agents (echinocandins and new azoles) have improved the chance of cure. Caspofungin (Cancidas-Merck) is a large lipopeptide molecule able to inhibit the enzyme complex 1,3-d-glucan synthetase; this action specifically damages the fungal cell wall. Caspofungin (CAS) is active, in vitro and in vivo, against most Candida species and Aspergillus species. We report on our experience with this drug as first-line therapy for proven or probable pulmonary IFI in immunocompromised patients with hematologic malignancies. Thirty-two consecutive patients (20 males and 12 females, with a median age of 52 yr) have been treated with CAS (27 acute leukemias, 1 chronic leukemia, 3 lymphomas and 1 multiple myeloma). Sixteen patients (50%) had a relapsed or resistant hematologic disease, while 12 patients were in complete remission and 4 were at onset of disease; 8/32 (25%) developed IFI after a hematopoietic stem cell transplant (HSCT) procedure. Seven out of 32 patients (22%) had a proven pulmonary IFI (7/7 Aspergillosis) and 25 (78%) had a probable IFI with pulmonary localization as defined according to international consensus. Thirty-one patients (97%) had less than 1000 granulocytes/mL at onset of infection and at the start of CAS therapy. The CAS was given at the dose of 70 mg on day 1, followed by 50 mg/day. Median duration of CAS therapy was 20 d (range 8-64); all the 31 neutropenic patients received concomitant granulocyte colony-stimulating factor (G-CSF). The overall response rate was 56% (18/32) with 12/18 complete responses and 6/18 partial responses; two patients (6%) had a stable disease. Twelve out of 32 (38%) did not respond and seven died of mycotic infection. Univariate analysis showed that granulocytes recovery (>500/mL vs. <500/mL) and status of hematologic disease (remission/onset vs. refractory/relapsed) were significantly associated to favourable outcome. No clinical adverse events (AE) were reported and only a grades I and II transient increase of serum alkaline phosphatase and/or transaminases occurred in 4/32 (12%) patients. After CAS therapy six non-responders and six cases with a partial or stable response were rescued with voriconazole. Two out of six patients (33%) in the former group and 6/6 (100%) in the latter obtained a complete resolution of IFI. Our experience suggests an efficacy of CAS, in combination with G-CSF, as first-line treatment of proven or probable IFI with pulmonary localization. The drug was well tolerated and there were no significant hepatic AE even in patients receiving CAS with cyclosporine after a HSCT. A significant proportion of non-responders or partial responders to CAS can be rescued with a subsequent voriconazole-based therapy.
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http://dx.doi.org/10.1111/j.1600-0609.2005.00500.xDOI Listing
September 2005

Effect of amifostine on the cytotoxicity of daunorubicin and daunoxome in tumor and normal cells.

Cancer Chemother Pharmacol 2006 Apr 5;57(4):517-24. Epub 2005 Jul 5.

Division of Hematology, Department of Medical and Morphological Research, University Hospital, P.le S. Maria della Misericordia, 33100, Udine, Italy.

Anthracyclines are powerful cytotoxic agents, used as first-line treatment of leukemias and many other tumors, but host-tissue toxicity is their main dose-limiting factor. However, their therapeutic effects depend not only on the toxicity, hence on the dose, but also on drug resistance. Among the mechanisms that can account for cell sensitivity to anthracyclines, there is an overexpression of drug transport proteins, like the transmembrane P-glycoprotein (PGP), the multidrug- resistance-related protein (MRP) and the lung-resistance-related protein (LRP). Attempts to reduce the toxicity of chemotherapeutic agents without affecting their efficacy have been made using liposomal anthracyclines or cytoprotective agents, as Amifostine. The aim of this study was to evaluate and compare the toxic effects of Daunorubicin, in normal or liposomal formulation, used in combination with WR1065, the active metabolite of Amifostine, against normal and tumor cells. In conclusion these data show that the preincubation with WR-1065 does not inhibit the drug toxic effect on blast cells and on tumor cell lines, independently by their multidrug resistance phenotype, but has a cytoprotective effect on stem cells causing a drug cytotoxicity reduction of 10-20%. This advantage is even higher using the liposomal formulation of DNR. Therefore, Amifostine can offer a chance of protecting normal cells from the toxicity of anthracyclines, in normal or liposomal formulation. The combination of liposomal anthracyclines with Amifostine can confer further advantages in management of leukemic patients, especially the elderly where treatment toxicity is a main problem. These patients may be candidates for alternative therapeutic strategies and the combination of DNX and Amifostine is an attractive treatment for these cases where a low nonhematological toxicity is required.
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http://dx.doi.org/10.1007/s00280-005-0043-2DOI Listing
April 2006

Aberrant expression of TRAIL in B chronic lymphocytic leukemia (B-CLL) cells.

J Cell Physiol 2005 Nov;205(2):246-52

Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Ferrara, Italy.

Analysis of peripheral blood (>85% CD19+/CD5+ B) lymphocytes, obtained from 44 patients affected by B chronic lymphoid leukemia (B-CLL), showed that surface TNF-related apoptosis inducing ligand (TRAIL) was expressed in all samples and at higher levels with respect to unfractionated lymphocytes and purified CD19+ B cells, obtained from 15 normal blood donors. Of note, in a subset of B-CLL samples, the addition to B-CLL cultures of a TRAIL-R1-Fc chimera, which binds at high affinity to surface TRAIL, significantly decreased the percentage of viable cells with respect to untreated control B-CLL cells, suggesting that surface TRAIL may play an unexpected role in promoting B-CLL cell survival. In spite of the majority of B-CLL lymphocytes expressed variable surface levels of "death receptors" TRAIL-R1 and TRAIL-R2, the addition in culture of recombinant TRAIL increased (>20% vs. controls) the degree of spontaneous apoptosis in only 11/44 of the B-CLL samples, had no effect in 19/44, while it significantly increased leukemic cell survival in 14/44. Taken together, these findings suggest that an aberrant expression of TRAIL might contribute to the pathogenesis of B-CLL by promoting the survival in a subset of B-CLL cells.
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http://dx.doi.org/10.1002/jcp.20392DOI Listing
November 2005

Bodipy-FL-verapamil: a fluorescent probe for the study of multidrug resistance proteins.

Cell Oncol 2004 ;26(1-2):3-11

Department of Biomedical Sciences, University of Trieste, I-34127 Triste, Italy.

Most of the substances used as fluorescent probes to study drug transport and the effect of efflux blockers in multidrug resistant cells have many drawbacks, such as toxicity, unspecific background, accumulation in mitochondria. New fluorescent compounds, among which Bodipy-FL-verapamil (BV), have been therefore proposed as more useful tools. The uptake of BV has been evaluated by cytofluorimetry and fluorescence microscopy using cell lines that overexpress P-glycoprotein (P388/ADR and LLC-PK(1)/ADR) or MRP (multidrug resistance-related protein) (PANC-1) and clinical specimens from patients. The effect of specific inhibitors for P-glycoprotein (verapamil and vinblastine) or MRP (MK571 and probenecid) has been also studied. BV intracellular concentrations were significantly lower in the two P-glycoprotein overexpressing cell lines in comparison with the parental lines. In addition, verapamil and vinblastine increased the intracellular concentrations of the dye; MK571 and probenecid, two MRP inhibitors, increased BV levels in PANC-1 cells, that express this protein. These findings were confirmed in clinical specimens from patients. Fluorescence microscopy revealed a faint fluorescence emission in P-glycoprotein or MRP expressing cell lines; however, treatment with specific inhibitors significantly increased the fluorescence. BV is a useful tool for studying multidrug resistance proteins with different techniques such as cytofluorimetry and fluorescence microscopy, but does not discriminate between P-glycoprotein and MRP. In comparison with other classic fluorescent probes, the assay with this dye is extremely rapid, simple, not toxic for cells, devoid of fluorescent background, and can be useful in the clinical settings.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611116PMC
http://dx.doi.org/10.1155/2004/576173DOI Listing
March 2005

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

Disposition of liposomal daunorubicin during cotreatment with cytarabine in patients with leukaemia.

Clin Pharmacokinet 2003 ;42(9):851-62

Department of Experimental and Clinical Pathology and Medicine, Institute of Clinical Pharmacology and Toxicology, University of Udine, Udine, Italy.

Objective: To investigate the pharmacokinetics and pharmacodynamics of liposomal daunorubicin (DaunoXome) 80 or 100 mg/m(2) on days 1, 2 and 3 coadministered with standard or high-dose cytarabine to patients with poor-risk acute leukaemia.

Design: Unblinded pharmacokinetic-pharmacodynamic study.

Participants: Twenty-three adult patients with acute leukaemia.

Methods: Blood, bone marrow and urine samples were collected at appropriate intervals on days 1-6. Total daunorubicin and daunorubicinol concentrations in plasma, bone marrow, peripheral blood cells and urine were measured by high performance liquid chromatography.

Results: Liposomal daunorubicin exhibited a markedly different pharmacokinetic behaviour from the free drug due to a slow distribution of the liposomal moiety into the body. The ratio of area under the concentration-time curve (AUC) for metabolite to parent drug was lower for liposomal daunorubicin than for free daunorubicin, mainly due to higher concentrations of the parent drug in plasma, whereas daunorubicinol exposure was more or less comparable, if not higher. After liposomal daunorubicin at both 80 and 100 mg/m(2), total daunorubicin concentrations in leukaemic cells were at least similar to those observed for free daunorubicin, and significant accumulation was also observed in bone marrow blast cells. Nineteen of 23 patients obtained a complete remission, although 13 had P-glycoprotein-overexpressing blast cells. Grade 3-4 mucositis was found only in three patients with very high AUCs for total daunorubicin and daunorubicinol.

Conclusions: Liposomal daunorubicin at both 80 and 100 mg/m(2) in combination with cytarabine may represent a valid treatment for high-risk acute leukaemia. Liposomal daunorubicin may be helpful in overcoming multidrug resistance, since it shows significant accumulation into tumour target cells, irrespective of P-glycoprotein expression. The tolerability profile suggests that toxicity may be related to exposure to both the parent drug and the metabolite.
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http://dx.doi.org/10.2165/00003088-200342090-00004DOI Listing
December 2003

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

Efficacy and safety of rituximab in type II mixed cryoglobulinemia.

Blood 2003 May 30;101(10):3827-34. Epub 2003 Jan 30.

Division of Hematology-Dipartimento di Ricerche Mediche e Morfologiche, University of Udine, Italy.

The best treatment of type II mixed cryoglobulinemia (MC) has still to be defined. Antiviral treatment for the frequent underlying infectious trigger hepatitis C virus (HCV) may be ineffective, contraindicated, or not tolerated in a fraction of cases, whereas current immunosuppressive treatments may lead to relevant complications. Selective B-cell blockade with rituximab was used in this study, based on favorable results in preliminary experience. Fifteen consecutive patients with type II MC (HCV-related in 12 of 15) were treated with rituximab, 375 mg/m(2) intravenously weekly for 4 weeks. Only medium- to low-dose steroids were allowed, if already administered at the time of recruitment. All patients had active disease, poorly controlled or difficult to manage with previous treatments, including corticosteroids in all. Efficacy and safety of rituximab therapy were evaluated in the following 6 months. The overall follow-up after rituximab treatment ranged from 9 to 31 months. Rituximab proved effective on skin vasculitis manifestations (ulcers, purpura, or urticaria), subjective symptoms of peripheral neuropathy, low-grade B-cell lymphoma, arthralgias, and fever. Nephritis of recent onset went into remission in one case. Laboratory features, that is, significantly decreased serum rheumatoid factor and cryoglobulins and increased C4, were consistent with the clinical efficacy. Treatment was well tolerated, with no infectious complications. Thrombosis of retinal artery or self-limiting panniculitis occurred in one patient each. Rituximab may represent a safe and effective alternative to standard immunosuppression in type II MC. Controlled studies are needed to better define drug indications and the cost-efficacy profile in the different systemic manifestations.
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http://dx.doi.org/10.1182/blood-2002-09-2856DOI Listing
May 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