Publications by authors named "Elisabetta Tedone"

12 Publications

  • Page 1 of 1

Prognostic relevance of a blastic plasmacytoid dendritic cell neoplasm-like immunophenotype in cytogenetically normal acute myeloid leukemia patients.

Leuk Lymphoma 2020 07 18;61(7):1695-1701. Epub 2020 Mar 18.

Department of Oncology and Hematology, Ospedale Policlinico San Martino, Genoa, Italy.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a poor prognosis myeloid malignancy characterized by an atypical phenotype (CD123+, CD56+, and CD4+). We reported that BPDCN-like phenotype (CD123+ and either CD56+ or CD4+ or both) confers poor prognosis to acute myeloblastic leukemia (AML) patients with mutated NPM1. Here, we evaluated the incidence and the prognostic relevance of BPDCN-like phenotype in cytogenetically normal AML (CN-AML) patients. From 2006 to 2016, 83 young (age <60 yrs), consecutive, CN-AML patients underwent intensive treatment. Fifteen patients (18%) showed a BPDCN-like phenotype with no difference between -mutated (mut) and -wt patients. It did not significantly affect survival neither in the whole cohort, nor in -wt patients. However, as reported, it conferred a dismal prognosis in -mut AML ( < 0.001), irrespectively of the mutational status for FLT3-ITD. In conclusion we show that BPDCN-like phenotype displays a negative prognostic relevance only in -mutated AML.
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http://dx.doi.org/10.1080/10428194.2020.1737685DOI Listing
July 2020

A simple cytofluorimetric score may optimize testing for biallelic CEBPA mutations in patients with acute myeloid leukemia.

Leuk Res 2019 11 6;86:106223. Epub 2019 Sep 6.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy; S. Martino Hospital IRCCS, Genoa, Italy.

Acute myeloid leukemia with biallelic mutation of CEBPA (CEBPA-dm AML) is a distinct good prognosis entity recognized by WHO 2016 classification. However, testing for CEBPA mutation is challenging, due to the intrinsic characteristics of the mutation itself. Indeed, molecular analysis cannot be performed with NGS technique and requires Sanger sequencing. The association of recurrent mutations or translocations with specific immunophenotypic patterns has been already reported in other AML subtypes. The aim of this study was the development of a specific cytofluorimetric score (CEBPA-dm score), in order to distinguish patients who are unlikely to harbor the mutation. To this end, the correlation of CEBPA-dm score with the presence of the mutation was analyzed in 50 consecutive AML patients with normal karyotype and without NPM1 mutation (that is mutually exclusive with CEBPA mutation). One point each was assigned for expression of HLA DR, CD7, CD13, CD15, CD33, CD34 and one point for lack of expression of CD14. OS was not influenced by sex, age and CEBPA-dm score. Multivariate OS analysis showed that CEBPA-dm (p < 0.02) and FLT3-ITD (p < 0.01) were the strongest independent predictors of OS. With a high negative predictive value (100%), CEBPA-dm score < 6 was able to identify patients who are unlikely to have the mutation. Therefore, the application of this simple score might optimize the use of expensive and time-consuming diagnostic and prognostic assessment in the baseline work up of AML patients.
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http://dx.doi.org/10.1016/j.leukres.2019.106223DOI Listing
November 2019

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.

CEINGE Biotecnologie Avanzate, Naples, 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

Functional Activation of Osteoclast Commitment in Chronic Lymphocytic Leukaemia: a Possible Role for RANK/RANKL Pathway.

Sci Rep 2017 10 26;7(1):14159. Epub 2017 Oct 26.

Nuclear Medicine IRCCS AOU San Martino-IST, Genoa, Italy.

Skeletal erosion has been found to represent an independent prognostic indicator in patients with advanced stages of chronic lymphocytic leukaemia (CLL). Whether this phenomenon also occurs in early CLL phases and its underlying mechanisms have yet to be fully elucidated. In this study, we prospectively enrolled 36 consecutive treatment-naïve patients to analyse skeletal structure and bone marrow distribution using a computational approach to PET/CT images. This evaluation was combined with the analysis of RANK/RANKL loop activation in the leukemic clone, given recent reports on its role in CLL progression. Bone erosion was particularly evident in long bone shafts, progressively increased from Binet stage A to Binet stage C, and was correlated with both local expansion of metabolically active bone marrow documented by FDG uptake and with the number of RANKL + cells present in the circulating blood. In immune-deficient NOD/Shi-scid, γcnull (NSG) mice, administration of CLL cells caused an appreciable compact bone erosion that was prevented by Denosumab. CLL cell proliferation in vitro correlated with RANK expression and was impaired by Denosumab-mediated disruption of the RANK/RANKL loop. This study suggests an interaction between CLL cells and stromal elements able to simultaneously impair bone structure and increase proliferating potential of leukemic clone.
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http://dx.doi.org/10.1038/s41598-017-12761-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658396PMC
October 2017

Impact of HLA Disparity in Haploidentical Bone Marrow Transplantation Followed by High-Dose Cyclophosphamide.

Biol Blood Marrow Transplant 2018 01 9;24(1):119-126. Epub 2017 Oct 9.

U.O. Ematologia, Ospedale Policlinico San Martino, Genova, Italy.

We studied the impact of HLA mismatching on the outcome of 318 consecutive patients who received an unmanipulated haploidentical bone marrow transplant, followed by post-transplant cyclophosphamide (PTCy). The number of HLA-mismatched antigens was tested for its impact on overall survival (OS) and nonrelapse mortality (NRM), whereas HLA mismatches in the graft-versus-host (GVH) direction were tested for prediction of graft-versus-host disease (GVHD and relapse. Finally, we studied whether graft rejection correlated with the number of HLA mismatched antigens in host-versus-graft (HVG) direction. Two hundred thirty-one donor-recipient pairs (72%) had 4/8 mismatches at the -A, -B, -C, -DRB1 HLA loci. HLA mismatches did not predict the 2-year OS (hazard ratio, .83; P = .58) and NRM (subhazard ratio, 1.08; P = .93). The cumulative incidence of acute GVHD (P = .13), 1-year chronic GVHD (P = .84), and relapse rate (P = .26) did not correlate with univectorial GVH mismatches. Similarly, no correlation was observed between the amount of HLA mismatch in the HVG direction and graft rejection. In multivariate analysis advanced disease at transplant was the strongest predictor of survival, NRM, relapse, and graft rejection. In conclusion, the degree of HLA mismatching should not be used as a criterion to select family haploidentical donors when using bone marrow as stem cell source and PTCy for GVHD prophylaxis.
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http://dx.doi.org/10.1016/j.bbmt.2017.10.002DOI Listing
January 2018

Wilms Tumor 1 Expression and Pre-emptive Immunotherapy in Patients with Acute Myeloid Leukemia Undergoing an Allogeneic Hemopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2016 07 10;22(7):1242-1246. Epub 2016 Mar 10.

Cattedra di Ematologia, Universita' Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Gemelli, Roma, Italy. Electronic address:

Minimal residual disease (MRD) was monitored by Wilms tumor 1 (WT1) expression in 207 patients with acute myeloid leukemia (AML) after an allogeneic hemopoietic stem cell transplantation (HSCT) as a trigger to initiate pre-emptive immunotherapy (IT) with cyclosporin discontinuation and/or donor lymphocyte infusion. The trigger for IT was WT1 ≥ 180 copies/10(4) Abelson cells in marrow cells in the first group of 122 patients (WT1-180) and ≥ 100 copies in a subsequent group of 85 patients (WT1-100). Forty patients received IT. The cumulative incidence (CI) of relapse was 76% in WT1-180 (n = 17) versus 29% in WT1-100 patients (n = 23) receiving IT (P = .006); the leukemia-free survival from MRD positivity was 23% versus 74%, respectively (P = .003). We then looked at the entire AML patient population (n = 207). WT1-180 and WT1-100 patients were comparable for disease phase and age. The overall 4-year CI of transplantation-related mortality was 13% in both groups; the CI of leukemia relapse was 38% in the WT1-180 and 28% in the WT1-100 patients (P = .05) and leukemia-free survival was 56% versus 48%, respectively (P = .07). In conclusion, we suggests that WT1-based pre-emptive immunotherapy is feasible in patients with undergoing an allogeneic HSCT. The protective effect on relapse is greater when IT is triggered at lower levels of WT1.
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http://dx.doi.org/10.1016/j.bbmt.2016.03.005DOI Listing
July 2016

Improved Outcome of Alternative Donor Transplantations in Patients with Myelofibrosis: From Unrelated to Haploidentical Family Donors.

Biol Blood Marrow Transplant 2016 Feb 9;22(2):324-329. Epub 2015 Oct 9.

Istituto di Ematologia, Universita' Cattolica del Sacro Cuore, Fondazione Policlinico A Gemelli, Roma, Italy. Electronic address:

This is a retrospective analysis of 95 patients with myelofibrosis who were allografted between 2001 and 2014. The aims of the study were to assess whether the outcome of alternative donor grafts has improved with time and how this compares with the outcome of identical sibling grafts. Patients were studied in 2 time intervals: 2000 to 2010 (n = 58) and 2011 to 2014 (n = 37). The Dynamic International Prognostic Scoring System score was comparable in the 2 time periods, but differences in the most recent group included older age (58 versus 53 years, P = .004), more family haploidentical donors (54% versus 5%, P < .0001), and the introduction of the thiotepa-fludarabine-busulfan conditioning regimen (70% of patients versus 2%, P < .0001). Acute and chronic graft-versus-host disease were comparable in the 2 time periods. The 3-year transplantation-related mortality (TRM) in the 2011 to 2014 period versus the 2000 to 2010 period is 16% versus 32% (P = .10), the relapse rate 16% versus 40% (P = .06), and actuarial survival 70% versus 39% (P = .08). Improved survival was most pronounced in alternative donor grafts (69% versus 21%, P = .02), compared with matched sibling grafts (72% versus 45%, P = .40). In conclusion, the outcome of allografts in patients with myelofibrosis has improved in recent years because of a reduction of both TRM and relapse. Improvement is most significant in alternative donor transplantations, with modifications in donor type and conditioning regimen.
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http://dx.doi.org/10.1016/j.bbmt.2015.09.028DOI Listing
February 2016

Leukaemia relapse after allogeneic transplants for acute myeloid leukaemia: predictive role of WT1 expression.

Br J Haematol 2013 Feb 7;160(4):503-9. Epub 2013 Jan 7.

Divisione Ematologia e Trapianto di Midollo, IRCCS San Martino-IST, Genova, Italy.

We assessed WT1 expression (expressed as messenger copies/10(4) ABL1) from marrow cells of 122 patients with acute myeloid leukaemia (AML), before and after an unmanipulated allogeneic haemopoietic stem cell transplant (HSCT). The median age was 44 years (15-69), 59% were in first remission, 74% received a myeloablative conditioning regimen and the median follow up was 865 d (34-2833). Relapse was higher in 67 patients with WT1 expression, at any time post-HSCT, exceeding 100 copies (54%), as compared to 16%, for 55 patients with post-HSCT WT1 expression <100 copies (P < 0·0001). Similarly, actuarial 5-year survival (OS) was 40% vs. 63%, respectively (P = 0·03). In multivariate Cox analysis, WT1 expression post-HSCT was the strongest predictor of relapse (Hazard Ratio [HR] 4·5, P = 0·0001), independent of disease phase (HR 2·3, P = 0·002). Donor lymphocyte infusions (DLI) were given to 17 patients because of increasing WT1 levels: their OS was 44%, vs. 14% for 21 patients with increasing WT1 expression who did not receive DLI (P = 0·004). In conclusion, WT1 expression post-HSCT is a strong predictor of leukaemia relapse and survival in AML; WT1 may be used as a marker for early interventional therapy.
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http://dx.doi.org/10.1111/bjh.12181DOI Listing
February 2013

CMV infection after transplant from cord blood compared to other alternative donors: the importance of donor-negative CMV serostatus.

Biol Blood Marrow Transplant 2012 Jan 27;18(1):92-9. Epub 2011 May 27.

Division of Infectious Diseases, San Martino University Hospital, Genoa, Italy.

Cytomegalovirus (CMV) infection and disease are important complications after hematopoietic stem cell transplant, particularly after transplant from alternative donors. Allogeneic cord blood transplantation (CBT) is being increasingly used, but immune recovery may be delayed. The aim of this study was to compare CMV infection in CBT with transplants from unrelated or mismatched related donors, from now on defined as alternative donors. A total of 165 consecutive transplants were divided in 2 groups: (1) alternative donors transplants (n = 85) and (2) CBT recipients (n = 80). Donor and recipient (D/R) CMV serostatus were recorded. The incidence of CMV infection, its severity, timing, and outcome were compared. Median follow-up was 257 days (1-1328). CMV infection was monitored by CMV antigenemia and expressed as CMV Ag positive cell/2 × 10(5) polymorphonuclear blood cells. There was a trend toward a higher cumulative incidence of CMV infection among CBT than alternative donor transplant recipients (64% vs 51%, P = .12). The median time to CMV reactivation was 35 days, and was comparable in the 2 groups (P = .8). The maximum number of CMV-positive cells was similar in the 2 groups (11 versus 16, P = .2). The time interval between the first and the last positive CMV antigenemia was almost 4 times longer in CBT compared with alternative donor transplants (109 vs 29 days, respectively, P = .008). The incidence of late CMV infection was also higher in CBT (62% vs 24%, P < .001). The incidence of early and late CMV infection in CBT was similar to D-/R+ alternative transplants, and higher than in D+/R+ alternative transplants: early infection, 72% in CBT versus 69% in D-/R+ alternative versus 55% in D+/R+ alternative (P = .21); and late infection, 67% in CBT versus 60% in D-/R+ alternative versus 7% in D+/R+ alternative (P < .001). Transplant-related mortality and overall survival were similar between the groups: 34% versus 36% (P = .6) and 54% versus 46% (P = .3) for alternative transplant and CBT, respectively. Longer duration and higher incidence of late CMV infection was seen in CBT patients, when compared with alternative donor transplants, whereas no difference in mortality was observed. The duration and incidence of late CMV infection were similar when D-/R+ CBT were compared with D-/R+ alternative donor transplants.
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http://dx.doi.org/10.1016/j.bbmt.2011.05.015DOI Listing
January 2012

Rituximab treatment for Epstein-Barr virus DNAemia after alternative-donor hematopoietic stem cell transplantation.

Biol Blood Marrow Transplant 2011 Jun 13;17(6):901-7. Epub 2010 Oct 13.

Division of Hematology and Bone Marrow Transplant, Ospedale San Martino, Genova, Italy.

We report 55 patients undergoing an alternative-donor hematopoietic stem cell transplantation (HSCT) who developed Epstein-Barr virus (EBV) DNAemia, with >1000 EBV copies/10(5) peripheral blood mononuclear cells (PBMCs), and were treated with rituximab (375 mg/m(2)). The median patient age was 47 years (range, 20-65 years), and graft sources were mismatched family members (n = 4), unrelated donors (n = 46), and unrelated cord blood (n = 5). The conditioning regimen included antithymocyte globulin (ATG) in all patients. The median time to development of EBV DNAemia was day 27 post-HSCT (range, day 5 to day 242), with a median of 60 EBV copies/10(5) PBMCs (range, 1-5770 copies/10(5) PBMCs). The number of EBV copies was reduced to <1000/10(5) PBMCs on day +7 after initiation of rituximab therapy in 51% of the patients, on day +14 in 73% of the patients, and on +21 in 92% of the patients. Overall, 50 of 55 patients (91%) cleared EBV after one dose (n = 25) or more than one dose (n = 25) of rituximab. Factors predicting transplantation-related mortality (TRM) in multivariate analysis were a reduction to <1000 EBV copies/10(5) PBMCs by day +7 of treatment (relative risk [RR], 0.2; P = .01) and disease phase in remission (RR, 0.3; P = .05). TRM was 23% in the 40 patients with none or one of the negative predictors and 60% in the 15 patients with both negative predictors (P = .001). Of these latter 15 patients, 3 developed clinical posttransplantation lymphoproliferative disorder (PTLD). All 3 of these patients had a high EBV load on day +7 of rituximab therapy. This study confirms the effectiveness of rituximab in controlling EBV DNAemia in patients undergoing allogeneic HSCT. Patients with increasing EBV copies despite rituximab therapy are at high risk for EBV PTLD and may be considered for alternative therapies.
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http://dx.doi.org/10.1016/j.bbmt.2010.10.003DOI Listing
June 2011

Boost of CD34+-selected peripheral blood cells without further conditioning in patients with poor graft function following allogeneic stem cell transplantation.

Haematologica 2006 Jul;91(7):935-40

Divisione Ematologia, Ospedale San Gerardo, Monza, Milano, Italy

Background And Objectives: A proportion of patients develop poor graft function (PGF) following an allogeneic hemopoietic stem cell transplant (HSCT). It is uncertain whether a boost of donor marrow or blood cells is beneficial in terms of trilineage recovery and non-relapse-related mortality (NRM).

Design And Methods: The aim of this study was to compare outcomes in patients with PGF and full donor chimerism following an allogeneic HSCT who did or did not receive a boost of donor stem cells. The study included patients with primary PGF--i.e. those failing to achieve sustained graft function- and secondary PGF--i.e. those developing PGF after complete hematologic recovery. We studied 54 patients with PGF: 20 patients received no further donor cell infusion (group A), 14 received a boost of unmanipulated marrow or blood cells from the original donor, without further conditioning (group B), and 20 received donor cells after CD34 selection without conditioning (group C). The three groups were comparable for disease phase, patients' age, donor type, primary or secondary PGF, full donor chimerism and duration of PGF.

Results: Trilineage recovery was seen in 40%, 36% and 75% of the patients in, respectively, groups A, B and C (p=0.02). In multivariate Cox analysis trilineage recovery was more frequent in patients with secondary PGF (RR of complete recovery 2.82, p=0.01) and in patients receiving CD34+-selected cells (RR of complete recovery 3.0; p=0.007). There was no effect of donor type on hematologic recovery. The rate of NRM was 55%, 64%, 20% in groups A, B and C, respectively (p=0.06) and was highly correlated with trilineage recovery (RR 0.36, p<0.0001). PGF was the primary cause of death in 30%, 21% and 10% of the patients in the three groups, graft-versus-host disease (GVHD) in 5%, 36%, and 10%.

Interpretations And Conclusions: In patients with poor graft function (a) a boost of CD34+-selected peripheral blood donor cells is associated with a high chance of trilineage recovery and a low risk of acute GVHD; (b) a boost of unmanipulated donor cells does not seem to offer a survival advantage over no infusion of cells; and (c) NRM is lower when using peripheral blood cells for the boost. These data may be useful when discussing second stem cell donations for patients with poor graft function.
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July 2006

Reducing transplant-related mortality after allogeneic hematopoietic stem cell transplantation.

Haematologica 2004 Oct;89(10):1238-47

Dipartimento di Emato-Oncologia, Ospedale San Martino, Genoa, Italy.

Background And Objectives: Transplant-related mortality (TRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to be related to disease stage, duratiion of disease and type of donor. Furthermore, the outcome of transplants performed in the 1990s appears to be better than that of transplants done in the previous decade. The aims of this study were to determine whether these relationships still hold and whether the outcome of transplants is continuing to improve.

Design And Methods: We analyzed 1180 consecutive patients with leukemia (n=979) or other hematologic malignancies (n=201) undergoing HSCT in 4 time periods: before 1990, 1991-1995, 1996-2000, and 2001-2002. Changes during these eras include increasing patient age, more unrelated transplants, more patients with advanced disease, different graft-versus-host disease (GvHD) prophylaxis, and different management of infections.

Results: The actuarial 2-year transplant-related mortality (TRM) differed significantly between the transplant eras (p<0.001) with a significant interaction with disease phase (p=0.018). In patients in first remission (n=585) TRM was 34%, 25%, 21% and 6% in the four transplant eras. The reduction in TRM was less evident in patients in second remission (n=284) (37%, 35%, 30%, 25%) and absent in relapsed patients (n=311) (TRM=45%, 41%, 29%, 51%). This is a consequence of reductions in GvHD, infections and multiorgan failure among patients in remission but not among those who relapse. The actuarial 2-year survival has improved significantly in patients in first remission (54%, 66%, 72%, 78%) but not in those in second remission (38%, 46%, 52%,45%), or relapsed patients (31%, 25%, 36%, 21%).

Interpretation And Conclusions: In conclusion, TRM has been significantly reduced in first remission patients, suggesting an allograft should be considered in this phase, when appropriate, without delay. There has been no improvement in survival for patients beyond first remission, due to persisting high risk of infections and organ toxicity, a possible consequence of prolonged pre-transplant chemotherapy and neutropenia.
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October 2004