Publications by authors named "Paolo Bernasconi"

74 Publications

GITMO REGISTRY STUDY ON ALLOGENEIC TRANSPLANTATION IN PATIENTS AGED OVER 60 FROM 2000 TO 2017. IMPROVEMENTS AND CRITICISMS.

Transplant Cell Ther 2021 Nov 21. Epub 2021 Nov 21.

Unit of Haematology and Stem Cell Transplant Centre, "San Camillo" Hospital, Rome, Italy.

Background: Nowadays, allogeneic stem cell transplantation (Allo-SCT) can be offered to patients up to the age of 70-72 years and represents one of the most effective curative treatments for many hematological malignancies.

Objectives: The primary objective of the study is to collect data from the allo-SCTs performed in Italy from 2000 to 2017 in patients over 60 years of age to evaluate the changes in safety and efficacy outcomes as well as their distribution and characteristics over time.

Study Design: The GITMO AlloEld study (ClinicalTrials.gov: NCT04469985) is a retrospective, analysis of the allo-SCTs performed 30 Italian transplant Centers on older patients (≥ 60 years) from 2000 to 2017 (n=1,996).

Results: For the purpose of analysis, patients were grouped into three time periods: time A: 2000-2005, n=256 (12%); time B: 2006-2011, n=584 (29%); and time C: 2012-2017, n=1156 (59%). After a median follow-up of 5.6 years, the 5-year Non Relapse Mortality (NRM) remained stable (time A: 32.8%; time B: 36.2%; and time C: 35.0%, p = 0.5); the Overall Survival (OS) improved (time A: 28.4%; time B: 31.8%; and time C: 37.3%, p = 0.012); and the Cumulative Incidence of Relapse (CIR) reduced (time A: 45.3%; time B: 38.2%; time C: 30.0%, p < 0.0001). The 2-year incidence of extensive cGVHD reduced significantly (time A: 17.2%; time B: 15.8%; and time C: 12.2%, p = 0.004). Considering times A and B together (2000-2011), the 2-year NRM was positively correlated to the HCT-CI score; patients with HCT-CI of 0, 1 or 2, or ≥3 had rates of NRM of 25.2%, 33.9%, and 36.1%, respectively, (p < 0.001). Meanwhile, after 2012, the HCT-CI score was not significantlly predictive of NRM.

Conclusions: The study shows that the transplant procedure in elderly patients became more effective over time. Relapse incidence remains the major problem and strategies to prevent it are under investigation (e.g. post-transplant maintenance). Today, the selection of patients aged over 60 could be improved by combining HCT-CI and frailty assessments to better predict NRM.
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http://dx.doi.org/10.1016/j.jtct.2021.11.006DOI Listing
November 2021

Eradication of Measurable Residual Disease in AML: A Challenging Clinical Goal.

Cancers (Basel) 2021 Jun 25;13(13). Epub 2021 Jun 25.

Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.

In non-promyelocytic (non-M3) AML measurable residual disease (MRD) detected by multi-parameter flow cytometry and molecular technologies, which are guided by Consensus-based guidelines and discover very low leukemic cell numbers far below the 5% threshold of morphological assessment, has emerged as the most relevant predictor of clinical outcome. Currently, it is well-established that MRD positivity after standard induction and consolidation chemotherapy, as well as during the period preceding an allogeneic hematopoietic stem cell transplant (allo-HSCT), portends to a significantly inferior relapse-free survival (RFS) and overall survival (OS). In addition, it has become absolutely clear that conversion from an MRD-positive to an MRD-negative state provides a favorable clinical outcome similar to that associated with early MRD negativity. Thus, the complete eradication of MRD, i.e., the clearance of the few leukemic stem cells-which, due to their chemo-radiotherapy resistance, might eventually be responsible of disease recurrence-has become an un-met clinical need in AML. Nowadays, this goal might potentially be achieved thanks to the development of novel innovative treatment strategies, including those targeting driver mutations, apoptosis, methylation patterns and leukemic proteins. The aim of this review is to analyze these strategies and to suggest any potential combination able to induce MRD negativity in the pre- and post-HSCT period.
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http://dx.doi.org/10.3390/cancers13133170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268140PMC
June 2021

Impact of prior JAK-inhibitor therapy with ruxolitinib on outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis: a study of the CMWP of EBMT.

Leukemia 2021 Dec 22;35(12):3551-3560. Epub 2021 May 22.

CHU de Lille, Univ Lille, INSERM U1286, Infinite, Lille, France.

JAK1/2 inhibitor ruxolitinib (RUX) is approved in patients with myelofibrosis but the impact of pretreatment with RUX on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) remains to be determined. We evaluated the impact of RUX on outcome in 551 myelofibrosis patients who received HSCT without (n = 274) or with (n = 277) RUX pretreatment. The overall leukocyte engraftment on day 45 was 92% and significantly higher in RUX responsive patients than those who had no or lost response to RUX (94% vs. 85%, p = 0.05). The 1-year non-relapse mortality was 22% without significant difference between the arms. In a multivariate analysis (MVA) RUX pretreated patients with ongoing spleen response at transplant had a significantly lower risk of relapse (8.1% vs. 19.1%; p = 0.04)] and better 2-year event-free survival (68.9% vs. 53.7%; p = 0.02) in comparison to patients without RUX pretreatment. For overall survival the only significant factors were age > 58 years (p = 0.03) and HLA mismatch donor (p = 0.001). RUX prior to HSCT did not negatively impact outcome after transplantation and patients with ongoing spleen response at time of transplantation had best outcome.
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http://dx.doi.org/10.1038/s41375-021-01276-4DOI Listing
December 2021

Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti.

Transplant Cell Ther 2021 05 16;27(5):406.e1-406.e11. Epub 2021 Feb 16.

Stem Cell Transplant and Cellular Therapies Unit, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy.

HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade ≥II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and ≤8/10 HLA allele-matched pairs were associated with worse OS (P = .04 and .007, respectively), NRM (P = .007 and P < .0001, respectively), and grade III-IV aGVHD (P = .0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P = .001) and chronic GVHD (P = .002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P = .006) and a poorer OS (P = .001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence.
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http://dx.doi.org/10.1016/j.jtct.2020.11.021DOI Listing
May 2021

Outcome of T-cell-replete haploidentical stem cell transplantation improves with time in adults with acute lymphoblastic leukemia: A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Cancer 2021 Jul 19;127(14):2507-2514. Epub 2021 Mar 19.

European Society for Blood and Marrow Transplantation Acute Leukemia Working Party, St Anthony Hospital, Paris, France.

Background: The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide prophylaxis is gaining traction in patients with acute lymphoblastic leukemia (ALL).

Methods: The Acute Leukemia Working Party/European Society for Blood and Marrow Transplantation registry was used to evaluate the outcomes of adult patients with ALL who underwent haplo-HCT during 2011 through 2015 and compared them with the outcomes of those who underwent transplantation during 2016 through 2018.

Results: The analysis consisted of 195 patients, including 79 who underwent transplantation during 2011 through 2015 and 116 who underwent transplantation during 2016 through 2018. Overall, the 2-year leukemia-free survival and relapse incidence rates were 56.5% and 21%, respectively. The 100-day incidence of grade 2 through 4 acute graft-vs-host disease (GVHD) was 34.5%. The rates of nonrelapse mortality (NRM) and overall survival (OS) were 22.5% and 64.7%, respectively. Patients who underwent transplantation during 2016 through 2018 experienced improved rates of leukemia-free survival (64.9% vs 47.3%; P = .019) and OS (75.5% vs 53.5%; P = .006). Patients who underwent transplantation during 2016 through 2018 developed more grade 2 through 4 acute GVHD (42% vs 26.4%; P = .047). The incidence of relapse, GVHD-free/relapse-free survival, grade 3 and 4 acute GVHD, chronic GVHD, and extensive chronic GVHD did not differ significantly between groups. In multivariate analysis, more recently transplanted patients had a significantly reduced risk of NRM (hazard ratio, 0.44; 95% CI, 0.22-0.89; P = .022) and improved OS (hazard ratio, 0.47; 95% CI, 0.26-0.86; P = .014). A comparable analysis of patients who had acute myeloid leukemia during the same timeframes did not reveal any statistically significant differences in any outcomes.

Conclusions: The outcome of adult patients with ALL who receive posttransplant cyclophosphamide has improved over time, with an impressive 2-year OS of 75% and, most recently, an NRM rate of only 17%.
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http://dx.doi.org/10.1002/cncr.33522DOI Listing
July 2021

Human Herpesvirus 6 Encephalitis in Immunocompetent and Immunocompromised Hosts.

Neurol Neuroimmunol Neuroinflamm 2021 03 12;8(2). Epub 2021 Jan 12.

From the Neuroncology Unit (G.B., E.V., E.M.), and Neuroradiology Unit (M.P., A.P.), IRCCS Mondino Foundation, Pavia; Molecular Virology Unit (G.C., F.B.), Microbiology and Virology Department, Diagnostic Radiology, Interventional Radiology and Neuroradiology Unit (A.M.S.), Bone Marrow Transplantation Unit (A.A.C., P.B., O.B.), Infectious and Tropical Diseases Unit (A.D.M.), Pediatric Clinic (V.R., T.F., S.S.), and Pediatric Hematology/Oncology (F.C., M.Z.), Fondazione IRCCS Policlinico San Matteo, Pavia; and Department of Brain and Behavioral Sciences (A.P.), Department of Molecular Medicine (P.B., O.B.), and Department of Clinical, Surgical, Diagnostic and Paediatric Sciences (F.B.), University of Pavia, Italy.

Objective: The aim of this study was to analyze the clinical, radiologic, and biological features associated with human herpesvirus 6 (HHV-6) encephalitis in immunocompetent and immunocompromised hosts to establish which clinical settings should prompt HHV-6 testing.

Methods: We performed a retrospective research in the virology database of Fondazione IRCCS Policlinico San Matteo (Pavia, Italy) for all patients who tested positive for HHV-6 DNA in the CSF and/or in blood from January 2008 to September 2018 and separately assessed the number of patients meeting the criteria for HHV-6 encephalitis in the group of immunocompetent and immunocompromised hosts.

Results: Of the 926 patients tested for HHV-6 during the period of interest, 45 met the study criteria. Among immunocompetent hosts (n = 17), HHV-6 encephalitis was diagnosed to 4 infants or children presenting with seizures or mild encephalopathy during primary HHV-6 infection (CSF/blood replication ratio <<1 in all cases). Among immunocompromised hosts (n = 28), HHV-6 encephalitis was diagnosed to 7 adolescents/adults with hematologic conditions presenting with altered mental status (7/7), seizures (3/7), vigilance impairment (3/7), behavioral changes (2/7), hyponatremia (2/7), and anterograde amnesia (1/7). Initial brain MRI was altered only in 2 patients, but 6 of the 7 had a CSF/blood replication ratio >1.

Conclusions: The detection of a CSF/blood replication ratio >1 represented a specific feature of immunocompromised patients with HHV-6 encephalitis and could be of special help to establish a diagnosis of HHV-6 encephalitis in hematopoietic stem cell transplant recipients lacking radiologic evidence of limbic involvement.
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http://dx.doi.org/10.1212/NXI.0000000000000942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963435PMC
March 2021

Early T cell reconstitution and cytokine profile may help to guide a personalized management of human cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.

J Clin Virol 2021 02 9;135:104734. Epub 2021 Jan 9.

Genetics, Transplantology and Cardiovascular Diseases Laboratories, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Biochemistry-Biotechnology and Advanced Diagnostics Laboratory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Molecular Virology Unit, Department of Microbiology and Virology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Electronic address:

Human cytomegalovirus (HCMV) infection is one of the major causes of mortality and morbidity after allo-hematopoietic stem cell transplantation (HSCT). Antiviral therapies are associated with toxicity and high economic burden. The aim of this retrospective study was to identify allo-HSCT HCMV-seropositive recipients at low risk of clinically significant HCMV infection who could avoid antiviral therapies. Sixty adult patients who underwent allo-HSCT were clustered in two groups: i) 22 (37%) spontaneously controlling HCMV reactivation (Controllers); ii) 38 (63%) developing clinically significant HCMV infection and receiving pre-emptive therapy (Non-Controllers). We analyzed several patient baseline characteristics, total/HCMV-specific CD4 and CD8 T-cell counts and their cytokine production (IFNγ, TNFα, IL2). Controllers presented a higher number of total/HCMV-specific CD4 and CD8 T-cells (P=0.001 and P=0.017 for total CD4 and CD8 T-cells respectively; P<0.001 for HCMV-specific T-cells) and a lower percentage of mono-functional IFNγ-producing HCMV-specific CD8 T-cells (P=0.002). In bi-variable models, the prognostic impact of the percentage of mono-functional HCMV-specific CD8 T-cells on treatment-free survival, adjusted for total/HCMVspecific CD4 and CD8 T-cells, was confirmed. An HCMV-seronegative donor was the only baseline characteristic associated with a clinically significant infection. These data, when confirmed by a larger prospective study, may provide information for guiding the personalized management of HCMV infection in allo-HSCT recipients.
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http://dx.doi.org/10.1016/j.jcv.2021.104734DOI Listing
February 2021

Positive HCMV DNAemia in stem cell recipients undergoing letermovir prophylaxis is expression of abortive infection.

Am J Transplant 2021 04 8;21(4):1622-1628. Epub 2021 Feb 8.

Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Letermovir (LMV) inhibits HCMV replication by binding to components of the HCMV-terminase complex showing a potential role in prevention of HCMV-related complications in allogenic hematopoietic stem cell transplant recipients (allo-HSCTRs). However, little is known about breakthrough HCMV infection and the relevance of HCMV DNAemia during prophylaxis. We reported the results of a multicenter prospective study involving five Italian centers in the management of HCMV DNAemia in 75 adult HCMV-seropositive allo-HSCTRs undergoing LMV prophylaxis. The aim of the present study was to characterize the presence of real HCMV reactivation during LMV prophylaxis. Then, the presence of circulating infectious HCMV particles was determined by virus isolation and degradation of free-floating viral DNA. This report provides the first evidence that during LMV prophylaxis the clinical relevance of HCMV DNAemia should be critically considered.
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http://dx.doi.org/10.1111/ajt.16450DOI Listing
April 2021

Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party.

Bone Marrow Transplant 2021 04 18;56(4):917-927. Epub 2020 Nov 18.

Sorbonne University, Department of Clinical Hematology and Cellular Therapy, Saint Antoine Hospital, INSERM UMR 938, Paris, France.

Allogeneic hematopoietic cell transplantation (alloHCT) is a complex, potentially fatal therapy featuring a myriad of complications. Triggering event(s) of such complications vary significantly, but often a so-called "multi-organ failure" (MOF) is reported as the leading cause of death. The identification of the exact trigger of MOF is critical towards early and disease-specific intervention to improve outcome. We examined data from 202 alloHCT patients reported to have died of MOF from the EBMT registry aiming to determine their exact cause of death focusing on veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) due to its life-threatening, often difficult to capture yet preventable nature. We identified a total of 70 patients (35%) for whom VOD/SOS could be considered as trigger for MOF and leading cause of death, among which 48 (69%) were previously undiagnosed. Multivariate analysis highlighted history of hepatic comorbidity or gentuzumab use and disease status beyond CR1 as the only significant factors predictive of VOD/SOS incidence (OR = 6.6; p = 0.001 and OR = 3.3; p = 0.004 respectively). VOD/SOS-related MOF was widely under-reported, accounting for 27% of deaths attributed to MOF of unknown origin without a previous VOD/SOS diagnosis. Our results suggest most missed cases developed late VOD/SOS beyond 21 days post-alloHCT, highlighting the importance of the newly revised EBMT criteria.
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http://dx.doi.org/10.1038/s41409-020-01135-3DOI Listing
April 2021

Bone marrow versus mobilized peripheral blood stem cell graft in T-cell-replete haploidentical transplantation in acute lymphoblastic leukemia.

Leukemia 2020 10 11;34(10):2766-2775. Epub 2020 May 11.

EBMT ALWP Office, Saint Antoine Hospital, Paris, France.

The ideal stem cell graft source remains unknown in haploidentical haematopietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide (PTCy). This study compared outcomes of bone marrow (BM) versus peripheral blood (PB) stem cell graft for haplo-HCT in acute lymphoblastic leukemia (ALL). A total of 314 patients with ALL (BM-157; PB-157) were included in this study. The cumulative incidence of engraftment at day 30 was higher in the PB group compared with BM (93% vs. 88%, p < 0.01). The incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were not significantly different between the study cohorts. In the multivariate analysis, there were tendencies toward a higher incidence of grade II-IV acute GVHD (hazard ratio (HR) = 1.52, p = 0.07), chronic GVHD (HR = 1.58, p = 0.05), and nonrelapse mortality (NRM) (HR = 1.66, p = 0.06) in patients receiving PB versus BM graft, respectively. The use of PB grafts was associated with lower leukemia-free survival (LFS) (HR = 1.43, p = 0.05), overall survival (OS) (HR = 1.59, p = 0.02), and GVHD-free, relapse-free survival (GRFS) (HR = 1.42, p = 0.03) compared with BM grafts. There was no difference in relapse incidence (HR = 1.23, p = 0.41) between the study groups. In conclusion, use of BM graft results in better survival after haplo-HCT with PTCy in patients with ALL, compared with PB stem cell graft.
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http://dx.doi.org/10.1038/s41375-020-0850-9DOI Listing
October 2020

Detection of cocaine on euro banknotes; Development of a practical approach for the interpretation of suspect cases.

Forensic Sci Int 2020 Apr 29;309:110227. Epub 2020 Feb 29.

Institute of Forensic Medicine, Forensic Toxicology and Chemistry, University of Bern, Bühlstrasse 20, 3012, Bern, Switzerland.

The presence of traces of narcotics, particularly cocaine, on banknotes in circulation is a known and widespread fact in all countries. While linked to consumption and trafficking (primary contamination), their spread is due to direct contact with other banknotes during machine counting and cash financial transactions. The mere detection of traces of cocaine on a sample of banknotes is therefore not sufficient evidence to establish the banknote's illegal origin. Increasing levels of contamination are recorded close to (in terms of both place and time) the first direct contact with the substance. The analysis must thus be able to demonstrate that the concentration of narcotics on the banknotes is significantly higher (statistically) in terms of value and frequency than would be expected from background noise alone. Even in that event, however, this evidence has to be substantiated with additional confirmations linking banknotes to the person and this latter to drug trafficking and/or dealing. In general, an in-depth and systematic analysis of all seized banknotes to search for traces of narcotics is not only prohibitive in terms of cost, but also unnecessary. If the sampling procedure is respected, the Swiss Federal Supreme Court actually recognizes IMS (ion mobility spectrometry) as a lawful method for checking the degree of banknote contamination, as well as all the statistical conclusions that can be drawn from it. In special cases, the prosecutor may require confirmation of IMS results by a laboratory test (liquid/gas chromatography-mass spectrometry). Using a non-destructive sampling procedure (suction on swabs) we determined the presence of cocaine on 978 circulating euro banknotes, randomly collected at 5 swiss customs offices, with IMS and LC-MS/MS in order to establish a normal (background) contamination level. A significant proportion (46.4%) of the euro banknotes analysed by LC-MS/MS had cocaine concentrations above the quantification limit (1 ng/swab). However, the extent of contamination is a determining factor: 94.6% of the banknotes in circulation have cocaine concentrations equal to or less than 10 ng/swab and only 3.4% have cocaine concentrations above 20 ng/swab. By comparison, only 27.3% and 13.4% respectively of the seized banknotes (2 real cases) had cocaine concentrations equal to or less than 10 ng/swab, but 63.5% and 86.7% respectively had cocaine concentrations above 20 ng/swab. We also describe a Komolgorov-Smirnov test model used to determine the presence of an "abnormal" level of contamination relative to the reference banknotes (banknotes in circulation or background noise) effectively and within realistic practical and theoretical frameworks. This model provides a quantifiable and statistically significant result that not only simplifies data interpretation, but also facilitates admissibility as forensic evidence in proceedings. When applied to the sized banknotes using both IMS and LC-MS/MS data, we obtain fully consistent and sounding conclusions.
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http://dx.doi.org/10.1016/j.forsciint.2020.110227DOI Listing
April 2020

Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for T Cell Acute Lymphoblastic Leukemia: A Report from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party.

Biol Blood Marrow Transplant 2020 05 9;26(5):936-942. Epub 2020 Jan 9.

Department of Hematology-BMT, Hopital St Antoine, Paris, France.

Allogeneic hematopoietic cell transplantation (HCT) is recommended in high-risk patients with T cell acute lymphoblastic leukemia (T-ALL). For patients without an HLA-identical donor, haploidentical (haplo-) HCT is becoming the leading source of stem cell donation. However, data are scarce on predictive factors for outcome in that setting. We identified 122 adults (20% female; median age, 31 years; range, 18 to 68 years) with T-ALL who underwent haplo-HCT with post-transplantation cyclophosphamide (ptCy) between 2010 and 2017. The median duration of follow-up of living patients was 23 months. The 2-year incidences of relapse and nonrelapse mortality were 45% and 21%, respectively. The 2-year leukemia-free survival (LFS), overall survival (OS), and graft-versus-host disease, relapse-free survival (GRFS) were 34%, 42%, and 27%, respectively. The 2-year LFS and OS were highly influenced by disease status at transplantation, being 49% and 55%, respectively, for patients in first complete remission (CR1); 34% and 50%, respectively, for those in second CR (CR2); and 8% and 12%, respectively, for patients with active disease. On multivariate analysis, only disease status was found to affect LFS and OS. Transplantation in CR2 negatively affected LFS, whereas active disease at the time of haplo-HCT negatively affected LFS and OS. In conclusion, haplo-HCT with ptCy produced encouraging results in this challenging disease, particularly when performed in patients in CR. Despite the limitation of the small sample size, our results were not affected by the type of conditioning, calling into question the need for total body irradiation-based myeloablative conditioning in that setting.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.003DOI Listing
May 2020

Immune Escape after Hematopoietic Stem Cell Transplantation (HSCT): From Mechanisms to Novel Therapies.

Cancers (Basel) 2019 Dec 25;12(1). Epub 2019 Dec 25.

Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Recent advances in understanding its molecular basis have opened the way to new therapeutic strategies, including targeted therapies. However, despite an improvement in prognosis it has been documented in recent years (especially in younger patients) that allogenic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment in AML and the first therapeutic option for high-risk patients. After allo-HSCT, relapse is still a major complication, and is observed in about 50% of patients. Current evidence suggests that relapse is not due to clonal evolution, but instead to the ability of the AML cell population to escape immune control by a variety of mechanisms including the altered expression of HLA-molecules, production of anti-inflammatory cytokines, relevant metabolic changes and expression of immune checkpoint (ICP) inhibitors capable of "switching-off" the immune response against leukemic cells. Here, we review the main mechanisms of immune escape and identify potential strategies to overcome these mechanisms.
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http://dx.doi.org/10.3390/cancers12010069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016529PMC
December 2019

Diagnosing acute encephalitis in patients with hematological disorders: caveats and pitfalls.

J Neurovirol 2020 04 20;26(2):257-263. Epub 2019 Dec 20.

Neuroncology Unit, IRCCS Mondino Foundation, Pavia, Italy.

The aim of this study was to review the quality of the diagnostic work-up for acute encephalitis carried out at our center in a cohort of patients with hematological disorders. Our data showed substantial heterogeneity in investigating patients. Not all patients had their CSF tested for viruses commonly responsible for encephalitis in immunocompetent individuals (e.g., VZV, enterovirus). A blood sample for the calculation of the CSF/blood replication ratio was collected in 74% of cases. CSF cultures and immunophenotyping of CSF cells were performed in 77% and 21% of patients, respectively. A multidisciplinary consensus is needed to improve current guidelines and standardize diagnostic protocols.
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http://dx.doi.org/10.1007/s13365-019-00817-zDOI Listing
April 2020

Targeting Leukemia Stem Cell-Niche Dynamics: A New Challenge in AML Treatment.

J Oncol 2019 7;2019:8323592. Epub 2019 Aug 7.

University of Pavia, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

One of the most urgent needs in AML is to improve the disease cure rate as relapse still occurs in 60-80% of patients. Recent evidence suggests that dismal clinical outcomes may be improved by a better definition of the tight interaction between the AML cell population and the bone marrow (BM) microenvironment ("the niche"); the latter has been progressively highlighted to have an active role in the disease process. It has now been well established that the leukemic population may misinterpret niche-derived signals and remodel the niche, providing a shelter to AML cells and protecting them from the cytotoxic effects of chemoradiotherapy. Novel imaging technological advances and preclinical disease models have revealed that, due to the finite number of BM niches, leukemic stem cells (LSCs) and normal hematopoietic stem cells (HSCs) compete for the same functional areas. Thus, the removal of LSCs from the BM niche and the promotion of normal HSC engraftment should be the primary goals in antileukemic research. In addition, it is now becoming increasingly clear that AML-niche dynamics are disease stage specific. In AML, the niche has been linked to disease pathogenesis in the preleukemic stage, the niche becomes permissive once leukemic cells are established, and the niche is transformed into a self-reinforcing structure at a later disease stage. These concepts have been fostered by the demonstration that, in unrelated AML types, endosteal vessel loss occurs as a primary AML-induced niche alteration, and additional AML-induced alterations of the niche and normal hematopoiesis evolve focally and in parallel. Obviously, this endosteal vessel loss plays a fundamental role in AML pathogenesis by causing excessive vascular permeability, hypoxia, altered perfusion, and reduced drug delivery. Each of these alterations may be effectively targeted by various therapeutic procedures, but preservation of endosteal vessel integrity might be the best option for any future antileukemic treatment.
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http://dx.doi.org/10.1155/2019/8323592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702816PMC
August 2019

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors: A Registry-Based Study of the Italian Blood and Marrow Transplantation Society (GITMO).

Biol Blood Marrow Transplant 2019 12 7;25(12):2388-2397. Epub 2019 Aug 7.

Centro Unico Regionale Trapianto Cellule Staminali e Terapie Cellulari A. Neri, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.

We performed a nationwide registry-based analysis to describe the clinical outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) who underwent an allogeneic hematopoietic stem cell transplantation (HSCT) after a tyrosine kinase inhibitor (TKI)-based treatment A total of 441 patients were included in the study. The median age at HSCT was 44 years (range, 18 to 70 years). All 441 patients (100%) received TKI before HSCT (performed between 2005 and 2016). Of these 441 patients, 404 (92%) were in cytologic complete remission (CR), whereas the remaining 37 (8%) had active disease at the time of HSCT. Molecular minimal residual disease (MRD) was negative in 147 patients (36%) at the time of HSCT. The donor was unrelated in 46% of patients. The most prevalent source of stem cells was peripheral blood (70%). The conditioning regimen was myeloablative in 82% of cases (total body irradiation-based in 50%) and included antithymocyte globulin in 51% of patients. With a median follow-up after HSCT of 39.4 months (range, 1 to 145 months), the probability of overall survival (OS) at 1, 2, and 5 years was 69.6%, 61.1% and 50.3%, respectively, with a median OS of 62 months. Progression-free survival (PFS) at 1, 2, and 5 years was 60.2%, 52.1% and 43.7%, respectively. OS and PFS were significantly better in patients who were in CR and MRD-negative at the time of HSCT compared with patients who were in CR but MRD-positive (50% OS not reached versus 36 months; P = .015; 50% PFS not reached versus 26 months, P = .003). The subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT had a better outcome (5-year OS, 70%). Conversely, the 37 patients who underwent a HSCT with active Ph ALL had a median OS of 7 months and a median PFS of 5 months. The 5-year cumulative incidence of relapse was significantly lower in MRD-negative patients (19.5% versus 35.4%; P = .001). Nonrelapse mortality (NRM) after 1, 2, and 5 years was 19.1% (95% confidence interval [CI], 15.5% to 22.9%), 20.7% (95% CI, 17% to 24.7%), and 24.1% (95% CI, 20% to 28.5%), respectively. NRM was significantly lower with a modified European Society for Blood and Marrow Transplantation (mEBMT) risk score of 0 to 2 compared with ≥3 (15% versus 25%; P = .016). The median OS for Ph ALL patients who underwent a TKI-based treatment followed by an allogeneic HSCT, in recent years at the GITMO centers, was 62 months. Evaluation of the mEBMT risk score can be useful to predict NRM. Our data confirm that HSCT is a potentially curative treatment for Ph ALL with an excellent outcome for the subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT (5-year OS, 70%).
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http://dx.doi.org/10.1016/j.bbmt.2019.07.037DOI Listing
December 2019

Comparison of Dynamic International Prognostic Scoring System and MYelofibrosis SECondary to PV and ET Prognostic Model for Prediction of Outcome in Polycythemia Vera and Essential Thrombocythemia Myelofibrosis after Allogeneic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 06 28;25(6):e204-e208. Epub 2019 Mar 28.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C > .5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P = .78). Overall, the DIPSS was not significantly predictive of outcome (P = .28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P = .05), whereas groups with intermediate 2 and high risk showed no significant difference (P = .44). Assessment of prognostic utility yielded a C-index of .575 (95% CI, .502 to .648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of .636 (95% CI, .563 to .708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P = .04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P = .01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification.
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http://dx.doi.org/10.1016/j.bbmt.2019.03.024DOI Listing
June 2019

Optimized EBMT transplant-specific risk score in myelodysplastic syndromes after allogeneic stem-cell transplantation.

Haematologica 2019 05 17;104(5):929-936. Epub 2019 Jan 17.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany

The aim of this study was to develop and validate a clinical and transplant-specific prognostic score using data from a large cohort of patients with myelodysplastic syndromes reported to the European Society for Blood and Marrow Transplantation registry. A Cox model was fitted to detect clinical and transplant-related variables prognostic of outcome. Then, cross-validation was performed to evaluate the validity and consistency of the model. Seven independent risk factors for survival were identified: age ≥50 years, matched unrelated donor, Karnofsky Performance Status <90%, very poor cytogenetics or monosomal karyotype, positive cytomegalovirus status of the recipient, blood blasts >1%, and platelet count ≤50 × 10/L prior to transplantation. Incorporating these factors into a four-level risk score yielded hazard ratios for death, with low-risk (score of 0-1) as reference, of 2.02 (95% CI: 1.41-2.90) for the intermediate-risk group (score of 2-3), 3.49 (95% CI: 2.45-4.97) for the high-risk group (score of 4-5), and 5.90 (95% CI: 4.01-8.67) for the very high-risk group (score of >5). The score was predictive of survival, relapse-free survival, relapse, and non-relapse mortality (<0.001, respectively). Cross-validation yielded significant and reproducible improvement in prognostic ability with C-statistics being 0.609 (95% CI: 0.588-0.629) 0.555 for the registry and 0.579 for the Center for Blood and Marrow Transplant Research registry. Prediction was even further augmented after applying a nomogram using age and platelets as continuous variables showing C-statistics of 0.628 (95% CI: 0.616-0.637). In conclusion, compared to existing prognostic systems, this proposed transplant-specific risk score offers improved performance with respect to post-transplant risk stratification in myelodysplastic syndromes.
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http://dx.doi.org/10.3324/haematol.2018.200808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518902PMC
May 2019

Endosteal vessel integrity: a new therapeutic goal in acute myeloid leukemia?

Stem Cell Investig 2018 22;5:36. Epub 2018 Oct 22.

Division of Hematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.21037/sci.2018.10.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232056PMC
October 2018

Cutaneous relapse after allogenic hematopoietic stem cell transplantation for acute myeloid leukemia: a clinical and immunophenotype study of seven patients.

G Ital Dermatol Venereol 2020 Apr 17;155(2):250-252. Epub 2018 Jul 17.

Institute of Dermatology, Department of Clinical-Surgical, Diagnostic and Pediatric Science, Policlinico San Matteo IRCCS Foundation, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.23736/S0392-0488.18.06010-8DOI Listing
April 2020

The spleen of patients with myelofibrosis harbors defective mesenchymal stromal cells.

Am J Hematol 2018 05 8;93(5):615-622. Epub 2018 Feb 8.

Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.

Splenic hematopoiesis is a major feature in the course of myelofibrosis (MF). In fact, the spleen of patients with MF contains malignant hematopoietic stem cells retaining a complete differentiation program, suggesting both a pivotal role of the spleen in maintaining the disease and a tight regulation of hematopoiesis by the splenic microenvironment, in particular by mesenchymal stromal cells (MSCs). Little is known about splenic MSCs (Sp-MSCs), both in normal and in pathological context. In this work, we have in vitro expanded and characterized Sp-MSCs from 25 patients with MF and 13 healthy subjects (HS). They shared similar phenotype, growth kinetics, and differentiation capacity. However, MF Sp-MSCs expressed significant lower levels of nestin, and favored megakaryocyte (Mk) differentiation in vitro at a larger extent than their normal counterpart. Moreover, they showed a significant upregulation of matrix metalloprotease 2 (MMP2) and fibronectin 1 (FN1) genes both at mRNA expression and at protein level, and, finally, developed genetic abnormalities which were never detected in HS-derived Sp-MSCs. Our data point toward the existence of a defective splenic niche in patients with MF that could be responsible of some pathological features of the disease, including the increased trafficking of CD34+ cells and the expansion of the megakaryocytic lineage.
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http://dx.doi.org/10.1002/ajh.25047DOI Listing
May 2018

Alternative splicing of hTERT: a further mechanism for the control of active hTERT in acute myeloid leukemia.

Leuk Lymphoma 2018 03 6;59(3):702-709. Epub 2017 Jul 6.

a Division of Hematology , Fondazione IRCCS Policlinico San Matteo University of Pavia , Pavia , Italy.

hTERT component is the key regulator of telomerase. Alternatively spliced variants of hTERT generate different telomerase activity. The goal of the study was to determine the role of different hTERT isoforms in the regulation of telomerase expression in AML patients. Among the 97 studied patients, 45 had a complex karyotype and 52 a normal karyotype. hTERT isoforms expression was determined in bone marrow samples by q-RT-PCR, using SYBR Green I. hTERT expression was lower in AML patients than controls (median 2.5 vs. 10.1, p = .003), though no difference was observed between the complex and normal karyotype (median 3.2 vs. 2.3, p = .37). High trans-dominant negative isoform expression increased the response rate by two. High expression of inactive product (-α - β) was shown to increase the risk of relapse by about three times. In conclusion, our data suggest an intriguing link between the control of hTERT isoforms expression and AML outcome.
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http://dx.doi.org/10.1080/10428194.2017.1346252DOI Listing
March 2018

MDS/AML del(11)(q14) Share Common Morphological Features Despite Different Chromosomal Breakpoints.

Anticancer Res 2017 02;37(2):645-649

Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

In myelodysplatic syndromes and acute myeloid leukemia (MDS/AML) deletion of the 11q14 region is a rare chromosomal defect (incidence: 0.6-1.0%), included within the intermediate risk criteria by the International Prognostic Scoring System. No fluorescence in situ hybridization (FISH) study has yet been performed to identify a common breakpoint region (CBR). In our study through FISH with bacterial artificial chromosomes and commercial probes, we analyzed seven patients with MDS/AML harboring 11q14 deletion on conventional cytogenetic analysis. FISH revealed deletions in five patients and amplifications in two. Three patients with deletion carried a CBR, two had a deletion involving a more centromeric breakpoint. These five patients exhibited multilineage dysplasia, blast cells with large round nuclei, loose chromatin, small and abundant nucleoli, and vacuolated cytoplasm with very thin Auer bodies. In conclusion, the morphological features which occur independently of the extent of the deletion are of multilineage dysplasia in MDS and leukemic blasts strongly reactive to peroxidase in AML; despite the variable size of the deleted area, some patients harbor a CBR.
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http://dx.doi.org/10.21873/anticanres.11359DOI Listing
February 2017

Therapeutically targeting SELF-reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

Am J Hematol 2016 May 4;91(5):507-17. Epub 2016 Apr 4.

Division of Hematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

A tight relationship between the acute myeloid leukemia (AML) population and the bone marrow (BM) microenvironment has been convincingly established. The AML clone contains leukemic stem cells (LSCs) that compete with normal hematopoietic stem cells (HSCs) for niche occupancy and remodel the niche; whereas, the BM microenvironment might promote AML development and progression not only through hypoxia and homing/adhesion molecules, but also through genetic defects. Although it is still unknown whether the niche influences treatment results or contains any potential target for treatment, this dynamic AML-niche interaction might be a promising therapeutic objective to significantly improve the AML cure rate.
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http://dx.doi.org/10.1002/ajh.24312DOI Listing
May 2016

Particulate cytoplasmic structures with high concentration of ubiquitin-proteasome accumulate in myeloid neoplasms.

J Hematol Oncol 2015 Jun 18;8:71. Epub 2015 Jun 18.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Background: Increased plasma levels of proteasome have been associated with various neoplasms, especially myeloid malignancies. Little is known of the cellular origin and release mechanisms of such proteasome. We recently identified and characterized a novel particulate cytoplasmic structure (PaCS) showing selective accumulation of ubiquitin-proteasome system (UPS) components. PaCSs have been reported in some epithelial neoplasms and in two genetic disorders characterized by hematopoietic cell dysplasia and increased risk of leukemia. However, no information is available about PaCSs in hematopoietic neoplasms.

Methods: PaCSs were investigated by ultrastructural, immunogold, and immunofluorescence analysis of bone marrow (BM) biopsies and peripheral blood (PB) cell preparations of 33 consecutive, untreated, or relapsed patients affected by different hematopoietic neoplasms. BM and PB samples from individuals with non-neoplastic BM or healthy donors were studied as controls. Granulocytes and platelet proteasome content was measured by immunoblotting and plasma proteasome levels by ELISA.

Results: PaCSs with typical, selective immunoreactivity for polyubiquitinated proteins and proteasome were widespread in granulocytic cells, megakaryocytes, and platelets of patients with myeloproliferative neoplasms (MPN). In acute myeloid leukemia and myelodysplastic syndromes (MDS), PaCSs were only occasionally detected in blast cells and were found consistently in cells showing granulocytic and megakaryocytic maturation. Conversely, PaCSs were poorly represented or absent in non-neoplastic hematopoietic tissue or lymphoid neoplasms. In MPN granulocytes and platelets, the presence of PaCSs was associated with increased amounts of proteasome in cell lysates. PaCSs were often localized in cytoplasmic blebs generating PaCSs-filled plasma membrane vesicles observable in the BM intercellular space. In MPN and MDS, accumulation of PaCSs was associated with significant increase in plasma proteasome. Immunogold analysis showed that PaCSs of myeloid neoplasia selectively concentrated the chaperone proteins Hsp40, Hsp70, and Hsp90.

Conclusions: PaCSs accumulate in cells of myeloid neoplasms in a lineage- and maturation-restricted manner; in particular, they are widespread in granulocytic and megakaryocytic lineages of MPN patients. PaCSs development was associated with excess accumulation of polyubiquitinated proteins, proteasome, and chaperone molecules, indicating impairment of the UPS-dependent protein homeostasis and a possible link with Hsp90-related leukemogenesis. A mechanism of PaCSs discharge by leukemic cells could contribute to increased plasma proteasome of MPN and MDS.
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http://dx.doi.org/10.1186/s13045-015-0169-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473848PMC
June 2015

Comprehensive characterization of mesenchymal stromal cells from patients with Fanconi anaemia.

Br J Haematol 2015 Sep 26;170(6):826-36. Epub 2015 May 26.

Department of Paediatric Haematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Fanconi anaemia (FA) is an inherited disorder characterized by pancytopenia, congenital malformations and a predisposition to develop malignancies. Alterations in the haematopoietic microenvironment of FA patients have been reported, but little is known regarding the components of their bone marrow (BM) stroma. We characterized mesenchymal stromal cells (MSCs) isolated from BM of 18 FA patients both before and after allogeneic haematopoietic stem cell transplantation (HSCT). Morphology, fibroblast colony-forming unit (CFU-F) ability, proliferative capacity, immunophenotype, differentiation potential, ability to support long-term haematopoiesis and immunomodulatory properties of FA-MSCs were analysed and compared with those of MSCs expanded from 15 age-matched healthy donors (HD-MSCs). FA-MSCs were genetically characterized through conventional karyotyping, diepoxybutane-test and array-comparative genomic hybridization. FA-MSCs generated before and after HSCT were compared. Morphology, immunophenotype, differentiation potential, ability in vitro to inhibit mitogen-induced T-cell proliferation and to support long-term haematopoiesis did not differ between FA-MSCs and HD-MSCs. CFU-F ability and proliferative capacity of FA-MSCs isolated after HSCT were significantly lower than those of HD-MSCs. FA-MSCs reached senescence significantly earlier than HD-MSCs and showed spontaneous chromosome fragility. Our findings indicate that FA-MSCs are defective in their ability to survive in vitro and display spontaneous chromosome breakages; whether these defects are involved in pathophysiology of BM failure syndromes deserves further investigation.
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http://dx.doi.org/10.1111/bjh.13504DOI Listing
September 2015

Autologous stem cell transplantation with in vivo purged progenitor cells shows long-term efficacy in relapsed/refractory follicular lymphoma.

Am J Hematol 2015 Mar;90(3):230-4

Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Hematology and Oncology, Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.

High-dose chemotherapy with autologous stem cell transplantation (ASCT) has been shown effective in the control of relapsed/refractory follicular lymphoma. We evaluate the long-term outcome of patients with relapsed or refractory follicular lymphoma treated with ASCT with in vivo purged progenitors cells. We report the long-term results of a prospective multicenter phase 2 trial on 124 relapsed/refractory follicular lymphoma patients treated with a program of anthracycline-based debulking chemotherapy, immunochemotherapy, mobilization of in vivo purged PBSC followed by ASCT. Median age was 52 years; 14% of patients had grade 3A histology. Debulking chemotherapy produced CR in 16% and PR in 71%, while 13% of patients progressed. After rituximab, cyclophosphamide, vincristine, prednisone (R-COP), CR was obtained in 60% and PR in 35%; 118 patients successfully mobilized PBSC and 117 proceeded to ASCT. The harvest in all the 32 molecularly informative patients was bcl-2 negative. TRM was 0%. The 5-year PFS was 54% and the 5-year OS was 83%. After a median f-up of 6.7 years (range 1.5-13.6), 54% are still in CR. These data show that prolonged PFS is achievable in relapsed/refractory patients with high dose autologous transplantation of in vivo purged progenitor cells.
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http://dx.doi.org/10.1002/ajh.23919DOI Listing
March 2015

Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised IPSS-R.

Blood 2014 Apr 20;123(15):2333-42. Epub 2014 Feb 20.

Department of Hematology Oncology, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy;

Approximately one-third of patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (HSCT) are cured by this treatment. Treatment failure may be due to transplant complications or relapse. To identify predictive factors for transplantation outcome, we studied 519 patients with MDS or oligoblastic acute myeloid leukemia (AML, <30% marrow blasts) who received an allogeneic HSCT and were reported to the Gruppo Italiano Trapianto di Midollo Osseo registry between 2000 and 2011. Univariate and multivariate survival analyses were performed using Cox proportional hazards regression. High-risk category, as defined by the revised International Prognostic Scoring System (IPSS-R), and monosomal karyotype were independently associated with relapse and lower overall survival after transplantation. On the other hand, older recipient age and high hematopoietic cell transplantation-comorbidity index (HCT-CI) were independent predictors of nonrelapse mortality. Accounting for various combinations of patient's age, IPSS-R category, monosomal karyotype, and HCT-CI, the 5-year probability of survival after allogeneic HSCT ranged from 0% to 94%. This study indicates that IPSS-R risk category and monosomal karyotype are important factors predicting transplantation failure both in MDS and oligoblastic AML. In addition, it reinforces the concept that allogeneic HSCT offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages.
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http://dx.doi.org/10.1182/blood-2013-12-542720DOI Listing
April 2014
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