Publications by authors named "Michele Malagola"

89 Publications

Management of Invasive Infections due to a Rare Arthroconidial Yeast, , in Two Patients with Acute Hematological Malignancies.

Vaccines (Basel) 2021 Nov 6;9(11). Epub 2021 Nov 6.

Department of Molecular and Translational Medicine, Institute of Microbiology, University of Brescia-ASST Spedali Civili, 25123 Brescia, Italy.

is an arthroconidial yeast, found principally in the environment, even if it belongs also to the normal microbial flora that colonize human subjects. This yeast is increasingly associated with invasive infections in hematological patients, in particular in those affected by acute leukemia. An important risk factor that predisposes to this infection is the profound neutropenia present in such immunocompromised patients. spp. were found resistant to both echinocandins and fluconazole so the treatment is often difficult. Here, we report two cases of sepsis in two patients with acute leukemia. All of them had fatal events, due to the worsening of their clinical condition. An early diagnosis and appropriate management of these pathogens is important in consideration of the poor prognosis associated to these fungal invasive infections.
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http://dx.doi.org/10.3390/vaccines9111289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619284PMC
November 2021

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

Comparative Mutational Profiling of Hematopoietic Progenitor Cells and Circulating Endothelial Cells (CECs) in Patients with Primary Myelofibrosis.

Cells 2021 10 15;10(10). Epub 2021 Oct 15.

Unit of Blood Diseases and Bone Marrow Transplantation, Cell Therapies and Hematology Research Program, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili di Brescia, P.le Spedali Civili, 1, 25123 Brescia, Italy.

A role of endothelial cells (ECs) in Primary Myelofibrosis (PMF) was supposed since mutation was found in endothelial precursor cells (EPCs) and in ECs captured by laser microdissection. By Cell Search method, the circulating endothelial cells (CECs) from 14 PMF patients and 5 healthy controls have been isolated and compared by NGS with CD34+Hematopoietic stem and progenitors cells (HSPCs) for panel of 54 myeloid-associated mutations. PMF patients had higher levels of CECs. No mutation was found in HSPCs and CECs from controls, while CECs from PMF patients presented several somatic mutations. 72% of evaluable patients shared at least one mutation between HSPCs and CECs. 2 patients shared the mutation, together with , , and , , respectively. 6 out of 8 shared only NON MPN-driver mutations: and in one case; individual paired mutations in , , , and , in the other cases. In conclusion, 70% of PMF patients shared at least one mutation between HSPCs and CECs. These latter harbored several myeloid-associated mutations, besides mutation. Our results support a primary involvement of EC in PMF and provide a new methodological approach for further studies exploring the role of the "neoplastic" vascular niche.
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http://dx.doi.org/10.3390/cells10102764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534986PMC
October 2021

Alignment of Qx100/Qx200 Droplet Digital (Bio-Rad) and QuantStudio 3D (Thermofisher) Digital PCR for Quantification of BCR-ABL1 in Ph+ Chronic Myeloid Leukemia.

Diseases 2021 May 5;9(2). Epub 2021 May 5.

Unit of Blood Diseases and Stem Cell Transplantation, DPT of Clinical and Experimental Sciences, University of Brescia, ASST SpedaliCivili di Brescia, 25123 Brescia, Italy.

In recent years, the digital polymerase chain reaction has received increasing interest as it has emerged as a tool to provide more sensitive and accurate detection of minimal residual disease. In order to start the process of data alignment, we assessed the consistency of the BCR-ABL1 quantification results of the analysis of 16 RNA samples at different levels of disease. The results were obtained by two different laboratories that relied on The Qx100/Qx200 Droplet Digital PCR System (Bio-Rad) and Quant Studio 3D dPCR System (Thermofisher) platforms. We assessed the compatibility between the estimated values by linear regression, Bland-Altman bias-plot, and Mann-Whitney nonparametric test. The results confirmed the compatibility of the measures, allowing us tocompute an 'alignment factor' (AF), equal to 1.41, which was further validated by a different series of experiments. We conclude that the performed measurements by the two laboratories are comparable, and also equalized through the introduction of an alignment factor.
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http://dx.doi.org/10.3390/diseases9020035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161814PMC
May 2021

Changes in Stem Cell Transplant activity and procedures during SARS-CoV2 pandemic in Italy: an Italian Bone Marrow Transplant Group (GITMO) nationwide analysis (TransCOVID-19 Survey).

Bone Marrow Transplant 2021 09 19;56(9):2272-2275. Epub 2021 Apr 19.

San Raffaele Scientific Institute, Milan, Italy.

The Transplant Centers belonging to Gruppo Italiano per il Trapianto di Midollo Osseo (GITMO) conducted a survey with the aim of evaluating the effect of SARS-CoV2 pandemic on the allogeneic transplant activity in Italy. The pandemic period from 1/3/2020 to 31/7/2020 was compared with the same period in 2019. Overall, in 2020 there was a 2.4% reduction in the number of allo-HCT cases compared to 2019. Interestingly, this deflection did not affect the acute leukemia cases (+5.7% in 2020). The use of peripheral blood-derived stem cells (+10.7%) and cryopreservation (97.4% of the centers) was highly adopted in 2020. Despite the sanitary emergency, almost all of the surveyed centers declared no impact of SARS-CoV2 pandemic on the transplant timing and outcomes, and the sanitary policy was positively evaluated by the majority of centers. The emergency measures ensured that only a minority of the allo-HCT patients had been infected by SARS-CoV2; however, a mortality of 42.1% among the allo-HCT patients hospitalized for COVID-19 was recorded. This survey gives us the information that the GITMO Group reacted positively to the pandemic. Thanks to the emergency strategies, the Italian allo-HCT activity continued safely, showing only a minor deflection and offering the same probability of cure to the transplanted patients.
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http://dx.doi.org/10.1038/s41409-021-01287-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054130PMC
September 2021

Development of BCR-ABL1 Transgenic Zebrafish Model Reproducing Chronic Myeloid Leukemia (CML) Like-Disease and Providing a New Insight into CML Mechanisms.

Cells 2021 02 19;10(2). Epub 2021 Feb 19.

Unit of Hematology, Department of Clinical and Experimental Sciences, University of Brescia, Bone Marrow Transplant Unit, ASST Spedali Civili, 25123 Brescia, Italy.

Zebrafish has proven to be a versatile and reliable experimental in vivo tool to study human hematopoiesis and model hematological malignancies. Transgenic technologies enable the generation of specific leukemia types by the expression of human oncogenes under specific promoters. Using this technology, a variety of myeloid and lymphoid malignancies zebrafish models have been described. Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the fusion gene, derived from the t (9;22) translocation causing the Philadelphia Chromosome (Ph). The BCR-ABL1 protein is a constitutively activated tyrosine kinas inducing the leukemogenesis and resulting in an accumulation of immature leukemic cells into bone marrow and peripheral blood. To model Ph+ CML, a transgenic zebrafish line expressing the human was generated by the Gal4/UAS system, and then crossed with the hsp70-Gal4 transgenic line. The new line named (pUAS:CFP/hsp70-Gal4), presented altered expression of hematopoietic markers during embryonic development compared to controls and transgenic larvae showed proliferating hematopoietic cells in the caudal hematopoietic tissue (CHT). The present transgenic zebrafish would be a robust CML model and a high-throughput drug screening tool.
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http://dx.doi.org/10.3390/cells10020445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922348PMC
February 2021

Molecular response and quality of life in chronic myeloid leukemia patients treated with intermittent TKIs: First interim analysis of OPTkIMA study.

Cancer Med 2021 03 16;10(5):1726-1737. Epub 2021 Feb 16.

Hematology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy.

Background: Intermittent treatment with TKIs is an option for the great majority (70%-80%) of CML patients who do not achieve a stable deep molecular response and are not eligible for treatment discontinuation. For these patients, the only alternative is to assume TKI continuously, lifelong.

Methods: The Italian phase III multicentric randomized OPTkIMA study started in 2015, with the aim to evaluate if a progressive de-escalation of TKIs (imatinib, nilotinib, and dasatinib) is able to maintain the molecular response (MR ) and to improve Health Related Quality of Life (HRQoL).

Results: Up to December 2018, 166/185 (90%) elderly CML patients in stable MR /MR completed the first year of any TKI intermittent schedule 1 month ON and 1 month OFF. The first year probability of maintaining the MR was 81% and 23.5% of the patients who lost the molecular response regained the MR after resuming TKI continuously. Patients' HRQoL at baseline was better than that of matched peers from healthy population. Women was the only factor independently associated with worse baseline HRQoL (p > 0.0001). Overall, global HRQoL worsened at 6 (p < 0.001) but returned to the baseline value at 12 months and it was statistically significantly worse in women (p = 0.001).

Conclusions: De-escalation of any TKI by 1 month ON/OFF schedule maintains the MR /MR in 81% of the patients during the first 12-24 months. No patients progressed to accelerated/blastic phase, all the patients (23.5%) losing MR regained the MR and none suffered from TKI withdrawn syndrome. The study firstly report on HRQoL in elderly CML patients moving from a continuous daily therapy to a de-escalated intermittent treatment.
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http://dx.doi.org/10.1002/cam4.3778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940223PMC
March 2021

A Systematic Review of the Literature and Perspectives on the Role of Biomarkers in the Management of Malnutrition After Allogeneic Hematopoietic Stem Cell Transplantation.

Front Immunol 2020 6;11:535890. Epub 2021 Jan 6.

Unit of Blood Disease and Stem Cell Transplantation, Chair of Hematology, University of Brescia, ASST Spedali Civili, Brescia, Italy.

Malnutrition is a common problem after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and could impair immune function. Immune dysfunction after allo-HSCT may be linked with infections, GVHD, and relapse and negatively affect the outcome. Aim of this review was to identify malnutrition biomarkers, potentially useful for immune-system monitoring, in the setting of allo-HSCT. After a systematic search, no satisfying biomarker was found, except for citrulline. Citrulline could be useful in monitoring gastrointestinal function after allo-HSCT and its role in the complex relationship with immune-system function ought to be better explored. A multi-omics approach, including biomarkers and PRO (patient reported outcomes) is, in our opinion, the optimal way to study the relationship between malnutrition and transplant outcomes.
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http://dx.doi.org/10.3389/fimmu.2020.535890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815932PMC
April 2021

Considerations on antimicrobial prophylaxis in patients with lymphoproliferative diseases: A SEIFEM group position paper.

Crit Rev Oncol Hematol 2021 Feb 31;158:103203. Epub 2020 Dec 31.

Fondazione Policlinico Universitario A. Gemelli - IRCCS - Istituto di Malattie Infettive -Università Cattolica del Sacro Cuore, Livio, Italy. Electronic address:

The therapeutic armamentarium for the treatment of patients with lymphoproliferative diseases has grown considerably over the most recent years, including a large use of new immunotherapeutic agents. As a consequence, the epidemiology of infectious complications in this group of patients is poorly documented, and even more importantly, the potential benefit of antimicrobial prophylaxis remains a matter of debate when considering the harmful effect from the emergence of multidrug resistant pathogens. The present position paper is addressed to all hematologists treating patients affected by lymphoproliferative malignancies with the aim to provide clinicians with a useful tool for the prevention of bacterial, fungal and viral infections.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103203DOI 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

RT-qPCR versus Digital PCR: How Do They Impact Differently on Clinical Management of Chronic Myeloid Leukemia Patients?

Case Rep Oncol 2020 Sep-Dec;13(3):1263-1269. Epub 2020 Oct 15.

Chair of Hematology, Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy.

Real-time quantitative PCR (RT-qPCR) is the gold standard to quantify the BCR-ABL1 transcript for molecular response monitoring in chronic myeloid leukemia (CML) patients, and it plays a pivotal role in clinical decision-making process, even if it presents technical limits. Increasing data suggest that digital PCR (dPCR) is more accurate and reliable than RT-qPCR in CML minimal residual disease monitoring and in patients' selection for treatment discontinuation. But what about the identification of treatment discontinuation failures? We present the case of a CML patient enrolled both in a study aiming to comparatively assess molecular response by RT-qPCR and dPCR and in the progressive arm of the OPTkIMA trial. This is a phase III trial including CML patients randomized to receive a fixed versus a progressive intermittent tyrosine kinase inhibitor regimen. At 24 months, because of two consecutive detections of MR2.0 by RT-qPCR, the patient resumed daily treatment. Conversely, dPCR revealed a stability of molecular response and even a slight decreasing of transcript over time. An additional specimen was sampled one month after the first MR2.0 detection because of clinical decision: RT-qPCR resulted MR3.0 and dPCR confirmed the transcript's stability. Nowadays, the resumption of therapy is RT-qPCR-driven despite its limits in detection and robustness. In this case, according to dPCR, the patient could have continued intermittent treatment and the stability of response was then confirmed by RT-qPCR. So, dPCR could be able to better identify peculiar clinical response to therapy.
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http://dx.doi.org/10.1159/000510440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670369PMC
October 2020

Haploidentical related donor compared to HLA-identical donor transplantation for chemosensitive Hodgkin lymphoma patients.

BMC Cancer 2020 Nov 24;20(1):1140. Epub 2020 Nov 24.

Hematology Department, Transplantation and Cellular Therapy Unit, Institut Paoli-Calmettes, Marseille, France.

Background: Allogeneic stem cell transplantation from haploidentical donor using an unmanipulated graft and post-transplantation cyclophosphamide (PT-Cy) is growing. Haploidentical transplantation with PT-Cy showed a major activity in Hodgkin lymphoma (HL), reducing the relapse incidence. The most important predictive factor of survival and toxicity was disease status before transplantation, which was better in patients with well controlled disease.

Methods: We included 198 HL in complete (CR) or partial remission (PR) before transplantation. Sixty-five patients were transplanted from haploidentical donor and 133 from a HLA identical donor (both sibling and unrelated donors). Survival analysis was defined according to the EBMT criteria. Survival curves were generated by using Kaplan-Meier method and differences between groups were compared by the log rank test or by the log rank test for trend when appropriated.

Results: The PFS, OS, and RI were significantly better in patients in CR compared to PR (55% vs 29% p = 0.001, 74% vs 55% p = 0.03, 27% vs 55% p <  0.001, respectively). The 2-year PFS was significantly better for HAPLO than HLA-id (63% vs 37%, p = 0.03), without difference in OS. The 1-year NRM was not different. The 2-year relapse incidence (RI) was lower in the HAPLO group (24% vs 44%, p = 0.008). Patients in CR receiving haplo HSCT showed higher 2-year PFS and lower 2-year RI than those allografted with HLA-id donor (75% vs 47%, p <  0.001 and 11% vs 34%, p < 0.001, respectively). In multivariate analysis, donor type and disease status before transplantation were independent predictors of PFS as well as they predict the risk of relapse. Disease status at transplantation and age were independently associated to OS.

Conclusions: Nonetheless this is a retrospective study, limiting the wide applicability of results, data from this analysis suggest that HLA mismatch can induce a strong graft versus lymphoma effect leading to an enhanced PFS.
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http://dx.doi.org/10.1186/s12885-020-07602-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685618PMC
November 2020

Advances in CMV Management: A Single Center Real-Life Experience.

Front Cell Dev Biol 2020 27;8:534268. Epub 2020 Oct 27.

Chair of Hematology, Bone Marrow Transplant Unit, ASST-Spedali Civili Brescia, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

CMV infection is a major challenge in allogeneic stem cell transplantation (allo-SCT). The changing landscape in CMV management includes the introduction of letermovir in prophylaxis of high-risk patients and the source of CMV DNA monitoring (plasma-PL vs. whole blood-WB), for pre-emptive therapy (PET) initiation. We report here how our real-life experience in CMV management evolved, following letermovir registration. We focus on: (i) the effects of systematic use of letermovir for CMV prophylaxis in high-risk patients, (ii) the results of a longitudinal comparison of CMV DNAemia monitoring in PL and WB. From December 2018 to April 2020, 60 allo-SCTs have been performed in our center (LET ), of whom 45 received letermovir in prophylaxis from day 0 to day + 100, because of recipient positivity of anti CMV IgG. These patients were compared with a cohort of 41 allo-SCTs performed between November 2017 and November 2018 (NO LET ). Firstly, the incidence of CMV clinically significant infections, CMV disease, bacterial infections, proven/probable fungal infections, hospital re-admissions after allo-SCT by day + 100 in the two ERA were 8 vs. 44% ( = 0.0006), 2 vs. 12% ( = 0.02), 37 vs. 56% ( = 0.05), 8 vs. 19% ( = 0.09), and 23 vs. 39% ( = 0.09), respectively. By day + 180 these differences were 17 vs. 68% ( < 0.00001), 2 vs. 12% ( = 0.02), 45 vs. 78% ( = 0.09), 8 vs. 22% ( = 0.05), and 40 vs. 66% ( = 0.01), respectively. Secondly, from February to May 2019, we comparatively measured CMV DNA from WB and PL and we confirmed that there is a linear correlation between CMV DNA level in WB and PL (Spearman's test = 0.86). Moreover, CMV DNAemia at the time of PET in the 12 patients with a clinically significant CMV infection was higher in WB vs. PL (5.202 vs. 4.981 copies/ml, = 0.1). Our real-life experience confirms that: (i) letermovir is highly effective, leading to a significant drop in CMV clinically significant infections and CMV-related complications by day + 100 and + 180 after allo-SCT; (ii) WB may be an effective alternative to PL as a source for CMV DNA monitoring, as a linear correlation of DNAemia was confirmed between WB and PL, even if the CMV DNAemia at PET initiation was comparable in the two sources.
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http://dx.doi.org/10.3389/fcell.2020.534268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652755PMC
October 2020

Case Report: Late Onset of Myelodysplastic Syndrome From Donor Progenitor Cells After Allogeneic Stem Cell Transplantation. Which Lessons Can We Draw From the Reported Case?

Front Oncol 2020 14;10:564521. Epub 2020 Oct 14.

Chair of Hematology, Unit of Blood Diseases and Stem Cell Transplantation, DPT of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy.

Background: Myelodysplastic syndromes and acute leukemias after allogeneic stem cell transplantation (allo-SCT) are mainly caused by recurrence of the primitive leukemic clones. More rarely, they originate from donor hematopoietic stem cells, developing the so-called donor cell leukemia (DCL) or myelodysplastic syndromes (DC-MDSs). DCL and DC-MDS can be considered as an model of leukemogenesis, and even if the pathogenetic mechanisms remain speculative, a genetic predisposition of donor progenitor cells, an altered host microenvironment, and the impairment of immune surveillance are considered the main causes.

Case Presentation: We report a case of DC-MDS diagnosed 5 years after an allo-SCT from a matched related donor (patient's sister) in a patient with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL). The sex-mismatch allowed us to identify the donor cell origin. At the onset, the DC-MDS was characterized by chromosome seven monosomy and , , and mutations. Because of a familiar history of colorectal neoplasia and the variant allele frequency (VAF) of mutation at the onset, this mutation was searched on germline DNA in both the donor and the recipient, but the result was negative. Moreover, after transplant (+4 months), the patient developed severe and long-lasting chronic graft-versus-host disease (cGVHD), requiring multiple lines of treatments. Because of the severe immunosuppression, recurrent infections occurred and, lately, the patient died due to septic shock.

Conclusion: This case report highlights the need, whenever possible, to evaluate the donor origin of the posttransplant myelodysplasia and acute leukemias. The potential key role of the impaired immune surveillance and of long-lasting immunosuppression appears to be emerging in the development of this case of DC-MDS. Finally, this case reminds the importance to investigate the familiar genetic predisposition in donors with a familiar history of neoplasia.
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http://dx.doi.org/10.3389/fonc.2020.564521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591784PMC
October 2020

Severe Acute Respiratory Syndrome Coronavirus-2 Pandemia: Facts and Perspectives in a Bone Marrow Transplant Unit.

Front Oncol 2020 4;10:1626. Epub 2020 Sep 4.

Bone Marrow Transplant Unit, Department of Clinical and Experimental Sciences, ASST Spedali Civili Brescia, University of Brescia, Brescia, Italy.

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http://dx.doi.org/10.3389/fonc.2020.01626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499469PMC
September 2020

Idelalisib treatment prior to allogeneic stem cell transplantation for patients with chronic lymphocytic leukemia: a report from the EBMT chronic malignancies working party.

Bone Marrow Transplant 2021 03 2;56(3):605-613. Epub 2020 Oct 2.

University of Heidelberg, Heidelberg, Germany.

No studies have been reported so far on bridging treatment with idelalisib for patients with chronic lymphocytic leukemia (CLL) prior to allogeneic hematopoietic cell transplantation (alloHCT). To study potential carry-over effects of idelalisib and to assess the impact of pathway-inhibitor (PI) failure we performed a retrospective EBMT registry-based study. Patients with CLL who had a history of idelalisib treatment and received a first alloHCT between 2015 and 2017 were eligible. Data on 72 patients (median age 58 years) were analyzed. Forty percent of patients had TP53 CLL and 64% had failed on at least one PI. No primary graft failure occurred. Cumulative incidences of acute GVHD °II-IV and chronic GVHD were 51% and 39%, respectively. Estimates for 2-year overall survival (OS), progression-free survival (PFS), and cumulative incidences of relapse/progression (CIR) and non-relapse mortality NRM were 59%, 44%, 25%, and 31%. In univariate analysis, drug sensitivity was a strong risk factor. For patients who had failed neither PI treatment nor chemoimmunotherapy (CIT) the corresponding 2-year estimates were 73%, 65%, 15%, and 20%, respectively. In conclusion, idelalisib may be considered as an option for bridging therapy prior to alloHCT. Owing to the high risk for acute GVHD intensified clinical monitoring is warranted.
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http://dx.doi.org/10.1038/s41409-020-01069-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589680PMC
March 2021

Successful hematopoietic stem cell transplantation for complete CTLA-4 haploinsufficiency due to a de novo monoallelic 2q33.2-2q33.3 deletion.

Clin Immunol 2020 11 12;220:108589. Epub 2020 Sep 12.

Paediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, ASST- Spedali Civili of Brescia, Brescia, Italy.

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http://dx.doi.org/10.1016/j.clim.2020.108589DOI Listing
November 2020

Chitosan-Hydrogel Polymeric Scaffold Acts as an Independent Primary Inducer of Osteogenic Differentiation in Human Mesenchymal Stromal Cells.

Materials (Basel) 2020 Aug 11;13(16). Epub 2020 Aug 11.

Department of Clinical and Experimental Sciences, Bone Marrow Transplant Unit, ASST Spedali Civili, University of Brescia, 25123 Brescia, Italy.

Regenerative medicine aims to restore damaged tissues and mainly takes advantage of human mesenchymal stromal cells (hMSCs), either alone or combined with three-dimensional scaffolds. The scaffold is generally considered a support, and its contribution to hMSC proliferation and differentiation is unknown or poorly investigated. The aim of this study was to evaluate the capability of an innovative three-dimensional gelatin-chitosan hybrid hydrogel scaffold (HC) to activate the osteogenic differentiation process in hMSCs. We seeded hMSCs from adipose tissue (AT-hMSCs) and bone marrow (BM-hMSCs) in highly performing HC of varying chitosan content in the presence of growing medium (GM) or osteogenic medium (OM) combined with Fetal Bovine Serum (FBS) or human platelet lysate (hPL). We primarily evaluated the viability and the proliferation of AT-hMSCs and BM-hMSCs under different conditions. Then, in order to analyse the activation of osteogenic differentiation, the osteopontin () transcript was absolutely quantified at day 21 by digital PCR. was expressed under all conditions, in both BM-hMSCs and AT-hMSCs. Cells seeded in HC cultured with OM+hPL presented the highest transcript levels, as expected. Interestingly, both BM-hMSCs and AT-hMSCs cultured with GM+FBS expressed . In particular, BM-hMSCs cultured with GM+FBS expressed more than those cultured with GM+hPL and OM+FBS; AT-hMSCs cultured with GM+FBS presented a lower expression of when compared with those cultured with GM+hPL, but no significant difference was detected when compared with AT-hMSCs cultured with OM+FBS. No expression was detected in negative controls. These results show the capability of HC to primarily and independently activate osteogenic differentiation pathways in hMCSs. Therefore, these scaffolds may be considered no more as a simple support, rather than active players in the differentiative and regenerative process.
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http://dx.doi.org/10.3390/ma13163546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475832PMC
August 2020

Multidimensional geriatric assessment for elderly hematological patients (≥60 years) submitted to allogeneic stem cell transplantation. A French-Italian 10-year experience on 228 patients.

Bone Marrow Transplant 2020 12 12;55(12):2224-2233. Epub 2020 May 12.

Unit of Blood Diseases and Stem Cells Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy.

Nowadays, the evaluation of elderly patients' eligibility for allogeneic stem cell transplantation (allo-SCT) is crucial. We evaluated the feasibility and efficacy of a multidimensional geriatric assessment, the Fondazione Italiana Linfomi (FIL) score, on a cohort of 228 patients older than 60 years submitted to allo-SCT in Italy and France from 2008 to 2018. Based on FIL score, available in 215 patients, 125 (58%) patients were classified as "fit" and 90 as "unfit/frail." The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was measured in 222 patients (97%); 71 (32%) patients had HCT-CI 0, 75 (34%) patients scored 1-2, and 76 (34%) ≥3. A total of 121 (53%) patients died after a median follow-up of 36 months. FIL score was found to highly predict survival, due to an excess of NRM in unfit/frail group, and confirmed its independent prognostic role on OS (HR: 0.37; 95% CI: 0.25-0.55; p < 0.0001). On the contrary, the HCI-CI failed in allo-SCT outcome prediction (HR: 1.06; 95% CI: 0.96-1.16; p = 0.27). In summary, a comprehensive geriatric assessment with FIL score seems to add significant prognostic information in elderly patients submitted to allo-SCT. The pretransplant adoption of this easy-to-use tool could help the patients' selection and management.
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http://dx.doi.org/10.1038/s41409-020-0934-1DOI Listing
December 2020

Minimal residual disease monitoring in acute myeloid leukaemia: are we ready to move from bone marrow to peripheral blood?

Br J Haematol 2020 07 19;190(2):135-136. Epub 2020 Mar 19.

Chair of Hematology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

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http://dx.doi.org/10.1111/bjh.16579DOI Listing
July 2020

: A Candidate Gene for Predisposition to "Blend Pedigrees"? A Case Report from the NEXT-Famly Clinical Trial.

Case Rep Hematol 2020 11;2020:2795656. Epub 2020 Jan 11.

Chair of Hematology, Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili di Brescia, 25123 Brescia, Italy.

Background: The identification of germline mutations in familial leukemia predisposition genes by next generation sequencing is of pivotal importance. Lately, some "blend pedigrees" characterized by both solid and hematologic malignancies have been described. Some genes were recognized as related to this double predisposition, while the involvement of others is still a matter of debate. was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known. . We present our recent experience in the identification of an was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known. was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known. was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known.

Conclusion: This evidence supports the involvement of in the predisposition to both solid and hematologic neoplasia and the importance of the investigation of the noncoding regions of the genes as recently suggested by different expert groups. was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known.
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http://dx.doi.org/10.1155/2020/2795656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057007PMC
January 2020

Exosomes in Chronic Myeloid Leukemia: Are We Reading a New Reliable Message?

Acta Haematol 2020 9;143(5):509-510. Epub 2020 Jan 9.

Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, Spedali Civili of Brescia, University of Brescia, Brescia, Italy.

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http://dx.doi.org/10.1159/000505088DOI Listing
October 2020

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP.

Blood Adv 2019 12;3(24):4280-4290

Università Federico II, Naples, Italy.

Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months, ≤0.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 >10% at 3 and 6 months, >1% at 12 months, and >0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR.
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http://dx.doi.org/10.1182/bloodadvances.2019000865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929396PMC
December 2019

Feasibility of tumor‑derived exosome enrichment in the onco‑hematology leukemic model of chronic myeloid leukemia.

Int J Mol Med 2019 Dec 14;44(6):2133-2144. Epub 2019 Oct 14.

Chair of Hematology, Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, Italy.

Due to the discovery of their role in intra‑cellular communications, exosomes, which carry information specific to the cell of origin, have garnered considerable attention in cancer research. Moreover, there is evidence to suggest the possibility of isolating different exosome sub‑populations based on target antigens at the cell surface. Philadelphia chromosome‑positive (Ph+) chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the breakpoint cluster region‑proto‑oncogene 1 tyrosine‑protein kinase (BCR‑ABL1) fusion‑gene, derived from the t (9;22) translocation. Tyrosine kinase inhibitors (TKIs) target BCR‑ABL1 protein and induce major or deep molecular responses in the majority of patients. Despite the fact that several studies have demonstrated the persistence of leukemic cells in the bone marrow niche, even following treatment, TKIs prolong patient survival time and facilitate treatment‑free remission. These characteristics render CML a plausible model for investigating the feasibility of tumor‑derived exosome fraction enrichment. In the present study, patients in the chronic phase (CP) of CML were treated with TKIs, and the quantification of the BCR‑ABL1 exosomal transcript was performed using digital PCR (dPCR). The possibility of tumor‑derived exosomes enrichment was confirmed, and for the first time, to the best of our knowledge, the detection of the BCR‑ABL1 transcript highlighted the presence of active leukemic cells in patients with CP‑CML. According to these findings, tumor‑derived exosomes may be considered a novel tool for the identification of active leukemic cells, and for the assessment of innovative monitoring focused on the biological functions of exosomes in CML.
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http://dx.doi.org/10.3892/ijmm.2019.4372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844640PMC
December 2019

CMV Management with Specific Immunoglobulins: A Multicentric Retrospective Analysis on 92 Allotransplanted Patients.

Mediterr J Hematol Infect Dis 2019 1;11(1):e2019048. Epub 2019 Sep 1.

IRCCS San Raffaele Scientific Institute, Milano, Italy, Hematology and Bone Marrow Transplantation Unit.

CMV represents one of the most severe life-threatening complications of allogeneic stem cell transplantation (allo-SCT). Pre-emptive treatment is highly effective, but toxicity and repetitive reactivation of CMV represent a significant challenge in the clinical practice. The use of anti-CMV specific immunoglobulins (Megalotect) is controversial. We retrospectively collected data on 92 patients submitted to allo-SCT for hematological malignancies, in whom Megalotect was used either for prophylaxis (n=14) or with pre-emptive therapy, together with an anti-CMV specific drug (n=78). All the patients were considered at high-risk, due to the presence of at least one risk factor for CMV reactivation. The treatment was well tolerated, with no reported infusion reactions, nor other adverse events, none of the 14 cases treated with Megalotect as prophylaxis developed CMV reactivation. 51/78 (65%) patients who received Megalotect during pre-emptive treatment achieved complete clearance of CMV viremia, and 14/51 patients (29%) developed a breakthrough CMV infection. 7/78 patients (9%) developed CMV disease. The projected 1-year OS, 1-year TRM, and 1-year RR is 74%, 15%, and 19%, respectively. No differences were observed in terms of OS, TRM, and RR by comparing patients who achieved a complete response after treatment versus those who did not. These retrospective data suggest that Megalotect is safe and well-tolerated. When used as prophylaxis, no CMV reactivation was recorded. Further prospective trials are warranted to identify the best set of patients who can benefit from Megalotect alone or in addition to anti-CMV specific drugs.
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http://dx.doi.org/10.4084/MJHID.2019.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736170PMC
September 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

Invasive pulmonary aspergillosis in acute leukemia: a still frequent condition with a negative impact on the overall treatment outcome.

Leuk Lymphoma 2019 12 23;60(12):3044-3050. Epub 2019 May 23.

Hematology, ASST-Spedali Civili, Brescia, Italy.

We evaluated the impact of invasive pulmonary aspergillosis (IPA) on epidemiology and outcome in acute leukemia (AL), analyzing all acute myeloid (AML) and acute lymphoblastic leukemia (ALL) consecutively admitted to our Institution during a 5-year period of observation. Only AML patients received anti-mold prophylaxis. Among 175 AL patients (136 AML/39 ALL), possible and proven/probable IPA were diagnosed in 28 (16%). Frequency of IPA was similar in AML (16.2%) and in ALL (15.4%). Two-year overall survival (OS) was significantly affected by IPA (no IPA: 69.8% vs IPA: 31.7%  = .002). OS was similar in patients with proven/probable (28.2%) and possible IPA (36.4%) ( = .003 and .065, respectively). When censoring patients at transplant, IPA still affected 2-year survival (49.6% vs 79.2%,  = .02), but only proven/probable IPA was associated with lower survival (34.7%,  = .0003). IPA negatively impacts on long-term survival of leukemia patients; antifungal prophylaxis should be adopted also during induction in ALL and in AML beyond induction therapy.
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http://dx.doi.org/10.1080/10428194.2019.1613535DOI Listing
December 2019

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation.

Cancer Med 2019 05 4;8(5):2041-2055. Epub 2019 Apr 4.

Unit of Blood Diseases and Stem Cell Transplantation, DPT of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy.

Treatment-free remission (TFR) by tyrosine kinase inhibitors (TKI) discontinuation in patients with deep molecular response (DMR) is a paramount goal in the current chronic myeloid leukemia (CML) therapeutic strategy. The best DMR level by real-time quantitative PCR (RT-qPCR) for TKI discontinuation is still a matter of debate. To compare the accuracy of digital PCR (dPCR) and RT-qPCR for BCR-ABL1 transcript levels detection, 142 CML patients were monitored for a median time of 24 months. Digital PCR detected BCR-ABL1 transcripts in the RT-qPCR undetectable cases. The dPCR analysis of the samples, grouped by the MR classes, revealed a significant difference between MR and MR (P = 0.0104) or MR (P = 0.0032). The clinical and hematological characteristics of the patients grouped according to DMR classes (MR vs MR ) were superimposable. Conversely, patients with dPCR values <0.468 BCR-ABL1 copies/µL (as we previously described) showed a longer DMR duration (P = 0.0220) and mainly belonged to MR (P = 0.0442) classes compared to patients with higher dPCR values. Among the 142 patients, 111 (78%) discontinued the TKI treatment; among the 111 patients, 24 (22%) lost the MR or MR . RT-qPCR was not able to discriminate patients with higher risk of MR loss after discontinuation (P = 0.8100). On the contrary, according to dPCR, 12/25 (48%) patients with BCR-ABL1 values ≥0.468 and 12/86 (14%) patients with BCR-ABL1 values <0.468 lost DMR in this cohort, respectively (P = 0.0003). Treatment-free remission of patients who discontinued TKI with a dPCR <0.468 was significantly higher compared to patients with dPCR ≥ 0.468 (TFR at 2 years 83% vs 52% P = 0.0017, respectively). In conclusion, dPCR resulted in an improved recognition of stable DMR and of candidates to TKI discontinuation.
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http://dx.doi.org/10.1002/cam4.2087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536984PMC
May 2019

Zebrafish disease models in hematology: Highlights on biological and translational impact.

Biochim Biophys Acta Mol Basis Dis 2019 03 26;1865(3):620-633. Epub 2018 Dec 26.

Unit of Blood Disease and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, ASST-Spedali Civili di Brescia, Italy. Electronic address:

Zebrafish (Danio rerio) has proven to be a versatile and reliable in vivo experimental model to study human hematopoiesis and hematological malignancies. As vertebrates, zebrafish has significant anatomical and biological similarities to humans, including the hematopoietic system. The powerful genome editing and genome-wide forward genetic screening tools have generated models that recapitulate human malignant hematopoietic pathologies in zebrafish and unravel cellular mechanisms involved in these diseases. Moreover, the use of zebrafish models in large-scale chemical screens has allowed the identification of new molecular targets and the design of alternative therapies. In this review we summarize the recent achievements in hematological research that highlight the power of the zebrafish model for discovery of new therapeutic molecules. We believe that the model is ready to give an immediate translational impact into the clinic.
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http://dx.doi.org/10.1016/j.bbadis.2018.12.015DOI Listing
March 2019
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