Publications by authors named "Massimo Bernardi"

82 Publications

A narrative review of consolidation strategies for young and fit patients with newly-diagnosed primary central nervous system lymphoma.

Expert Rev Hematol 2022 Jan 12:1-11. Epub 2022 Jan 12.

Lymphoma Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.

Introduction: The modern treatment of patients with primary central nervous system lymphoma (PCNSL) consists of two phases: induction, currently represented by a high-dose-methotrexate-based polychemotherapy, and consolidation. The optimal consolidation therapy has not been defined yet, but several strategies, such as whole-brain radiotherapy (WBRT), high-dose chemotherapy supported by autologous stem cell transplantation (HDC/ASCT) or nonmyeloablative chemotherapy, have been addressed in important randomized trials.

Areas Covered: This review provides an overview of the current role of consolidation strategies in young and fit patients with newly diagnosed PCNSL. Publications in English language, peer-reviewed, from high-quality international journals, edited from 2003 to 2021 were identified on PubMed.

Expert Opinion: Consolidation treatment significantly improved outcomes of PCNSL. Radiotherapy had represented for years the only choice in the consolidation therapy, but large randomized trials have demonstrated that HDC/ASCT is equally effective and associated with lower neurotoxicity risk in patients younger than 65-70 years. Encouraging results have been obtained using reduced-dose WBRT, while a recent randomized trial failed to demonstrate that consolidation with nonmyeloablative chemotherapy is more effective than HDC/ASCT in PCNSL patients. A personalized consolidation treatment, driven also by a response prediction model based on radiological and molecular details, may improve the management of PCNSL patients.
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http://dx.doi.org/10.1080/17474086.2022.2018297DOI Listing
January 2022

Treosulfan-Based Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation: Long-Term Results From a Phase 2 Clinical Trial.

Front Oncol 2021 10;11:731478. Epub 2021 Sep 10.

Haematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Introduction: Reducing toxicities while preserving efficacy in allogeneic stem cell transplant (allo-HCT) remains a particularly challenging problem. Different strategies to enhance the antitumor activity without increasing early and late adverse toxicities of the conditioning regimens have been investigated.

Methods: The aim of "AlloTreo" prospective phase 2 clinical trial was to evaluate the efficacy and safety of a conditioning regimen based on Treosulfan (42 g/m) and fludarabine (https://clinicaltrials.gov/ct2/show/NCT00598624). We enrolled 108 patients with hematological diseases who received a first allo-HCT between June 2005 and January 2011, inside the frame of this trial at our center. Median age at allo-HCT was 49 (21-69) years. Disease Risk Index was low in 14 (13%) patients, intermediate in 73 (67.7%), high in 17 (15.7%), and very high in 4 (3.7%). Donors were human leukocyte antigen (HLA)-matched related in 50 cases, 10/10-matched unrelated in 36, and 9/10-mismatched unrelated in 22. Graft--host disease (GvHD) prophylaxis consisted of cyclosporine-A and methotrexate. Anti-T-lymphocyte globulin (ATLG) was administered in patients receiving unrelated allo-HCT. Stem cell source was mainly peripheral blood stem cells (95%).

Results: Conditioning regimen was well tolerated. Full donor chimerism was documented for most patients (88%) at day +30. At 12 years, overall survival (OS) was 41.7% (32.2%-50.9%), progression-free survival (PFS) was 31.7% (23%-40.7%), GvHD-free/relapse-free survival was 20.9% (13.7%-29.1%), cumulative incidence (CI) of relapse was 44.5% (34.9%-53.6%), and transplant-related mortality (TRM) was 22.5% (15.1%-30.9%). CI of acute GvHD grades II-IV was 27.8% (19.7%-36.5%) at 100 days; 12-year CI of chronic GvHD was 40.7% (31.3%-49.9%). Relevant long-term adverse effects were 10 secondary malignancy, 3 fatal cardiovascular events, and 1 late-onset transplant-associated thrombotic microangiopathy. Ten successful pregnancies were reported after allo-HCT. In multivariate analysis, older age (≥60 years) at transplant [hazard ratio (HR), 2.157; p = 0.004] and a high/very high disease risk index (HR, 1.913; p = 0.026) were significantly associated with a lower OS.

Conclusions: Overall, our data confirmed the myeloablative potential and safe toxicity profile of full dose Treo (42 g/m) especially for the younger population.
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http://dx.doi.org/10.3389/fonc.2021.731478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461186PMC
September 2021

Long-term quality of life of patients with acute promyelocytic leukemia treated with arsenic trioxide vs chemotherapy.

Blood Adv 2021 11;5(21):4370-4379

Data Center and Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), Rome, Italy.

The main objective of this study was to compare the long-term health-related quality of life of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) vs ATRA plus standard chemotherapy. Patients previously enrolled in the randomized controlled trial APL0406 were considered eligible for this follow-up study. The following patient-reported outcome measures were used: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 (EORTC QLQ-C30), the EORTC Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20), and the Short Form Health Survey 36 (SF-36). The prevalence of late comorbidities and health problems was also assessed. The clinical significance of differences was evaluated based on predefined thresholds. A total of 161 of 232 potentially eligible patients were analyzed, of whom 83 were treated with ATRA-ATO and 78 were treated with ATRA chemotherapy. The median time since diagnosis of the study sample was 8 years. The 2 largest clinically meaningful differences in the EORTC QLQ-C30 were observed for role functioning (Δ = 8.4; 95% confidence interval [CI], 0.5 to 16.3) and dyspnea (Δ = -8.5; 95% CI, -16.4 to -0.7), favoring patients treated with ATRA-ATO. With regard to the SF-36 results, a clinically relevant better physical component score (Δ = 4.6; 95% CI, 1.3 to 7.8) was observed in patients treated with ATRA-ATO, but this was not the case for the mental component score. The 2 groups showed similar profiles in the scores of the EORTC QLQ-CIPN20 scales and in the prevalence of late comorbidities. Overall, our findings suggest that the greater and more sustained antileukemic efficacy of ATRA-ATO is also associated with better long-term patient-reported outcomes than ATRA chemotherapy. This study was registered at www.clinicaltrials.gov as #NCT03096496.
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http://dx.doi.org/10.1182/bloodadvances.2021004649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579253PMC
November 2021

Human T cells engineered with a leukemia lipid-specific TCR enables donor-unrestricted recognition of CD1c-expressing leukemia.

Nat Commun 2021 08 11;12(1):4844. Epub 2021 Aug 11.

Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy.

Acute leukemia relapsing after chemotherapy plus allogeneic hematopoietic stem cell transplantation can be treated with donor-derived T cells, but this is hampered by the need for donor/recipient MHC-matching and often results in graft-versus-host disease, prompting the search for new donor-unrestricted strategies targeting malignant cells. Leukemia blasts express CD1c antigen-presenting molecules, which are identical in all individuals and expressed only by mature leukocytes, and are recognized by T cell clones specific for the CD1c-restricted leukemia-associated methyl-lysophosphatidic acid (mLPA) lipid antigen. Here, we show that human T cells engineered to express an mLPA-specific TCR, target diverse CD1c-expressing leukemia blasts in vitro and significantly delay the progression of three models of leukemia xenograft in NSG mice, an effect that is boosted by mLPA-cellular immunization. These results highlight a strategy to redirect T cells against leukemia via transfer of a lipid-specific TCR that could be used across MHC barriers with reduced risk of graft-versus-host disease.
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http://dx.doi.org/10.1038/s41467-021-25223-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358059PMC
August 2021

Immune Reconstitution-Based Score for Risk Stratification of Chronic Graft-Versus-Host Disease Patients.

Front Oncol 2021 22;11:705568. Epub 2021 Jul 22.

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

Introduction: Allogeneic stem cell transplantation survivors are at a relevant risk of developing chronic GvHD (cGvHD), which importantly affects quality of life and increases morbidity and mortality. Early identification of patients at risk of cGvHD-related morbidity could represent a relevant tool to tailor preventive strategies. The aim of this study was to evaluate the prognostic power of immune reconstitution (IR) at cGvHD onset through an IR-based score.

Methods: We analyzed data from 411 adult patients consecutively transplanted between January 2011 and December 2016 at our Institution: 151 patients developed cGvHD (median follow-up 4 years). A first set of 111 consecutive patients with cGvHD entered the test cohort while an additional consecutive 40 patients represented the validation cohort. A Cox multivariate model for OS (overall survival) in patients with cGvHD of any severity allowed the identification of six variables independently predicting OS and TRM (transplant-related mortality). A formula for a prognostic risk index using the β coefficients derived from the model was designed. Each patient was assigned a score defining three groups of risk (low, intermediate, and high).

Results: Our multivariate model defined the variables independently predicting OS at cGvHD onset: CD4+ >233 cells/mm, NK <115 cells/mm, IgA <0.43g/L, IgM <0.45g/L, Karnofsky PS <80%, platelets <100x10/mm. Low-risk patients were defined as having a score ≤3.09, intermediate-risk patients >3.09 and ≤6.9, and high-risk patients >6.9. By ROC analysis, we identified a cut-off of 6.310 for both TRM and overall mortality.In the training cohort, the 6-year OS and TRM from cGvHD occurrence were 85% (95% CI, 70-92) and 13% (95% CI, 5-25) for low-risk, 64% (95% CI, 44-89) and 30% (95% CI, 15-47) for intermediate-risk, 26% (95% CI, 10-47), and 42% (95% CI, 19-63) for high-risk patients (OS p<0.0001; TRM p = 0.015).The validation cohort confirmed the model with a 6-year OS and TRM of 83% (95% CI, 48-96) and 8% (95% CI, 1-32) for low-risk, 78% (95% CI, 37-94) and 11% (95% CI, 1-41) for intermediate-risk, 37% (95% CI, 17-58), and 63% (95% CI, 36-81) for high-risk patients (OS p = 0.0075; TRM p = 0.0009).

Conclusions: IR score at diagnosis of cGvHD predicts GvHD severity and overall survival. IR score may contribute to the risk stratification of patients. If confirmed in a larger and multicenter-based study, IR score could be adopted to identify patients at high risk and modulate cGvHD treatments accordingly in the context of clinical trial.
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http://dx.doi.org/10.3389/fonc.2021.705568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341942PMC
July 2021

Drug treatment options for acute promyelocytic leukemia.

Expert Opin Pharmacother 2022 Jan 5;23(1):117-127. Epub 2021 Aug 5.

Haematology and BMT Unit IRCCS San Raffaele Scientific Institute via Olgettina 60, Milan.

Introduction: Until the late 1980s, acute promyelocytic leukemia (APL) was the most rapidly fatal leukemia; however, nowadays, it is a curable disease with survival rates exceeding 90-95%. The improvement of APL outcome is mainly due to two agents, which target the typical translocation t(15;17) and its fusion transcript α responsible for initiating and maintaining the disease: all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The story of APL represents a pioneering model for the development of precision medicine and curative chemotherapy-free approaches for acute leukemia.

Area Covered: The authors examine the major advances in the treatment of patients with APL focusing on three different eras: 1) the pre-ATRA era; 2) the ATRA era; 3) the ATO era.

Expert Opinion: The combination of ATRA and ATO is effective and curative for the majority of APL patients. It has been approved for low/intermediate risk cases while an experimental trial with a minimal addition of chemotherapy for high-risk ones is ongoing. Disease relapse is infrequent and can be cured with ATRA-ATO rechallenging, with or without subsequent transplantation depending on the interval between complete remission and relapse. New therapeutic landscapes contemplate the use of an oral chemo-free ATRA-ATO combination, implementing treatment as outpatient care, thus increasing quality of life and decreasing medical costs.
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http://dx.doi.org/10.1080/14656566.2021.1961744DOI Listing
January 2022

2021 BSH guidelines for the management of adult myelodysplastic syndromes: a practical approach to a challenging disease.

Br J Haematol 2021 07 28;194(2):235-237. Epub 2021 Jun 28.

Haematology and BMT Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

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http://dx.doi.org/10.1111/bjh.17640DOI Listing
July 2021

Ruxolitinib for chronic steroid-refractory graft versus host disease: a single center experience.

Leuk Res 2021 10 11;109:106642. Epub 2021 Jun 11.

Haematology and Bone Marrow Transplant Unit, IRCSS San Raffaele Scientific Institute, Italy. Electronic address:

Background: Chronic Graft versus Host Disease (GvHD) is a serious complication of allogeneic hematopoietic stem cell transplant that severely impacts quality of life and long-term survival. About 50-to-60 % of patients treated with steroids require a further line of therapy due to lack of sustained response. Ruxolitinib, a JAK1/2 inhibitor, has recently been approved for the treatment of acute GvHD.

Methods: We aimed to retrospectively evaluate ruxolitinib efficacy and safety in a cohort of patients diagnosed with moderate (25 %) or severe (75 %) steroid-refractory or steroid-dependent chronic GvHD. Response evaluation was performed at three and six months.

Results: Thirty-six patients received ruxolitinib after a median of three previous lines (range, r 1-11) for a median of 8.6 months (r 1-51.6). Cutaneous GvHD was the most frequent presentation. We observed an overall response of 59 % (CR 9%, PR 50 %) at three months and 62 % (CR 15 %, PR 46 %) at six months. Two patients had hematologic disease recurrence and were censored at relapse; no other permanent discontinuation due to adverse events were documented. Cutaneous, oral, genital and ocular GvHD significantly improved after treatment. 2-year overall survival and 2-year transplant related mortality were 74 % and 19 % respectively. Ruxolitinib was associated with a significant reduction of steroid dose.

Conclusion: Ruxolitinib was confirmed to be a safe and effective option as salvage treatment also for advanced stages of chronic GvHD. Longer follow up is needed to evaluate durability of response. Prospective analyses on larger cohorts are ongoing.
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http://dx.doi.org/10.1016/j.leukres.2021.106642DOI Listing
October 2021

Posttransplantation Cyclophosphamide- and Sirolimus-Based Graft-Versus-Host-Disease Prophylaxis in Allogeneic Stem Cell Transplant.

Transplant Cell Ther 2021 09 1;27(9):776.e1-776.e13. Epub 2021 Jun 1.

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

Post-transplantation cyclophosphamide (PTCy) has emerged as a promising graft-versus-host-disease (GVHD) prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) from haploidentical donors and more recently in matched donor transplants. Herein, we describe our real-life experience on 249 adult patients undergoing allogeneic HSCT, from HLA-matched related (MRD), HLA-matched unrelated (MUD), or mismatched related donors (MMRD). Patients received unmanipulated peripheral blood stem cells (PBSCs), using a GVHD prophylaxis with PTCy and sirolimus. Mycophenolate mofetil was added in MUD or MMRD. In the HLA-matched donor group (MRD, n = 48, MUD, n = 50), the cumulative incidence of grades II-IV and III-IV acute GvHD was 23% and 9% at 100 days, respectively. The cumulative incidence of chronic GvHD was 25% at 2 years, severe only for 5% of the patients. The cumulative incidences of relapse and transplant-related mortality (TRM) were 31% and 9% at 2 years, respectively. The 2-year overall survival (OS) was 72% and progression-free survival (PFS) 60%; the composite endpoint of GvHD/relapse-free survival (GRFS) was 52% at 2 years. In the haploidentical donor group (n = 151), we documented a cumulative incidence of grades II-IV and III-IV acute GVHD of 35% and 20% at 100 days, respectively, and a cumulative incidence of chronic GvHD of 39% at 2 years. We observed severe chronic GVHD in 15% of the patients. The cumulative incidence of relapse and TRM was 32% and 25% at 2 years, respectively. The 2-year OS was 48%, whereas PFS was 43%; GRFS was 28% at 2 years. However, more patients in the haploidentical group presented high/very high disease risk index (DRI) and higher HCT-comorbidity index. In patients classified in the low-intermediate DRI, 2-year GRFS was 53% in MRD, 65% in MUD, and 46% in haploidentical HSCT (P = .33). Sirolimus-PTCy platform deserves further investigation as an alternative to calcineurin-inhibitor-based GVHD prophylaxis for all donor sources. In patients presenting a low-intermediate DRI, this strategy translates in relevant survival independently from the transplant source.
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http://dx.doi.org/10.1016/j.jtct.2021.05.023DOI Listing
September 2021

The place of ceftazidime/avibactam and ceftolozane/tazobactam for therapy of haematological patients with febrile neutropenia.

Int J Antimicrob Agents 2021 Jun 7;57(6):106335. Epub 2021 Apr 7.

Clinic of Infectious Diseases, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; University Vita-Salute San Raffaele, Milan, Italy.

Objectives: To evaluate ceftazidime/avibactam (C/A) and ceftolozane/tazobactam (C/T) use in haematological patients with febrile neutropenia receiving high-dose chemotherapy and haematopoietic stem cell transplantation (HSCT).

Methods: A retrospective study was conducted to assess C/A and C/T efficacy through infection-related mortality (IRM) and bacteraemia clearance for carbapenem-resistant Gram-negative bacteria (CR-GNB) pre-engraftment blood-stream infections (PE-BSIs) between January-December 2018.

Results: Seventy patients underwent allogeneic HSCT: C/A and C/T were dispensed in 13% and 3%, respectively. C/A was administered as definite therapy for carbapenem-resistant Klebsiella pneumoniae (CR-Kp) PE-BSI in four carriers (bacteraemia clearance in 5 days), empirical therapy for a clinically documented infection in two patients (one carrier with pneumonia and one non-carrier with shock) and empirical therapy for fever of unknown origin in three CR-Kp carriers. C/T was administered as definite therapy for carbapenem-resistant Pseudomonas aeruginosa (CR-Pa) intra-abdominal infection in one carrier and empirical therapy for a clinically documented infection (pneumonia) in one non-carrier. Among patients without PE-BSIs and with Gram-positive bacteria PE-BSIs, IRM was 0% at +30 days; conversely, it was 30% in GNB PE-BSIs (two CR-Kp and one CR-Pa C/T-resistant). Thirty-nine patients underwent autologous HSCT: C/A and C/T were administered, respectively, as definite therapy for CR-Kp PE-BSI in one carrier (bacteraemia clearance in 3 days) and for Pa PE-BSI (three strains, one CR-Pa) in one non-carrier (bacteraemia clearance in 2 days). Overall, IRM at +30 days was 0%.

Conclusions: Monitoring multidrug-resistant GNB colonisation enabled selection of carriers who benefit from prompt administration of new antibiotics, improving HSCT outcomes in a high-risk population. C/A and C/T were effective in bacteraemia clearance; unfortunately, multidrug-resistant GNB PE-BSIs were still a burden to IRM.
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http://dx.doi.org/10.1016/j.ijantimicag.2021.106335DOI Listing
June 2021

Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes.

J Clin Oncol 2021 04 4;39(11):1223-1233. Epub 2021 Feb 4.

Department of Physics and Astronomy, University of Bologna, Bologna, Italy.

Purpose: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication.

Methods: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed.

Results: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (, , and ) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within - and -related MDS. MDS with complex karyotype and/or gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features.

Conclusion: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.
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http://dx.doi.org/10.1200/JCO.20.01659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078359PMC
April 2021

MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial.

Lancet Haematol 2021 Feb;8(2):e110-e121

Università Degli Studi di Perugia-AO Santa Maria, Terni, Italy.

Background: Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma.

Methods: This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m, intravenous infusion, day 0; methotrexate 3·5 g/m, the first 0·5 g/m in 15 min followed by 3 g/m in a 3 h intravenous infusion, day 1; cytarabine 2 g/m every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m, day 1; etoposide 100 mg/m per day in 500-1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine-thiotepa and autologous HSCT (carmustine 400 mg/m in 500 mL glucose 5% solution in a 1-2 h infusion, day -6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days -5 and -4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019.

Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55-61). 49 patients (65%; 95% CI 54-76) had an objective response after MATRix-RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51-71) had an objective response, with a median duration of objective response of 26 months (IQR 16-37). At a median follow-up of 29 months (IQR 20-40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39-53). Grade 3-4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07-9·93).

Interpretation: MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile.

Funding: Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.
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http://dx.doi.org/10.1016/S2352-3026(20)30366-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844712PMC
February 2021

Archosauriform footprints in the Lower Triassic of Western Alps and their role in understanding the effects of the Permian-Triassic hyperthermal.

PeerJ 2020 18;8:e10522. Epub 2020 Dec 18.

Dipartimento di Scienze della Terra, dell'Ambiente e della Vita, Università di Genova, Genoa, Italy.

The most accepted killing model for the Permian-Triassic mass extinction (PTME) postulates that massive volcanic eruption (i.e., the Siberian Traps Large Igneous Province) led to geologically rapid global warming, acid rain and ocean anoxia. On land, habitable zones were drastically reduced, due to the combined effects of heating, drought and acid rains. This hyperthermal had severe effects also on the paleobiogeography of several groups of organisms. Among those, the tetrapods, whose geographical distribution across the end-Permian mass extinction (EPME) was the subject of controversy in a number of recent papers. We here describe and interpret a new Early Triassic (?Olenekian) archosauriform track assemblage from the Gardetta Plateau (Briançonnais, Western Alps, Italy) which, at the Permian-Triassic boundary, was placed at about 11° North. The tracks, both arranged in trackways and documented by single, well-preserved imprints, are assigned to ichnosp. nov., and are here interpreted as produced by a non-archosaurian archosauriform (erytrosuchid?) trackmaker. This new discovery provides further evidence for the presence of archosauriformes at low latitudes during the Early Triassic epoch, supporting a model in which the PTME did not completely vacate low-latitude lands from tetrapods that therefore would have been able to cope with the extreme hot temperatures of Pangaea mainland.
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http://dx.doi.org/10.7717/peerj.10522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751423PMC
December 2020

Updated risk-oriented strategy for acute lymphoblastic leukemia in adult patients 18-65 years: NILG ALL 10/07.

Blood Cancer J 2020 11 13;10(11):119. Epub 2020 Nov 13.

U.O.C. Ematologia, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.

An updated strategy combining pediatric-based chemotherapy with risk-oriented allogeneic hematopoietic cell transplantation (HCT) was evaluated in Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) and compared with a published control series. Following induction-consolidation chemotherapy, responsive patients were assigned to receive maintenance chemotherapy or undergo early HCT according to the risk stratification criteria and minimal residual disease (MRD) status. Of the 203 study patients (median age 41 years, range 17-67), 140/161 with Ph- ALL achieved complete remission (86.9%; 91.6% ≤55 years, P = 0.0002), with complete MRD clearing in 68/109; 55 patients were assigned to maintenance chemotherapy, and 85 to HCT due to very high-risk characteristics (hyperleukocytosis, adverse genetics, early/mature T-precursor ALL, and MRD persistence). The 5-year relapse incidence was 36%, and the treatment-related mortality rate was 18%. Median overall and relapse-free survival were 7.4 and 6.2 years, with rates of 54 and 53% at 5 years, respectively, which were significantly better than those obtained with the historical protocol (P = 0.001 and P = 0.005, respectively), without significant differences between maintenance and HCT cohorts. In prognostic analysis, MRD negativity and age ≤55 years were the most favorable independent prognostic factors. A reduction in treatment toxicity and further improvements in the risk definitions and risk-oriented design are the focuses of this ongoing research.
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http://dx.doi.org/10.1038/s41408-020-00383-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666128PMC
November 2020

Validation of the "fitness criteria" for the treatment of older patients with acute myeloid leukemia: A multicenter study on a series of 699 patients by the Network Rete Ematologica Lombarda (REL).

J Geriatr Oncol 2021 05 20;12(4):550-556. Epub 2020 Oct 20.

Department of Hematology, ASST Spedali Civili of Brescia, Brescia, Italy.

Objectives: Treatment of older patients with acute myeloid leukemia (AML) is still controversial. To facilitate treatment decisions, the "fitness criteria" proposed by Ferrara et al. (Leukemia, 2013), including age > 75 years, performance status and comorbidities, were verified retrospectively in 699 patients with AML (419 de-novo, 280 secondary AML), diagnosed at 8 Hematological Centers (REL).

Methods: Patients were categorized in FIT to intensive chemotherapy (i-T) (292, 42.5%), UNFIT to i-T (289, 42.1%), or unfit even to non-intensive therapy (non i-T) (FRAIL) (105, 15.3%). Biological characteristics and treatment actually received by patients [i-T, 274 patients (39.2%); non i-T, 134 (19.2%), best-supportive care (BSC), 291 (41.6%)] were recorded.

Results: "Fitness criteria" were easily applicable in 98.1% of patients. Overall concordance between "fitness criteria" and treatment actually received by patients was high (79.4%), 76% in FIT, 82.7% in UNFIT and 80% in FRAIL patients. Fitness independently predicted survival (median survival: 10.9, 4.2 and 1.8 months in FIT, UNFIT and FRAIL patients, respectively; p = 0.000), as confirmed also by multivariate analysis. In FRAIL patients, survival with any treatment was no better than with BSC, in UNFIT non i-T was as effective as i-T and better than BSC, and in FIT patients i-T was better than non i-T or BSC. In addition, a non-adverse risk AML, an ECOG PS <2, and receiving any treatment other than BSC had a favorable effect on survival (p < 0.001).

Conclusion: These simple "fitness criteria" applied at the time of diagnosis could facilitate, together with AML biologic risk evaluation, the choice of the most appropriate treatment intensity in older AML patients.
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http://dx.doi.org/10.1016/j.jgo.2020.10.004DOI Listing
May 2021

Extinction and dawn of the modern world in the Carnian (Late Triassic).

Sci Adv 2020 Sep 16;6(38). Epub 2020 Sep 16.

School of Earth Sciences, University of Bristol, Bristol BS8 1RJ, UK.

The Carnian Pluvial Episode (Late Triassic) was a time of global environmental changes and possibly substantial coeval volcanism. The extent of the biological turnover in marine and terrestrial ecosystems is not well understood. Here, we present a meta-analysis of fossil data that suggests a substantial reduction in generic and species richness and the disappearance of 33% of marine genera. This crisis triggered major radiations. In the sea, the rise of the first scleractinian reefs and rock-forming calcareous nannofossils points to substantial changes in ocean chemistry. On land, there were major diversifications and originations of conifers, insects, dinosaurs, crocodiles, lizards, turtles, and mammals. Although there is uncertainty on the precise age of some of the recorded biological changes, these observations indicate that the Carnian Pluvial Episode was linked to a major extinction event and might have been the trigger of the spectacular radiation of many key groups that dominate modern ecosystems.
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http://dx.doi.org/10.1126/sciadv.aba0099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494334PMC
September 2020

Clinical significance of chromatin-spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06.

Haematologica 2021 10 1;106(10):2578-2587. Epub 2021 Oct 1.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.

Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P<0.0001; disease free survival, 26% in CS-AML and 22% in sAML vs 54% of de novo AML, P<0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06: ClinicalTrials.gov Identifier: NCT00495287).
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http://dx.doi.org/10.3324/haematol.2020.252825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485674PMC
October 2021

Infections after Allogenic Transplant with Post-Transplant Cyclophosphamide: Impact of Donor HLA Matching.

Biol Blood Marrow Transplant 2020 06 28;26(6):1179-1188. Epub 2020 Jan 28.

Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy; University Vita-Salute San Raffaele, Milan, Italy. Electronic address:

Incidence and outcome of infections after allogeneic hematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis are largely unknown. Study aims were to estimate the incidence of pre-engraftment bloodstream infections (PE-BSIs) and viral infections (VIs; cytomegalovirus [CMV], adenovirus [ADV], human herpes virus 6 [HHV6], and BK-polyomavirus hemorrhagic-cystitis [BKPyV-HC]), their predictive factors, and infection-related mortality (IRM) after HSCT with PT-Cy. We analyzed 235 patients: 62%, 21%, and 17% received haploidentical (haplo), matched-unrelated donor (MUD), and matched-related donor, respectively. Overall, 72 patients had 77 PE-BSI episodes at a median time of 13 days after HSCT: cumulative incidence function (CIF) at 28 days was 32%, without differences among donor types (P = .988). By multivariate analysis, CIF of PE-BSI was higher in patients with severe neutropenia before HSCT (adjusted hazard ratio [AHR] = 2.90) and in multidrug-resistant Gram-negative bacteria rectal carriers (AHR = 2.68). IRM at 30 days was 5%, without differences by donor type (P = .106). Overall, 208 patients experienced ≥1 VIs (first occurrence among CMV, HHV6, ADV, BKPyV-HC) at a median time of 20 days after HSCT: CIF at 90 days was 91%, significantly higher in MUD and haplo (P = .0089). By multivariate analysis, also acute GVHD grade ≥2 (AHR = 1.32) and host/donor CMV-serology mismatch (positive/positive versus negative/negative: AHR = 2.95, positive/negative versus negative/negative: AHR = 2.41, negative/positive versus negative/negative: AHR = 2.35) affected VIs occurrence. IRM at 180 days was 8%, without differences among donor types (P = .106). In conclusion, study results did not show a significant impact of donor type on PE-BSI incidence; conversely, MUD and haploidentical transplants retained a higher occurrence of VIs in the early phase after HSCT.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.013DOI Listing
June 2020

Lung Ultrasound to Evaluate Invasive Fungal Diseases after Allogeneic Hematopoietic Stem Cell Transplantation.

Infect Chemother 2019 Dec;51(4):386-392

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

Invasive fungal diseases (IFDs) are a leading cause of infection-related-mortality after allogeneic hematopoietic stem cell transplantation (HSCT). In this prospective pilot study, we investigated the use of bedside lung ultrasound (US) in IFD management. Ten consecutive hematological patients, who developed pulmonary IFD after HSCT, were included in the study. Standard computed tomography scan and lung US were performed at IFD diagnosis and 10 days after antifungal treatment. The lung US demonstrated a high sensitivity in the detection of lung lesions at IFD diagnosis and in the follow-up examinations. It is of potential clinical relevance for IFD management in hematological patients.
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http://dx.doi.org/10.3947/ic.2019.51.4.386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940370PMC
December 2019

Interleukin-6 as Biomarker for Acute GvHD and Survival After Allogeneic Transplant With Post-transplant Cyclophosphamide.

Front Immunol 2019 1;10:2319. Epub 2019 Oct 1.

Haematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Although the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has dramatically improved in the past decade, it is still compromised by transplant-related mortality (TRM), mainly caused by Graft-vs. -Host Disease (GvHD). We conducted a prospective observational study to ascertain the potential of serum interleukin-6 (IL6) levels, measured before conditioning and 7 days after allo-HSCT, in predicting acute GvHD, TRM and survival after allo-HSCT with Post-Transplant Cyclophosphamide (PT-Cy) based GvHD prophylaxis. Between April 2014 and June 2017, we collected samples from 166 consecutive allo-HSCT patients. By ROC analysis, we identified a threshold of 2.5 pg/ml for pre-transplant IL6 and 16.5 pg/ml for post-transplant IL6. Both univariate and multivariate analyses confirmed the ability of high baseline IL6 levels to predict worse OS (HR 4.3; < 0.01) and grade II-IV acute GvHD (HR 1.8; = 0.04), and of high post-transplant IL6 to identify patients with worse OS (HR 3.3; < 0.01) and higher risk of grade II-IV (HR 5; < 0.01) and grade III-IV acute GvHD (HR 10.2; < 0.01). In multivariate analysis, both baseline (HR 6.7; < 0.01) and post-transplant high IL6 levels (HR 3.5; = 0.02) predicted higher TRM. IL6 may contribute to the risk stratification of patients at major risk for aGvHD and TRM, potentially providing a window for additional prophylactic or preemptive strategies to improve the quality of life in the early post-transplant phase and the outcome of allo-HSCT.
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http://dx.doi.org/10.3389/fimmu.2019.02319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779849PMC
October 2020

Real-world experience with decitabine as a first-line treatment in 306 elderly acute myeloid leukaemia patients unfit for intensive chemotherapy.

Hematol Oncol 2019 Oct 20;37(4):447-455. Epub 2019 Aug 20.

UO Ematologia e Trapianto Midollo Osseo, IRCCS Istituto Scientifico Universitario San Raffaele, Milan, Italy.

Despite widespread use of decitabine to treat acute myeloid leukaemia (AML), data on its effectiveness and safety in the real-world setting are scanty. Thus, to analyze the performance of decitabine in clinical practice, we pooled together patient-level data of three multicentric observational studies conducted since 2013 throughout Italy, including 306 elderly AML patients (median age 75 years), unfit for intensive chemotherapy, treated with first-line decitabine therapy at the registered schedule of 20 mg/m /iv daily for 5 days every 4 weeks. Overall response rate (ORR), overall survival (OS) curves, and multivariate hazard ratios (HRs) of all-cause mortality were computed. Overall, 1940 cycles of therapy were administered (median, 5 cycles/patient). A total of 148 subjects were responders and, therefore, ORR was 48.4%. Seventy-one patients (23.2%) had complete remission, 32 (10.5%) had partial remission, and 45 (14.7%) had haematologic improvement. Median OS was 11.6 months for patients with favourable-intermediate cytogenetic risk and 7.9 months for those with adverse cytogenetic risk. Median relapse-free survival after CR was 10.9 months (95% confidence interval [CI]: 8.7-16.0). In multivariate analysis, mortality was higher in patients with adverse cytogenetic risk (HR=1.58; 95% CI: 1.13-2.21) and increased continuously with white blood cell (WBC) count (HR=1.12; 95% CI: 1.06-1.18). A total of 183 infectious adverse events occurred in 136 patients mainly (>90%) within the first five cycles of therapy. This pooled analysis of clinical care studies confirmed, outside of clinical trials, the effectiveness of decitabine as first-line therapy for AML in elderly patients unfit for intensive chemotherapy. An adverse cytogenetic profile and a higher WBC count at diagnosis were, in this real life setting, unfavourable predictors of survival.
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http://dx.doi.org/10.1002/hon.2663DOI Listing
October 2019

Nanosphere's Verigene Blood Culture Assay to Detect Multidrug-Resistant Gram-Negative Bacterial Outbreak: A Prospective Study on 79 Hematological Patients in a Country with High Prevalence of Antimicrobial Resistance.

Clin Hematol Int 2019 Jun 11;1(2):120-123. Epub 2019 Jun 11.

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

Infections are a major cause of morbidity and mortality in hematological patients. We prospectively tested a new molecular assay (Verigene) in 79 consecutive hematological patients, with sepsis by gram-negative bacteria. A total of 82 gram-negative microorganisms were isolated by blood cultures, of which 76 cases were mono-microbial. Considering the bacteria detectable by the system, the concordance with standard blood cultures was 100%. Resistance genes were detected in 20 of the isolates and 100% were concordant with the phenotypic antibiotic resistance. Overall, this new assay correctly identified 66/82 of all the gram-negative pathogens, yielding a general sensitivity of 80.5%, and providing information on genetic antibiotic resistance in a few hours. This new molecular assay could ameliorate patient management, resulting in a more rational use of antibiotics.
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http://dx.doi.org/10.2991/chi.d.190321.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432392PMC
June 2019

A comparative study of the mechanical properties of a dinosaur and crocodile fossil teeth.

J Mech Behav Biomed Mater 2019 09 18;97:365-374. Epub 2019 May 18.

Laboratory of Bio-inspired and Graphene Nanomechanics, Department of Civil, Environmental and Mechanical Engineering, University of Trento, 38123, Italy; School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London, E1 4NS, United Kingdom; Ket-Lab, Edoardo Amaldi Foundation, Via del Politecnico snc, 00133, Roma, Italy. Electronic address:

Vertebrate teeth are complex structures adapted in terms of shape and structure to serve a variety of functions like biting and grinding. Thus, examining the morphology, composition and mechanical properties of the teeth can aid in providing insights into the feeding behaviour of extinct species. We here provide the first mechanical characterisation of teeth in a spinosaurid dinosaur, Suchomimus tenerensis, and a pholidosaurid crocodylomorph, Sarcosuchus imperator. Our results show that both species have similar macrostructure of enamel, dental and interfacial layers, and similar composition, the main constituent being fluorapatite. Microindentation tests show that Suchomimus teeth have lower elastic modulus and hardness, as compared to Sarchosuchus. On the contrary, Sarcosuchus teeth have lower toughness. Nanoindentation showed the existence of mechanical gradients from dentin to enamel in Suchomimus and, less prominently, in Sarcosuchus. This was also supported by wear tests showing that in Suchomimus the dentin region is more wear-prone than the enamel region. With still scarce information available on the dietary regimes in extinct species, the analysis of micro and nano-mechanical properties of fossils teeth might be a help in targeting specific biological questions. However, much is still unknown concerning the changes underwent by organic material during diagenesis making at present impossible to definitely conclude if the differences in the mechanical properties of Suchomimus and Sarchosuchus here retrieved imply that the two species adopted different strategies when dealing with food processing or are the result of disparate taphonomic histories.
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http://dx.doi.org/10.1016/j.jmbbm.2019.05.025DOI Listing
September 2019

Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML.

Blood Adv 2019 04;3(7):1103-1117

Azienda Socio-Sanitaria Territoriale (ASST) Ospedale Papa Giovanni XXIII, Bergamo, Italy.

Here we evaluated whether sequential high-dose chemotherapy (sHD) increased the early complete remission (CR) rate in acute myelogenous leukemia (AML) compared with standard-intensity idarubicin-cytarabine-etoposide (ICE) chemotherapy. This study enrolled 574 patients (age, 16-73 years; median, 52 years) who were randomly assigned to ICE (n = 286 evaluable) or sHD (2 weekly 3-day blocks with cytarabine 2 g/m twice a day for 2 days plus idarubicin; n = 286 evaluable). Responsive patients were risk-stratified for a second randomization. Standard-risk patients received autograft or repetitive blood stem cell-supported high-dose courses. High-risk patients (and standard-risk patients not mobilizing stem cells) underwent allotransplantation. CR rates after 2 induction courses were comparable between ICE (80.8%) and sHD (83.6%; 38). sHD yielded a higher single-induction CR rate (69.2% vs 81.5%; 0007) with lower resistance risk ( < .0001), comparable mortality (39), and improved 5-year overall survival (39% vs 49%; 045) and relapse-free survival (36% vs 48%; 028), despite greater hematotoxicity delaying or reducing consolidation blocks. sHD improved the early CR rate in high-risk AML (odds ratio, 0.48; 95% confidence interval [CI], 0.31-0.74; 0008) and in patients aged 60 years and less with de novo AML (odds ratio, 0.46; 95% CI, 0.27-0.78; 003), and also improved overall/relapse-free survival in the latter group (hazard ratio, 0.70; 95% CI, 0.52-0.94; 01), in standard-risk AML, and postallograft (hazard ratio, 0.61; 95% CI, 0.39-0.96; 03). sHD was feasible, effectively achieved rapid CR, and improved outcomes in AML subsets. This study is registered at www.clinicaltrials.gov as #NCT00495287.
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http://dx.doi.org/10.1182/bloodadvances.2018026625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457212PMC
April 2019

Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation.

Nat Med 2019 04 25;25(4):603-611. Epub 2019 Mar 25.

Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.

Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-γ or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.
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http://dx.doi.org/10.1038/s41591-019-0400-zDOI Listing
April 2019

X-ray computed microtomography of Megachirella wachtleri.

Sci Data 2018 11 6;5:180244. Epub 2018 Nov 6.

Department of Anatomy, Arizona College of Osteopathic Medicine, Midwestern University, 19555N. 59th Dr., Glendale, AZ 85383, USA.

Understanding the origin and early evolution of squamates has been a considerable challenge given the extremely scarce fossil record of early squamates and their poor degree of preservation. In order to overcome those limitations, we conducted high-resolution X-ray computed tomography (CT) studies on the fossil reptile Megachirella wachtleri (Middle Triassic, northern Italy), which revealed an important set of features indicating this is the oldest known fossil squamate in the world, predating the previous oldest record by ca. 75 million years. We also compiled a new phylogenetic data set comprising a large sample of diapsid reptiles (including morphological and molecular data) to investigate the phylogenetic relationships of early squamates and other reptile groups along with the divergence time of those lineages. The re-description of Megachirella and a new phylogenetic hypothesis of diapsid relationships are presented in a separate study. Here we present the data descriptors for the tomographic scans of Megachirella, which holds fundamental information to our understanding on the early evolution of one of the largest vertebrate groups on Earth today.
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http://dx.doi.org/10.1038/sdata.2018.244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219415PMC
November 2018

Comparable outcomes of haploidentical, 10/10 and 9/10 unrelated donor transplantation in adverse karyotype AML in first complete remission.

Am J Hematol 2018 10 3;93(10):1236-1244. Epub 2018 Sep 3.

Université Pierre and Marie Curie, Paris, France.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most powerful therapy preventing relapse in patients with adverse cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1). In the absence of a matched related donor, potential alternatives include 10/10, 9/10 HLA-matched unrelated (UD) or haploidentical (Haplo) donors. We analyzed clinical outcomes of patients undergoing T-cell repleted Haplo (n = 74), 10/10 UD (n = 433) and 9/10 UD HSCT (n = 123) from 2007 to 2015, reported to the EBMT Registry. Adverse risk AML was defined according to the 2017 ELN cytogenetic risk classification. The 2-year nonrelapse mortality was 19% for Haplo, 18% for 10/10 UD and 18% for 9/10 UD (P = .9). The relapse incidence was not significantly affected by donor source, with a 2-year incidence of 27% for Haplo HSCT, 39% for 10/10 UD and 37% for 9/10 UD SCT (P = .3). We show comparable probabilities of leukemia-free survival (LFS) and overall survival (OS) at 2 years among Haplo HSCT, 10/10 UD SCT and 9/10 UD SCT (53% and 59%, 43% and 50%, 44% and 50%, respectively, P = .5 for both parameters). The type of donor was not significantly associated with either acute or chronic graft-vs.-host disease incidence. Using multivariable Cox model, Haplo HSCT recipients experienced comparable OS and LFS to 10/10 and 9/10 UD. In the present series of adverse cytogenetics AML patients in CR1, Haplo HSCT recipients had comparable outcomes to those of 10/10 and 9/10 UDs, suggesting that all these types of HSCT may be considered a valid option in this high risk population.
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http://dx.doi.org/10.1002/ajh.25231DOI Listing
October 2018
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