24 results on '"Becilli M"'
Search Results
2. Venetoclax-based therapies in pediatric advanced MDS and relapsed/refractory AML: a multicenter retrospective analysis
- Author
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Masetti, R., Baccelli, F., Leardini, D., Gottardi, F., Vendemini, F., Di Gangi, A., Becilli, M., Lodi, M., Tumino, M., Vinci, L., Erlacher, M., Strahm, B., Niemeyer, C. M., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Masetti, R., Baccelli, F., Leardini, D., Gottardi, F., Vendemini, F., Di Gangi, A., Becilli, M., Lodi, M., Tumino, M., Vinci, L., Erlacher, M., Strahm, B., Niemeyer, C. M., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
No abstract available
- Published
- 2023
3. Achievement of operational tolerance in a pediatric liver transplant recipient following successful hematopoietic stem cell transplantation from a different donor
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Algeri, M., Velardi, E., Spada, M., Galaverna, F., Carta, R., Vinti, L., Palumbo, G., Gaspari, S., Pietrobattista, A., Boccieri, E., Becilli, M., Francalanci, P., Bertaina, V., Merli, P., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Algeri, M., Velardi, E., Spada, M., Galaverna, F., Carta, R., Vinti, L., Palumbo, G., Gaspari, S., Pietrobattista, A., Boccieri, E., Becilli, M., Francalanci, P., Bertaina, V., Merli, P., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Hematopoietic stem cell transplantation (HSCT)–based approaches are increasingly investigated strategies to induce tolerance in recipients of solid allografts. However, in the majority of cases, these approaches rely on the infusion of hematopoietic stem cells recovered from the same solid organ donor. In this report, we describe the case of a boy who received liver transplantation from a deceased donor, who had successfully underwent allogeneic HSCT from an unrelated donor for hepatitis-associated aplastic anemia. In this patient, it was possible to permanently withdraw post-HSCT immune suppression without causing any sign of liver graft dysfunction. To the best of our knowledge, this is the first case of operational tolerance documented in a patient who received combined liver transplantation and HSCT from different donors.
- Published
- 2023
4. Human leukocyte antigen evolutionary divergence influences outcomes of paediatric patients and young adults affected by malignant disorders given allogeneic haematopoietic stem cell transplantation from unrelated donors
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Merli, P., Crivello, P., Strocchio, L., Pinto, R. M., Algeri, M., Del Bufalo, F., Pagliara, D., Becilli, M., Carta, R., Gaspari, S., Galaverna, F., Quagliarella, F., Boz, G., Catanoso, M. L., Boccieri, E., Troiano, M., Fleischhauer, K., Andreani, M., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Merli, P., Crivello, P., Strocchio, L., Pinto, R. M., Algeri, M., Del Bufalo, F., Pagliara, D., Becilli, M., Carta, R., Gaspari, S., Galaverna, F., Quagliarella, F., Boz, G., Catanoso, M. L., Boccieri, E., Troiano, M., Fleischhauer, K., Andreani, M., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
High genetic heterogeneity in the human leukocyte antigen (HLA) increases the likelihood of efficient immune response to pathogens and tumours. As measure of HLA diversity, HLA evolutionary divergence (HED) has been shown to predict the response of tumours to immunotherapy and haematopoietic stem cell transplantation (HSCT) in adults. We retrospectively investigated the association of HED with outcomes of 153 paediatric/young adults patients, treated for malignant disorders with HSCT from 9–10/10 HLA-matched unrelated donors. HED was calculated as pairwise genetic distance between alleles in patient HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1, using the locus median to stratify patients with ‘high’ or ‘low’ HED. Patients with high HED-B and -DRB1 showed significantly improved disease-free survival (DFS), especially when combined (70.8% vs 53.7% p = 0.008). High HED-B + -DRB1 was also associated with improved overall survival (OS) (82.1 vs 66.4% p = 0.014), and concomitant reduction of non-relapse-mortality (5.1% vs 21.1% p = 0.006). The impact on OS and DFS of combined HED-B + -DRB1 was confirmed in multivariate analysis [hazard ratio (HR) 0.39, p = 0.009; and HR 0.45, p = 0.007 respectively]. Only high HED scores for HLA-DPB1 were associated, in univariate analysis, with reduced incidence of relapse (15.9% vs 31.1%, p = 0.03). These results support HED as prognostic marker in allogeneic HSCT and, if confirmed in larger cohorts, would allow its use to inform clinical risk and potentially influence clinical practice.
- Published
- 2023
5. Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed/refractory BCP-ALL
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del Bufalo, F., Becilli, M., Rosignoli, C., De Angelis, B., Algeri, M., Hanssens, L., Gunetti, M., Iacovelli, S., Li Pira, G., Girolami, E., Leone, G., Lazzaro, S., Bertaina, V., Sinibaldi, M., Di Cecca, S., Iaffaldano, L., Kunkele, A., Boccieri, E., Del Baldo, G., Pagliara, D., Merli, P., Carta, R., Quintarelli, C., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), del Bufalo, F., Becilli, M., Rosignoli, C., De Angelis, B., Algeri, M., Hanssens, L., Gunetti, M., Iacovelli, S., Li Pira, G., Girolami, E., Leone, G., Lazzaro, S., Bertaina, V., Sinibaldi, M., Di Cecca, S., Iaffaldano, L., Kunkele, A., Boccieri, E., Del Baldo, G., Pagliara, D., Merli, P., Carta, R., Quintarelli, C., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Autologous CD19-directed chimeric antigen receptor (CAR)-T cells have shown unprecedented efficacy in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, patients either relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or displaying profound lymphopenia and/or rapidly progressing disease often cannot access autologous products. These hurdles may be overcome by allogeneic, donor-derived CAR-T cells. We tested donor-derived T cells transduced with a second-generation (4.1BB) CD19-directed CAR for treatment of patients with BCP-ALL in a hospital-exemption setting. Two constructs were tested: a retroviral construct incorporating the suicide gene inducible caspase-9 (CD19-CAR–Retro_ALLO) first and then a lentiviral construct and an automated, Prodigy-based manufacturing process (CD19-CAR–Lenti_ALLO). Thirteen children/young adults received ALLO–CAR-T cells between March 2021 and October 2022. Doses ranged between 1.0 × 106 and 3.0 × 106 CAR-T cells per kg. The toxicity profile was comparable with that of autologous CAR-T cells, characterized mainly by cytopenia, cytokine release syndrome (maximum grade 1), and grade 2 immune-effector cell–associated neurotoxicity syndrome. One case of acute graft-versus-host disease (GVHD) occurred and was rapidly controlled with steroids and ruxolitinib. None of the other patients, including 3 given ALLO–CAR-T cells from an HLA-haploidentical donor, experienced GVHD. Two patients received ALLO–CAR-T cells before HSCT and showed a significant expansion of CAR-T cells without any sign of GVHD. All patients obtained complete remission (CR) with absence of minimal residual disease in the bone marrow. With a median follow-up of 12 months (range, 5-21), 8 of 13 patients maintained CR. Allogeneic anti-CD19 CAR-T cells can effectively treat highly refractory BCP-ALL relapsing after allo-HSCT without showing increased toxicity as compared with autologous CAR-T cells.
- Published
- 2023
6. Cow's milk allergy non-responsive to amino acid-based formula? A successful transplanted patient with immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome
- Author
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Veramendi-Espinoza, L., Renteria-Valdiviezo, C. A., Diaz-Subauste, R., Aldave-Becerra, J. C., Alva-Lozada, G., Becilli, M., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Veramendi-Espinoza, L., Renteria-Valdiviezo, C. A., Diaz-Subauste, R., Aldave-Becerra, J. C., Alva-Lozada, G., Becilli, M., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
The wide variety of IPEX symptoms leads to diagnosis and treatment delay with fatal outcomes if left untreated before two first years of life. Cow's milk allergy non-responsive to amino acid-based formula must raise suspicion of this syndrome.
- Published
- 2021
7. Wernicke’s Encephalopathy in A Young Adult Affected by T Cell Acute Lymphoblastic Leukemia and Ileotiphlytis with Review of the Literature
- Author
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A. Scardocci, Giuseppe Avvisati, D. Armiento, Becilli M, Ombretta Annibali, Mallio Ca, Anastasia Pagano, and Sala Swd
- Subjects
Pediatrics ,medicine.medical_specialty ,Weakness ,business.industry ,Encephalopathy ,Nystagmus ,medicine.disease ,Wernicke's encephalopathy ,Leukemia ,Parenteral nutrition ,medicine ,Thiamine ,medicine.symptom ,Young adult ,business - Abstract
Wernicke-Korsackoff Syndrome is a potentially fatal neurological complication caused by a deficiency of thiamine. The clinical diagnosis is a challenge and the syndrome is frequently misdiagnosed. In this paper we describe the case of a young man affected by T-ALL and ileotyphlitis who developed Wernicke’s Encephalopathy after a month of total parenteral nutrition. Neurological symptomatology, consisting of confusion, nystagmus on lateral gaze, impairment of consciousness state, prosopagnosia and weakness in the four limbs, appeared progressively. An MRI of brain permitted to confirm the diagnosis and high-dose thiamine reintegrating therapy was started obtaining complete resolution of the syndrome.
- Published
- 2017
8. 15 - Hematopoietic Stem/Progenitor Cells and Engineering: LONG-TERM DATA ON IMMUNE MONITORING OF CHILDREN GIVEN TCRαβ/CD19 CELL DEPLETED HLA-HAPLOIDENTICAL STEM TRANSPLANTATION (HAPLO-HSCT).
- Author
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Bertaina, V., Sborgia, R., Marini, O., De Luca, C., Carta, R., Becilli, M., Pagliara, D., Quagliarella, F., Lucarelli, B., Boccieri, E., Velardi, E., Algeri, M., Merli, P., Galaverna, F., and Locatelli, F.
- Subjects
- *
HEMATOPOIETIC stem cell transplantation , *PROGENITOR cells , *ENGINEERING , *TISSUE engineering - Published
- 2023
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9. Autologous CD19-Targeting CAR T Cells in a Patient With Refractory Juvenile Dermatomyositis.
- Author
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Nicolai R, Merli P, Moran Alvarez P, Bracaglia C, Del Bufalo F, Marasco E, Caiello I, Prencipe G, Algeri M, Cefalo MG, Becilli M, Quintarelli C, Sinibaldi M, Hanssens L, De Benedetti F, and Locatelli F
- Subjects
- Humans, Male, Child, Receptors, Chimeric Antigen therapeutic use, Receptors, Chimeric Antigen immunology, T-Lymphocytes immunology, Treatment Outcome, Dermatomyositis immunology, Dermatomyositis therapy, Antigens, CD19 immunology, Immunotherapy, Adoptive methods
- Abstract
Objective: The aim of this study is to report the safety and efficacy of CD19-targeting chimeric antigen receptor (CAR) T cells in a child with refractory juvenile dermatomyositis (JDM)., Methods: We describe a 12-year-old White male with severe, chronically active JDM refractory to multiple immunosuppressive treatment lines, including B cell depletion with rituximab. The patient received a single infusion of fresh, autologous, second-generation anti-CD19 CAR T cell product (lentiviral vector) manufactured on the Prodigy device (1 × 10
6 CAR T cells/kg), after lymphodepletion with cyclophosphamide (1,000 mg/m2 over two days) and fludarabine (90 mg/m2 over three days). Immunosuppressive and glucocorticoid treatment were withdrawn before leukapheresis and CAR T cell infusion., Results: Before anti-CD19 CAR T cell therapy, the patient had persistent severe skin and muscular disease activity. CAR T cells expanded significantly (peak at day 7, 32.69 cells/μL). Complete B cell depletion was documented on day 5 in the blood and at week 2 in the bone marrow. The patient presented with fever as part of mild cytokine release syndrome (grade 1), transient anemia (grade 2), and neutropenia (grade 4). Neither infection nor neurotoxicity were observed. Laboratory tests, magnetic resonance imaging, Physician Global Assessment of disease activity, Childhood Myositis Assessment Scale, and Cutaneous Assessment Tool for myositis were performed at baseline and follow-up to assess treatment response, showing remarkable progressive improvement that persists over time, even after B cell recovery., Conclusion: This patient with JDM with severe chronic disease, refractory to multiple treatments, achieved sustained B cell depletion and ongoing immunosuppressive drug-free clinical and radiologic improvement eight months after a single infusion of anti-CD19 CAR T cells., (© 2024 American College of Rheumatology.)- Published
- 2024
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10. Mucosal-associated invariant T cells are functionally impaired in pediatric and young adult patients following allogeneic hematopoietic stem cell transplantation and their recovery correlates with clinical outcomes.
- Author
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Galaverna F, Flamini S, De Luca CD, Pili I, Boccieri E, Benini F, Quagliarella F, Rosignoli C, Rosichini M, Genah S, Catanoso M, Cardinale A, Volpe G, Coccetti M, Pitisci A, Li Pira G, Carta R, Lucarelli B, Del Bufalo F, Bertaina V, Becilli M, Pagliara D, Algeri M, Merli P, Locatelli F, and Velardi E
- Subjects
- Humans, Child, Adolescent, Male, Female, Young Adult, Child, Preschool, Adult, Retrospective Studies, Hematologic Neoplasms therapy, Hematologic Neoplasms immunology, Hematologic Neoplasms mortality, Infant, Treatment Outcome, Transplantation Conditioning, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Mucosal-Associated Invariant T Cells immunology, Graft vs Host Disease etiology, Graft vs Host Disease immunology, Transplantation, Homologous
- Abstract
Mucosal-associated invariant T (MAIT) cells are innate-like T cells implicated in the response to fungal and bacterial infections. Their contribution to restoring T-cell immunity and influencing hematopoietic stem cell transplant (HSCT) outcomes remains poorly understood. We retrospectively studied MAIT-cell recovery in 145 consecutive children and young adults with hematologic malignancies undergoing allogeneic (allo)-HSCT between April 2019 and May 2022, from unrelated matched donor (MUD, N=52), with standard graft-versus-host-disease (GvHD) prophylaxis, or HLA-haploidentical (Haplo, N=93) donor after in vitro αβT/CD19-cell depletion, without post-HSCT pharmacological prophylaxis. With a median follow-up of 33 months (range, 12-49 months), overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) were 79.5%, 72%, and 7%, respectively; GvHD-free relapse-free survival (GRFS) was 63%, while cumulative incidence of relapse was 23%. While αβT cells were reconstituted 1-2 years post HSCT, MAIT cells showed delayed recovery and prolonged functional impairment, characterized by expression of activation (CD25, CD38), exhaustion (PD1, TIM3) and senescence (CD57) markers, and suboptimal ex vivo response. OS, DFS, and NRM were not affected by MAIT cells. Interestingly, higher MAIT cells at day +30 correlated with higher incidence of grade II-IV acute GvHD (19% vs. 7%, P=0.06). Furthermore, a greater MAIT-cell count tended to be associated with a higher incidence of chronic GvHD (cGvHD) (17% vs. 6%, P=0.07) resulting in lower GRFS (55% vs. 73%, P=0.05). Higher MAIT cells also correlated with greater cytomegalovirus (CMV) reactivation and lower late blood stream infections (BSI) (44% vs. 24%, P=0.02 and 9% vs. 18%, P=0.08, respectively). Future studies are needed to confirm the impact of early MAIT-cell recovery on cGvHD, CMV reactivation, and late BSI.
- Published
- 2024
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11. Fratricide-resistant CD7-CAR T cells in T-ALL.
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Oh BLZ, Shimasaki N, Coustan-Smith E, Chan E, Poon L, Lee SHR, Yeap F, Tan LK, Chai LYA, Le Bert N, Tan N, Bertoletti A, Chen SP, Del Bufalo F, Becilli M, Locatelli F, Yeoh AEJ, and Campana D
- Abstract
T cell acute lymphoblastic leukemia (T-ALL) is difficult to treat when it relapses after therapy or is chemoresistant; the prognosis of patients with relapsed or refractory T-ALL is generally poor. We report a case series of 17 such patients who received autologous chimeric antigen receptor (CAR) T cells expressing an anti-CD7 CAR and an anti-CD7 protein expression blocker (PEBL), which prevented CAR T cell fratricide. Despite high leukemic burden and low CAR T cell dosing, 16 of the 17 patients attained minimal residual disease-negative complete remission within 1 month. The remaining patient had CD7
- T-ALL cells before infusion, which persisted after infusion. Toxicities were mild: cytokine release syndrome grade 1 in ten patients and grade 2 in three patients; immune effector cell-associated neurotoxicity syndrome grade 1 in two patients. Eleven patients remained relapse-free (median follow-up, 15 months), including all nine patients who received an allotransplant. The first patient is in remission 55 months after infusion without further chemotherapy or transplantation; circulating CAR T cells were detectable for 2 years. T cells regenerating after lymphodepletion lacked CD7 expression, were polyclonal and responded to SARS-CoV-2 vaccination; CD7+ immune cells reemerged concomitantly with CAR T cell disappearance. In conclusion, autologous anti-CD7 PEBL-CAR T cells have powerful antileukemic activity and are potentially an effective option for the treatment of T-ALL., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2024
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12. GD2-Targeting CAR T-cell Therapy for Patients with GD2+ Medulloblastoma.
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Ciccone R, Quintarelli C, Camera A, Pezzella M, Caruso S, Manni S, Ottaviani A, Guercio M, Del Bufalo F, Quadraccia MC, Orlando D, Di Cecca S, Sinibaldi M, Aurigemma M, Iaffaldano L, Sarcinelli A, D'Amore ML, Ceccarelli M, Nazio F, Marabitti V, Giorda E, Pezzullo M, De Stefanis C, Carai A, Rossi S, Alaggio R, Del Baldo G, Becilli M, Mastronuzzi A, De Angelis B, and Locatelli F
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Child, Female, T-Lymphocytes immunology, T-Lymphocytes metabolism, Cerebellar Neoplasms therapy, Cerebellar Neoplasms immunology, Cerebellar Neoplasms pathology, Cerebellar Neoplasms metabolism, Morpholines pharmacology, Male, Child, Preschool, Benzamides, Biphenyl Compounds, Pyridones, Medulloblastoma therapy, Medulloblastoma immunology, Medulloblastoma pathology, Medulloblastoma genetics, Medulloblastoma metabolism, Gangliosides metabolism, Gangliosides immunology, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen metabolism, Immunotherapy, Adoptive methods, Immunotherapy, Adoptive adverse effects, Xenograft Model Antitumor Assays
- Abstract
Purpose: Medulloblastoma (MB), the most common childhood malignant brain tumor, has a poor prognosis in about 30% of patients. The current standard of care, which includes surgery, radiation, and chemotherapy, is often responsible for cognitive, neurologic, and endocrine side effects. We investigated whether chimeric antigen receptor (CAR) T cells directed toward the disialoganglioside GD2 can represent a potentially more effective treatment with reduced long-term side effects., Experimental Design: GD2 expression was evaluated on primary tumor biopsies of MB children by flow cytometry. GD2 expression in MB cells was also evaluated in response to an EZH2 inhibitor (tazemetostat). In in vitro and in vivo models, GD2+ MB cells were targeted by a CAR-GD2.CD28.4-1BBζ (CAR.GD2)-T construct, including the suicide gene inducible caspase-9., Results: GD2 was expressed in 82.68% of MB tumors. The SHH and G3-G4 subtypes expressed the highest levels of GD2, whereas the WNT subtype expressed the lowest. In in vitro coculture assays, CAR.GD2 T cells were able to kill GD2+ MB cells. Pretreatment with tazemetostat upregulated GD2 expression, sensitizing GD2dimMB cells to CAR.GD2 T cells cytotoxic activity. In orthotopic mouse models of MB, intravenously injected CAR.GD2 T cells significantly controlled tumor growth, prolonging the overall survival of treated mice. Moreover, the dimerizing drug AP1903 was able to cross the murine blood-brain barrier and to eliminate both blood-circulating and tumor-infiltrating CAR.GD2 T cells., Conclusions: Our experimental data indicate the potential efficacy of CAR.GD2 T-cell therapy. A phase I/II clinical trial is ongoing in our center (NCT05298995) to evaluate the safety and therapeutic efficacy of CAR.GD2 therapy in high-risk MB patients., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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13. TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis.
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Merli P, Algeri M, Galaverna F, Bertaina V, Lucarelli B, Boccieri E, Becilli M, Quagliarella F, Rosignoli C, Biagini S, Girolami E, Meschini A, Del Principe G, Sborgia R, Catanoso ML, Carta R, Strocchio L, Pinto RM, Buldini B, Falco M, Meazza R, Pende D, Andreani M, Li Pira G, Pagliara D, and Locatelli F
- Subjects
- Child, Humans, Receptors, Antigen, T-Cell, alpha-beta, Transplantation, Haploidentical adverse effects, HLA Antigens, Histocompatibility Antigens Class II, Recurrence, Transplantation Conditioning methods, Retrospective Studies, Graft vs Host Disease, Leukemia, Myeloid, Acute, Hematopoietic Stem Cell Transplantation methods
- Abstract
Abstract: TCRαβ/CD19 cell depletion is a promising graft manipulation technique frequently used in the context of human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (HSCT). We previously reported the results of a phase I-II clinical trial (NCT01810120) to assess the safety and the efficacy of this type of exvivo T-cell depletion in 80 children with acute leukemia, showing promising survival outcomes. We now report an updated analysis on a cohort of 213 children with a longer follow-up (median, 47.6 months for surviving patients). With a 5-year cumulative incidence of nonrelapse mortality of 5.2% (95% confidence interval [CI], 2.8%-8.8%) and a cumulative incidence of relapse of 22.7% (95% CI, 16.9%-29.2%), projected 10-year overall and disease-free survival (DFS) were 75.4% (95% CI, 68.6%-80.9%) and 71.6% (95% CI, 64.4%-77.6%), respectively. Cumulative incidence of both grade II-IV acute and chronic graft-versus-host disease were low (14.7% and 8.1%, respectively). In a multivariable analysis for DFS including type of disease, use of total body irradiation in the conditioning regimen (hazard ratio [HR], 0.5; 95% CI, 0.26-0.98; P = .04), disease status at HSCT (complete remission [CR] ≥3 vs CR 1/2; HR, 2.23; 95% CI, 1.20-4.16; P = .01), and high levels of pre-HSCT minimal residual disease (HR, 2.09; 95% CI, 1.01-4.33; P = .04) were independently associated with outcome. In summary, besides confirming the good outcome results already reported (which are almost superimposable on those of transplant from HLA-matched donors), this clinical update allows the identification of patients at higher risk of treatment failure for whom personalized approaches, aimed at reducing the risk of relapse, are warranted., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
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14. Utilization of volumetric absorptive microsampling and dried plasma spot for quantification of anti-fungal triazole agents in pediatric patients by using liquid chromatography-tandem mass spectrometry.
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Simeoli R, Cairoli S, Galaverna F, Becilli M, Boccieri E, Antonetti G, Vitale A, Mancini A, Rossi C, Vici CD, and Goffredo BM
- Abstract
Background: Recently, increasing attention has been paid to the use of microsampling techniques for therapeutic drug monitoring (TDM) in neonatal and pediatric populations. Volumetric Absorptive Microsampling (VAMS) has been introduced in the market under the name Mitra® (Neoteryx). These devices consist of porous absorbent tips that allow collection of fixed blood volumes (10-30 µL) to overcome the DBS-related hematocrit effect. Here, the authors analyzed the concentrations of triazole agents (voriconazole, posaconazole, and isavuconazole) in VAMS and dried plasma spot (DPS) samples., Methods: Fifty whole blood samples were obtained from pediatric patients subjected to systemic anti-fungal therapy. VAMS were collected by dipping the tip into whole blood before centrifugation for plasma recovery. Then, 30 µL of plasma was carefully spotted on filter paper to obtain DPS. Anti-fungal concentrations were measured using a validated LC-MS/MS kit (MassTox® Antimycotic Drugs/EXTENDED) provided by Chromsystems (Chromsystems Instruments & Chemicals). Drug concentrations in VAMS and DPS samples were compared to those in fresh plasma using Passing-Bablok and Bland-Altman tests., Results: Plasma concentrations of voriconazole, posaconazole, and isavuconazole were positively and significantly correlated with those obtained in VAMS and DPS samples (Spearman r range, 0.82-0.94, p < 0.001). Data were further analyzed using the Bland-Altman test, which showed a % mean difference compared to fresh plasma of -15.06-10.98 (range). The stability of both VAMS and DPS was ensured for at least 14 d at room temperature., Conclusions: These results demonstrate that VAMS and DPS can be used for the TDM of anti-fungal agents. Owing to their stability, both sampling devices can be easily stored and shipped, without the need for refrigeration, to TDM laboratories that facilitate remote TDM applications. Finally, VAMS could be particularly suitable for pediatric and neonatal patients because they allow the collection of a few microliters of blood, thus improving ethical and compliance limitations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
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15. Achievement of operational tolerance in a pediatric liver transplant recipient following successful hematopoietic stem cell transplantation from a different donor.
- Author
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Algeri M, Velardi E, Spada M, Galaverna F, Carta R, Vinti L, Palumbo G, Gaspari S, Pietrobattista A, Boccieri E, Becilli M, Francalanci P, Bertaina V, Merli P, and Locatelli F
- Subjects
- Male, Humans, Child, Tissue Donors, Immune Tolerance, Transplantation, Homologous adverse effects, Liver Transplantation adverse effects, Hematopoietic Stem Cell Transplantation adverse effects, Anemia, Aplastic etiology, Graft vs Host Disease etiology
- Abstract
Hematopoietic stem cell transplantation (HSCT)-based approaches are increasingly investigated strategies to induce tolerance in recipients of solid allografts. However, in the majority of cases, these approaches rely on the infusion of hematopoietic stem cells recovered from the same solid organ donor. In this report, we describe the case of a boy who received liver transplantation from a deceased donor, who had successfully underwent allogeneic HSCT from an unrelated donor for hepatitis-associated aplastic anemia. In this patient, it was possible to permanently withdraw post-HSCT immune suppression without causing any sign of liver graft dysfunction. To the best of our knowledge, this is the first case of operational tolerance documented in a patient who received combined liver transplantation and HSCT from different donors., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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16. Venetoclax-based therapies in pediatric advanced MDS and relapsed/refractory AML: a multicenter retrospective analysis.
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Masetti R, Baccelli F, Leardini D, Gottardi F, Vendemini F, Di Gangi A, Becilli M, Lodi M, Tumino M, Vinci L, Erlacher M, Strahm B, Niemeyer CM, and Locatelli F
- Subjects
- Humans, Child, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Sulfonamides therapeutic use, Retrospective Studies, Leukemia, Myeloid, Acute drug therapy
- Published
- 2023
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17. Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed/refractory BCP-ALL.
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Del Bufalo F, Becilli M, Rosignoli C, De Angelis B, Algeri M, Hanssens L, Gunetti M, Iacovelli S, Li Pira G, Girolami E, Leone G, Lazzaro S, Bertaina V, Sinibaldi M, Di Cecca S, Iaffaldano L, Künkele A, Boccieri E, Del Baldo G, Pagliara D, Merli P, Carta R, Quintarelli C, and Locatelli F
- Subjects
- Young Adult, Humans, Child, T-Lymphocytes, Immunotherapy, Adoptive adverse effects, Antigens, CD19, Hematopoietic Stem Cell Transplantation, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Graft vs Host Disease etiology
- Abstract
Autologous CD19-directed chimeric antigen receptor (CAR)-T cells have shown unprecedented efficacy in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, patients either relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or displaying profound lymphopenia and/or rapidly progressing disease often cannot access autologous products. These hurdles may be overcome by allogeneic, donor-derived CAR-T cells. We tested donor-derived T cells transduced with a second-generation (4.1BB) CD19-directed CAR for treatment of patients with BCP-ALL in a hospital-exemption setting. Two constructs were tested: a retroviral construct incorporating the suicide gene inducible caspase-9 (CD19-CAR-Retro_ALLO) first and then a lentiviral construct and an automated, Prodigy-based manufacturing process (CD19-CAR-Lenti_ALLO). Thirteen children/young adults received ALLO-CAR-T cells between March 2021 and October 2022. Doses ranged between 1.0 × 106 and 3.0 × 106 CAR-T cells per kg. The toxicity profile was comparable with that of autologous CAR-T cells, characterized mainly by cytopenia, cytokine release syndrome (maximum grade 1), and grade 2 immune-effector cell-associated neurotoxicity syndrome. One case of acute graft-versus-host disease (GVHD) occurred and was rapidly controlled with steroids and ruxolitinib. None of the other patients, including 3 given ALLO-CAR-T cells from an HLA-haploidentical donor, experienced GVHD. Two patients received ALLO-CAR-T cells before HSCT and showed a significant expansion of CAR-T cells without any sign of GVHD. All patients obtained complete remission (CR) with absence of minimal residual disease in the bone marrow. With a median follow-up of 12 months (range, 5-21), 8 of 13 patients maintained CR. Allogeneic anti-CD19 CAR-T cells can effectively treat highly refractory BCP-ALL relapsing after allo-HSCT without showing increased toxicity as compared with autologous CAR-T cells., (© 2023 by The American Society of Hematology.)
- Published
- 2023
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18. Ruxolitinib as the first post-steroid treatment for acute and chronic graft-versus-host disease.
- Author
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Algeri M, Becilli M, and Locatelli F
- Abstract
Introduction: Acute and chronic graft-versus-host disease (GvHD) are potentially life-threatening complications occurring after allogeneic stem cell transplantation (allo-HSCT). Although steroids represent the first-line treatment for both conditions, in those patients who do not adequately benefit from steroid therapy, standardized treatment algorithms are lacking. In recent years, ruxolitinib has emerged as the most promising agent for the second-line therapy of steroid-refractory (SR)-GvHD., Areas Covered: This review will summarize the biological properties and the mechanistic aspects that justify the therapeutic role of ruxolitinib in GvHD. In addition, current treatment options for SR-GvHD will be briefly discussed. Finally, results of the most relevant clinical trials on the use of ruxolitinib for SR-GvHD will be analyzed, with a particular focus on two phase-III randomized trials in which ruxolitinib demonstrated its superiority in comparison with the best available therapy., Expert Opinion: Ruxolitinib has considerably improved the outcome of patients with SR-acute/chronic-GvHD and should be regarded as the standard-of-care option when corticosteroids fail or cannot be tapered. Nevertheless, a number of questions still remain unanswered and significant room for improvement exists. Additional observations derived from a longer follow-up will certainly increase our expertise in the management of this powerful therapy.
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- 2023
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19. Human leukocyte antigen evolutionary divergence influences outcomes of paediatric patients and young adults affected by malignant disorders given allogeneic haematopoietic stem cell transplantation from unrelated donors.
- Author
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Merli P, Crivello P, Strocchio L, Pinto RM, Algeri M, Del Bufalo F, Pagliara D, Becilli M, Carta R, Gaspari S, Galaverna F, Quagliarella F, Boz G, Catanoso ML, Boccieri E, Troiano M, Fleischhauer K, Andreani M, and Locatelli F
- Subjects
- Humans, Child, Young Adult, Unrelated Donors, Retrospective Studies, Histocompatibility Testing, Hematopoietic Stem Cell Transplantation adverse effects, Neoplasms etiology, Graft vs Host Disease
- Abstract
High genetic heterogeneity in the human leukocyte antigen (HLA) increases the likelihood of efficient immune response to pathogens and tumours. As measure of HLA diversity, HLA evolutionary divergence (HED) has been shown to predict the response of tumours to immunotherapy and haematopoietic stem cell transplantation (HSCT) in adults. We retrospectively investigated the association of HED with outcomes of 153 paediatric/young adults patients, treated for malignant disorders with HSCT from 9-10/10 HLA-matched unrelated donors. HED was calculated as pairwise genetic distance between alleles in patient HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1, using the locus median to stratify patients with 'high' or 'low' HED. Patients with high HED-B and -DRB1 showed significantly improved disease-free survival (DFS), especially when combined (70.8% vs 53.7% p = 0.008). High HED-B + -DRB1 was also associated with improved overall survival (OS) (82.1 vs 66.4% p = 0.014), and concomitant reduction of non-relapse-mortality (5.1% vs 21.1% p = 0.006). The impact on OS and DFS of combined HED-B + -DRB1 was confirmed in multivariate analysis [hazard ratio (HR) 0.39, p = 0.009; and HR 0.45, p = 0.007 respectively]. Only high HED scores for HLA-DPB1 were associated, in univariate analysis, with reduced incidence of relapse (15.9% vs 31.1%, p = 0.03). These results support HED as prognostic marker in allogeneic HSCT and, if confirmed in larger cohorts, would allow its use to inform clinical risk and potentially influence clinical practice., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2023
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20. αβT- and B-cell-depleted HLA-haploidentical hematopoietic stem cell transplantation in children with myelodysplastic syndromes.
- Author
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Merli P, Pagliara D, Mina T, Bertaina V, Li Pira G, Lazzaro S, Biagini S, Galaverna F, Strocchio L, Carta R, Catanoso ML, Quagliarella F, Becilli M, Boccieri E, Del Bufalo F, Panigari A, Agostini A, Pedace L, Pizzi S, Perotti C, Algeri M, Zecca M, and Locatelli F
- Subjects
- Child, Humans, B-Lymphocytes, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Myelodysplastic Syndromes therapy
- Published
- 2022
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21. Case Report: Early Association of Vemurafenib to Standard Chemotherapy in Multisystem Langerhans Cell Histiocytosis in a Newborn: Taking a Chance for a Better Outcome?
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Gaspari S, Di Ruscio V, Stocchi F, Carta R, Becilli M, and De Ioris MA
- Abstract
Langerhans cell histiocytosis (LCH) is due to aberrant monoclonal proliferation and accumulation of dendritic cells, ranging from a self-limiting local condition to a rapidly progressive multisystem disease with poor prognosis. Pathogenic cells originate from a myeloid-derived precursor characterized by an activation of the MAPK/ERK signaling pathway in about 70% of cases. In particular, BRAF V600E mutation is usually associated with a more severe clinical course and poor response to chemotherapy. We report on a newborn with multisystem LCH in life-threatening medical conditions. At diagnosis, the patient was successfully treated with the early association of BRAF inhibitor Vemurafenib to standard chemotherapy representing a new approach in first-line treatment. A rapid clinical improvement with a prompt fever regression from day 2 and complete resolution of skin lesions by week 2 were observed; laboratory data normalized as well. Vemurafenib was discontinued after 12 months of treatment. No signs of relapse occurred after 12 months of discontinuation. This case indicates that early combination of target therapy with standard treatment may induce rapid response and prolonged disease remission without significant toxicities in infants. This approach represents a valid and safe option as first-line treatment in multisystem disease, especially in high-risk patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gaspari, Di Ruscio, Stocchi, Carta, Becilli and De Ioris.)
- Published
- 2021
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22. Cow's milk allergy non-responsive to amino acid-based formula? A successful transplanted patient with immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome.
- Author
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Veramendi-Espinoza L, Rentería-Valdiviezo CA, Díaz-Subauste R, Aldave-Becerra JC, Alva-Lozada G, Becilli M, and Locatelli F
- Abstract
The wide variety of IPEX symptoms leads to diagnosis and treatment delay with fatal outcomes if left untreated before two first years of life. Cow's milk allergy non-responsive to amino acid-based formula must raise suspicion of this syndrome., Competing Interests: The authors declare that this case report was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)
- Published
- 2021
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23. Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia.
- Author
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Merli P, Algeri M, Galaverna F, Milano GM, Bertaina V, Biagini S, Girolami E, Palumbo G, Sinibaldi M, Becilli M, Leone G, Boccieri E, Grapulin L, Gaspari S, Airoldi I, Strocchio L, Pagliara D, and Locatelli F
- Subjects
- Adolescent, B-Lymphocytes immunology, Child, Child, Preschool, Cohort Studies, Disease-Free Survival, Feasibility Studies, Female, Graft vs Host Disease immunology, Graft vs Host Disease prevention & control, Humans, Immunologic Factors adverse effects, Infant, Male, T-Lymphocytes immunology, Transplantation, Homologous methods, Young Adult, Zoledronic Acid adverse effects, Antigens, CD19 immunology, Hematopoietic Stem Cell Transplantation methods, Immunologic Factors administration & dosage, Leukemia, Myeloid, Acute therapy, Lymphocyte Depletion methods, Receptors, Antigen, T-Cell, alpha-beta immunology, Receptors, Antigen, T-Cell, gamma-delta immunology, T-Lymphocytes drug effects, Transplantation Conditioning methods, Transplantation, Haploidentical methods, Zoledronic Acid administration & dosage
- Abstract
TcRαβ/CD19-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a promising new platform for children affected by acute leukemia in need of an allograft and lacking a matched donor, disease recurrence being the main cause of treatment failure. The use of zoledronic acid to enhance TcRγδ+ lymphocyte function after TcRαβ/CD19-cell depleted haplo-HSCT was tested in an open-label, feasibility, proof-of-principle study. Forty-six children affected by high-risk acute leukemia underwent haplo-HSCT after removal of TcRαβ+ and CD19+ B lymphocytes. No post-transplant pharmacological graft-versus-host disease (GvHD) prophylaxis was given. Zoledronic acid was administered monthly at a dose of 0.05 mg/kg/dose (maximum dose 4 mg), starting from day +20 after transplantation. A total of 139 infusions were administered, with a mean of 3 infusions per patient. No severe adverse event was observed. Common side effects were represented by asymptomatic hypocalcemia and acute phase reactions (including fever, chills, malaise, and/or arthralgia) within 24-48 h from zoledronic acid infusion. The cumulative incidence of acute and chronic GvHD was 17.3% (all grade I-II) and 4.8% (all limited), respectively. Patients given 3 or more infusions of zoledronic acid had a lower incidence of both acute GvHD (8.8 vs. 41.6%, p = 0.015) and chronic GvHD (0 vs. 22.2%, p = 0.006). Transplant-related mortality (TRM) and relapse incidence at 3 years were 4.3 and 30.4%, respectively. Patients receiving repeated infusions of zoledronic acid had a lower TRM as compared to those receiving 1 or 2 administration of the drug (0 vs. 16.7%, p = 0.01). Five-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 67.2 and 65.2%, respectively, with a trend toward a better OS for patients receiving 3 or more infusions (73.1 vs. 50.0%, p = 0.05). The probability of GvHD/relapse-free survival was significantly worse in patients receiving 1-2 infusions of zoledonic acid than in those given ≥3 infusions (33.3 vs. 70.6%, respectively, p = 0.006). Multivariable analysis showed an independent positive effect on outcome given by repeated infusions of zoledronic acid (HR 0.27, p = 0.03). These data indicate that the use of zoledronic acid after TcRαβ/CD19-cell depleted haploHSCT is safe and may result in a lower incidence of acute GvHD, chronic GvHD, and TRM., (Copyright © 2020 Merli, Algeri, Galaverna, Milano, Bertaina, Biagini, Girolami, Palumbo, Sinibaldi, Becilli, Leone, Boccieri, Grapulin, Gaspari, Airoldi, Strocchio, Pagliara and Locatelli.)
- Published
- 2020
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24. The neutrophil/lymphocyte ratio ≥3.5 is a prognostic marker in diffuse large B-cell lymphoma: a retrospective analysis from the database of the Italian regional network 'Rete Ematologica del Lazio per i Linfomi' (RELLI).
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Annibali O, Hohaus S, Marchesi F, Cantonetti M, Di Rocco A, Tomarchio V, Di Napoli A, Pelliccia S, Battistini R, Anticoli Borza P, Abruzzese E, Cenfra N, Andriani A, Tesei C, Alma E, Palombi F, Pupo L, Petrucci L, Becilli M, Maiolo E, Bellesi S, Cuccaro A, D'Alò F, and Cox MC
- Subjects
- Adult, Aged, Aged, 80 and over, Cyclophosphamide administration & dosage, Databases, Factual, Doxorubicin administration & dosage, Female, Follow-Up Studies, Humans, Italy, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Prednisone administration & dosage, Prognosis, Retrospective Studies, Rituximab administration & dosage, Survival Rate, Vincristine administration & dosage, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor analysis, Lymphocytes pathology, Lymphoma, Large B-Cell, Diffuse mortality, Neutrophils pathology
- Abstract
In solid tumors and lymphomas, the neutrophil/lymphocyte (N/L) ratio at diagnosis has been shown to be a prognostic factor. The aim of our study was to validate the originally reported N/L ratio cut-point of 3.5 in patients with diffuse large B-cell lymphoma (DLBCL) registered in an Italian real-life database. The prognostic role of the N/L ratio at diagnosis on event-free survival (EFS) and overall survival (OS) was assessed in 505 patients with DLBCL. Patients with an N/L ratio <3.5 ( n = 249) had a 4-year EFS probability of 76% and OS probability of 86%, significantly higher than the 4 year EFS rate of 48% and OS rate of 64% in patients with N/L ratio ≥3.5 ( n = 256, both p <.0001). The N/L ratio was an independent prognostic factor in the multivariate analysis including the IPI score, and could separate patients with a low/intermediate risk IPI (IPI <3).
- Published
- 2019
- Full Text
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