Publications by authors named "Maura Faraci"

95 Publications

A UHPLC-MS/MS Method for Therapeutic Drug Monitoring of Aciclovir and Ganciclovir in Plasma and Dried Plasma Spots.

Biomedicines 2021 Oct 2;9(10). Epub 2021 Oct 2.

Chromatography and Mass Spectrometry Section, Central Laboratory of Analysis, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.

The role of therapeutic drug monitoring (TDM) of valaciclovir (VA)/aciclovir (A) and valganciclovir/ganciclovir (VG/G) in critically ill patients is still a matter of debate. More data on the dose-concentration relationship might therefore be useful, especially in pediatrics where clinical practice is not adequately supported by robust PK studies. We developed and validated a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) micro-method to simultaneously quantify A and G from plasma and dried plasma spots (DPS). The method was based on rapid organic extraction from DPS and separation on a reversed-phase C-18 UHPLC column after addition of deuterated internal standards. Accurate analyte quantification using SRM detection was then obtained using a Thermo Fisher Quantiva triple-quadrupole MS coupled to an Ultimate 3000 UHPLC. It was validated following international (EMA) guidelines for bioanalytical method validation and was tested on samples from pediatric patients treated with A, VG, or G for cytomegalovirus infection following solid organ or hematopoietic stem cell transplantation. Concentrations obtained from plasma and DPS were compared using Passing-Bablok and Bland-Altman statistical tests. The assay was linear over wide concentration ranges (0.01-20 mg/L) in both plasma and DPS for A and G, suitable for the expected therapeutic ranges for both Cmin and Cmax, accurate, and reproducible in the absence of matrix effects. The results obtained from plasma and DPS were comparable. Using an LC-MS/MS method allowed us to obtain a very specific, sensitive, and rapid quantification of these antiviral drugs starting from very low volumes (50 μL) of plasma samples and DPS. The stability of analytes for at least 30 days allows for cost-effective shipment and storage at room temperature. Our method is suitable for TDM and could be helpful for improving knowledge on PK/PD targets of antivirals in critically ill pediatric patients.
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http://dx.doi.org/10.3390/biomedicines9101379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533239PMC
October 2021

Hematopoietic stem cell transplantation for classical inherited bone marrow failure syndromes: an update.

Expert Rev Hematol 2021 Oct 15;14(10):911-925. Epub 2021 Sep 15.

Hematology Unit, Department of Hematology-Oncology, IRCSS-Istituto G. Gaslini, Genova, Italy.

Introduction: Inherited bone marrow failure syndromes (IBMFS) feature complex molecular pathophysiology resulting in ineffective hematopoiesis and increased risk of progression to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Allogenic hematopoietic stem cell transplantation (HSCT) is the only well-established cure for the hematological manifestations of these diseases.

Areas Covered: In recent years, analysis of large series from international databases (mainly from the European Bone Marrow Transplantation [EBMT] database) has improved knowledge about HSCT in IBMFS. This review, following a thorough Medline search of the pertinent published studies, reports the most recent data on HSCT in IBMFS.

Expert Opinion: Despite the common features, IBMFS are very different in their manifestations and in the occurrence and management of HSCT complications. Thus, a 'disease-specific' HSCT using an optimized conditioning regimen based on the characteristics of the disease is essential for achieving long-term survival. The phenotypical heterogeneity associated with extramedullary abnormalities has to be carefully evaluated before HSCT because transplantation may only correct impaired hematopoiesis. HSCT may be associated with the risk of treatment-related mortality and with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks.
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http://dx.doi.org/10.1080/17474086.2021.1977119DOI Listing
October 2021

Impact of in Vivo Lymphodepletion on Outcome in Children with Nonmalignant Disorders Receiving Peripheral Blood Stem Cell Transplantation.

Transplant Cell Ther 2021 Dec 24;27(12):1020.e1-1020.e5. Epub 2021 Aug 24.

Bone Marrow Transplant Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

Peripheral blood stem cell transplantation (PBSCT) with in vivo lymphodepletion can provide faster neutrophil recovery with limited risk of severe graft-versus-host disease (GVHD) in children with nonmalignant disorders (NMDs). We aimed to provide an historical comparison of these 2 strategies regarding the prevalence of GVHD, viral reactivation, timing of immune reconstitution, and final outcomes. Data on 98 children undergoing PBSCT were collected from 5 European pediatric transplantation centers. Only patients with NMDs receiving treosulfan or myeloablative busulfan conditioning and 9-10/10 HLA-matched transplant were included. The patients were divided into 2 groups according to in vivo lymphodepletion with antithymocyte globulin (ATG) or with alemtuzumab. We compared rates of acute and chronic GVHD; Epstein-Barr virus, cytomegalovirus, and adenovirus reactivation; chimerism; lymphocyte recovery; overall survival (OS) and event-free survival (EFS) between the 2 groups. The rate of severe acute GVHD (grade III-IV) was significantly higher in patients receiving ATG (26% vs 10% in alemtuzumab recipients; P < .05), whereas viral reactivations occurred with a similar rate in the 2 groups (alemtuzumab, 56%; ATG, 57%). Alemtuzumab was the major risk factor for delayed T cell immune reconstitution in the first 3 months after transplantation (odds ratio [OR], 6.0; 95% confidence interval [CI], 1.8 to 19; P < .005). Extended chronic GVHD, ADV reactivation, slower CD3 cell recovery, and HLA-mismatch reduced the probability of survival. Infections were the main cause of mortality in our cohort, and delayed T cell recovery was significantly associated with mortality in multivariate analysis (OR, 12; 95% CI, 1.2 to 114; P < .05). Ultimately, no differences in OS and EFS survival were seen between the ATG and alemtuzumab groups. ATG and alemtuzumab showed similar impacts on outcomes of children undergoing PBSCT for NMDs. The 2 strategies of in vivo lymphodepletion showed specific drawbacks that were counterbalanced by benefits that ultimately led to a comparable survival rate. A patient-centered lymphodepletion strategy can be advised in children undergoing PBSCT for NMDs, by favoring T cell recovery in the presence of invasive infection or GVHD prevention in high-risk mismatched donor transplantation.
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http://dx.doi.org/10.1016/j.jtct.2021.08.015DOI Listing
December 2021

The role of pharmacies in haematopoietic stem cell transplantation process: A nationwide survey by Gruppo Italiano Trapianto di Midollo Osseo.

J Clin Pharm Ther 2021 Dec 16;46(6):1665-1679. Epub 2021 Aug 16.

Hematology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

What Is Known And Objective: The aim of this survey, conducted by the Gruppo Italiano per il Trapianto di Midollo Osseo (GITMO), was to evaluate the involvement of pharmacists in the haematopoietic stem cell transplant (HSCT) program in Italian adult and paediatric centres.

Methods: A 63-item online questionnaire was developed and sent to the Italian Transplant Programs on behalf of GITMO.

Results And Discussion: Overall, 54.7% of the Italian HSCT centres participated in the survey (88.5% adult, 7.7% paediatric, 3.8% mixed), of which 50% were in public hospitals and 50% affiliated with public universities. Just over 80% declared that a pharmacist is involved in the HSCT centre, and 86.5% reported the presence of a documentation system to signal of adverse events, accessible by physicians, nurses and pharmacists in 57.7%. Chemotherapy drugs were centralized in the pharmacy in 98.1% of HSCT centres, while parenteral nutrition was centralized in 55.8%. The use of off-label drugs was authorized by an internal committee and by the regional health authorities in 88.5% of the centres. On univariate analysis, few statistically significant differences were found on response frequencies between public hospitals and university centres or between HSCT centres performing only autologous stem cell transplantation versus other centres performing autologous and allogeneic stem cell transplantation.

What Is New And Conclusion: This survey suggests that there is good collaboration between pharmacists and physicians and nurses in Italian HSCT transplantation centres. The enhancement of pharmacists dedicated to HSCT programs could improve some problems, for example, the centralization of parenteral nutrition.
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http://dx.doi.org/10.1111/jcpt.13498DOI Listing
December 2021

Outcomes of Unmanipulated Haploidentical Transplantation Using Post-Transplant Cyclophosphamide (PT-Cy) in Pediatric Patients With Acute Lymphoblastic Leukemia.

Transplant Cell Ther 2021 05 21;27(5):424.e1-424.e9. Epub 2021 Jan 21.

Pediatric Hematology, Oncology and Stem Cell Transplantation Department, University of Regensburg, Regensburg, Germany.

HLA-haploidentical transplantation (haplo-HCT) using post-transplantation-cyclophosphamide (PT-Cy) is a feasible procedure in children with malignancies. However, large studies on Haplo-HCT with PT-Cy for childhood acute lymphoblastic leukemia (ALL) are lacking. We analyzed haplo-HCT outcomes in 180 children with ALL. Median age was 9 years, and median follow-up was 2.7 years. Disease status was CR1 for 24%, CR2 for 45%, CR+3 for 12%, and active disease for 19%. All patients received PT-Cy day +3 and +4. Bone marrow (BM) was the stem cell source in 115 patients (64%). Cumulative incidence of 42-day engraftment was 88.9%. Cumulative incidence of day-100 acute graft-versus-host disease (GVHD) grade II-IV was 28%, and 2-year chronic GVHD was 21.9%. At 2 years, cumulative incidence of nonrelapse mortality (NRM) was 19.6%. Cumulative incidence was 41.9% for relapse and 25% for patients in CR1. Estimated 2-year leukemia free survival was 65%, 44%, and 18.8% for patients transplanted in CR1, CR2, CR3+ and 3% at 1 year for active disease. In multivariable analysis for patients in CR1 and CR2, disease status (CR2 [hazard ratio {HR} = 2.19; P = .04]), age at HCT older than 13 (HR = 2.07; P = .03) and use of peripheral blood stem cell (PBSC) (HR = 1.98; P = .04) were independent factors associated with decreased overall survival. Use of PBSC was also associated with higher NRM (HR = 3.13; P = .04). Haplo-HCT with PT-Cy is an option for children with ALL, namely those transplanted in CR1 and CR2. Age and disease status remain the most important factors for outcomes. BM cells as a graft source is associated with improved survival.
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http://dx.doi.org/10.1016/j.jtct.2021.01.016DOI Listing
May 2021

Stem Cell Transplantation for Diamond-Blackfan Anemia. A Retrospective Study on Behalf of the Severe Aplastic Anemia Working Party of the European Blood and Marrow Transplantation Group (EBMT).

Transplant Cell Ther 2021 03 25;27(3):274.e1-274.e5. Epub 2020 Dec 25.

Hospital Universitario La Paz, Madrid, Spain.

Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients.
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http://dx.doi.org/10.1016/j.jtct.2020.12.024DOI Listing
March 2021

Mesial Temporal Sclerosis as Late Consequence of Posterior Reversible Encephalopathy Syndrome in Pediatric Hemato-oncologic Patients.

J Pediatr Hematol Oncol 2022 Jan;44(1):e168-e175

Child Neuropsychiatry Unit.

Objectives: Drug resistant epilepsy has rarely been reported following posterior reversible encephalopathy syndrome (PRES), with few cases of mesial temporal sclerosis (MTS). The aim of this study was to report clinical and neuroimaging features of MTS subsequent to PRES in hemato-oncologic/stem cell transplanted children.

Materials And Methods: Among 70 children treated in 2 pediatric hemato-oncologic Italian centers between 1994 and 2018 and presenting an episode of PRES, we retrospectively identified and analyzed a subgroup of patients who developed epilepsy and MTS.

Results: Nine of 70 patients (12.8%) developed post-PRES persistent seizures with magnetic resonance imaging evidence of MTS. One patient died few months after MTS diagnosis, because of hematologic complications; the remaining 8 patients showed unprovoked seizures over time leading to the diagnosis of epilepsy, focal in all and drug resistant in 4. At PRES diagnosis, all patients with further evidence of epilepsy and MTS suffered of convulsive seizures, evolving into status epilepticus in 3. In 3 patients a borderline cognitive level or intellectual disability were diagnosed after the onset of epilepsy, and 2 had behavioral problems impacting their quality of life.

Conclusions: MTS and long-term focal epilepsy, along with potential cognitive and behavioral disorders, are not uncommon in older pediatric patients following PRES.
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http://dx.doi.org/10.1097/MPH.0000000000002139DOI Listing
January 2022

Haplo-identical or mismatched unrelated donor hematopoietic cell transplantation for Fanconi anemia: Results from the Severe Aplastic Anemia Working Party of the EBMT.

Am J Hematol 2021 05 4;96(5):571-579. Epub 2021 Mar 4.

French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Saint Louis Hospital and University Paris Diderot, Paris, France.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53-71%) for MMUD, versus 80% (66-95%) for HDs with only in vivo T cell depletion and 60% (47-73%) for HDs with in vivo and ex vivo T cell depletion (p = .22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73-99%) than for those transplanted from a MMUD 58% (48-68%) or those with graft manipulation 56% (42-69%) (p = .046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p = .005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts.
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http://dx.doi.org/10.1002/ajh.26135DOI Listing
May 2021

Adoptive Transfer of JC Virus-Specific T Lymphocytes for the Treatment of Progressive Multifocal Leukoencephalopathy.

Ann Neurol 2021 04 10;89(4):769-779. Epub 2021 Feb 10.

Cell Factory, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.

Objective: Progressive multifocal leukoencephalopathy (PML) is still burdened by high mortality in a subset of patients, such as those affected by hematological malignancies. The aim of this study was to analyze the safety and carry out preliminary evaluation of the efficacy of polyomavirus JC (JCPyV)-specific T cell therapy in a cohort of hematological patients with PML.

Methods: Between 2014 and 2019, 9 patients with a diagnosis of "definite PML" according to the 2013 consensus who were showing progressive clinical deterioration received JCPyV-specific T cells. Cell lines were expanded from autologous or allogenic peripheral blood mononuclear cells by stimulation with JCPyV antigen-derived peptides.

Results: None of the patients experienced treatment-related adverse events. In the evaluable patients, an increase in the frequency of circulating JCPyV-specific lymphocytes was observed, with a decrease or clearance of JCPyV viral load in cerebrospinal fluid. In responsive patients, transient appearance of punctate areas of contrast enhancement within, or close to, PML lesions was observed, which was interpreted as a sign of immune control and which regressed spontaneously without the need for steroid treatment. Six of 9 patients achieved PML control, with 5 alive and in good clinical condition at their last follow-up.

Interpretation: Among other novel treatments, T cell therapy is emerging as a viable treatment option in patients with PML, particularly for those not amenable to restoration of specific immunity. Neurologists should be encouraged to refer PML patients to specialized centers to allow access to this treatment strategy. ANN NEUROL 2021;89:769-779.
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http://dx.doi.org/10.1002/ana.26020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248385PMC
April 2021

Haploidentical α/β T-cell and B-cell depleted stem cell transplantation in severe mevalonate kinase deficiency.

Rheumatology (Oxford) 2021 10;60(10):4850-4854

Centro Malattie Auto-infiammatorie e Immunodeficienze, Istituto G. Gaslini, Genova, Italy.

Objective: Mevalonic aciduria represents the most severe form of mevalonate kinase deficiency (MKD). Patients with mevalonic aciduria have an incomplete response even to high doses of anti-cytokine drugs such as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease.

Methods: We report the first two children affected by severe MKD who received haploidentical α/β T-cell and B-cell depleted SCT. Both patients received a treosulfan-based conditioning regimen and one received a second haploidentical-SCT for secondary rejection of the first.

Results: Both patients obtained a stable full donor engraftment with a complete regression of clinical and biochemical inflammatory signs, without acute organ toxicity or acute and chronic GvHD. In both, the urinary excretion of mevalonic acid remained high post-transplant in the absence of any inflammatory signs.

Conclusion: Haploidentical α/β T-cell and B-cell depleted SCT represents a potential curative strategy in patients affected by MKD. The persistence of urinary excretion of mevalonic acid after SCT, probably related to the ubiquitous expression of MVK enzyme, suggests that these patients should be carefully monitored after SCT to exclude MKD clinical recurrence. Prophylaxis with anakinra in the acute phase after transplant could represent a safe and effective approach. Further biological studies are required to clarify the pathophysiology of inflammatory attacks in MKD in order to better define the therapeutic role of SCT.
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http://dx.doi.org/10.1093/rheumatology/keaa912DOI Listing
October 2021

Thalidomide as treatment of crohn-like disease occurred after allogeneic hematopoietic stem cell transplantation in a pediatric patient.

Pediatr Transplant 2021 May 12;25(3):e13941. Epub 2020 Dec 12.

Hematopoetic Stem Cell Transplant Unit, Hematology-Oncology, IRCSS, Institute G. Gaslini, Genova, Italy.

Background: Autoimmune diseases may occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and inflammatory bowel disease (IBD or Crohn disease) is rarely described. We describe a child who developed CD after allo-HSCT, successfully treated with thalidomide.

Case Report: A child affected by mucopolysaccharidosis type I received two allogeneic HSCTs for rejection after the first one. After cutaneous and intestinal chronic GvHD and 6 months after HSCT, the patients developed a trilinear autoimmune cytopenia successfully treated with rituximab and sirolimus. Due to persisting intestinal symptoms, colonoscopies were performed and histological findings demonstrated a picture of CD. Based on this observation and according to the recommendations for the treatment of CD, thalidomide was started. A complete stable clinical response was obtained 8 weeks after start of thalidomide. Colonoscopy performed 4.8 years later demonstrated a complete endoscopic and histological remission of CD.

Discussion: In this case, the diagnosis of CD after HSCT was based on histological findings. Indeed, repeated colonscopies were necessary for diagnosis, since both clinical and endoscopic features are often common to chronic GvHD and CD. Thalidomide was started at the dose of 1.7 mg/Kg/day, and it was well tolerated. Mild peripheral neurotoxicity occurred 5 years later but disappeared completely with the dose reduction. Currently, the patient is in complete remission from CD, despite the discontinuation of all the immunosuppressive therapies.

Conclusions: Thalidomide could represent a therapeutic option to treat CD as autoimmune disease after allogeneic HSCT.
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http://dx.doi.org/10.1111/petr.13941DOI Listing
May 2021

CD34+ selected peripheral blood Stem Cell Boost (SCB) for Poor Graft Function (PGF) or mixed chimerism in pediatric patients, after hematopoietic stem cell transplantation: Results of a retrospective multicenter study.

Pediatr Transplant 2021 Aug 3;25(5):e13909. Epub 2020 Nov 3.

Pediatric Onco-Hematology, Regina Margherita Children Hospital, City of Health and Science, University of Turin, Turin, Italy.

Background: PGF is historically associated with high morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Methods: In this study, we report our multicenter experience on stem cell boost (SCB) for PGF, or incomplete donor engraftment, in 16 pediatric patients. Donors were HLA-matched siblings (n = 4), unrelated donors (n = 11), or haploidentical family members (n = 1). Ten patients had two-lineage cytopenia, 5 had one-lineage cytopenia, and 1 had poor immunological reconstitution together with a low percentage of donor cell engraftment. A median of 6.6x10 selected CD34+/Kg was infused after 194 days from allo-HSCT (48-607).

Results: In 4 out of 5 patients, one-lineage cytopenia was resolved, while among the 10 patients with two-lineage cytopenia, 4 resolved both cytopenia, 5 resolved one-lineage, and one did not respond. All patients reverted their mixed chimera to full donor chimera. OS was 56%, transplant-related mortality (TRM) 32%, and RI 12%. The main causes of failure were related to infections with 4 out of 7 deaths caused by this.

Conclusions: SCB may rescue over 50% of patients with PGF after allo-HSCT. An earlier treatment may reduce the infectious complications and improve survival.
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http://dx.doi.org/10.1111/petr.13909DOI Listing
August 2021

Spontaneous pregnancy after hematopoietic stem cell transplantation for chronic granulomatous disease.

Pediatr Blood Cancer 2021 04 28;68(4):e28783. Epub 2020 Oct 28.

Hematopoietic Stem Cell Transplant Unit, Department of Hematology and Oncology, IRCCS Istituto Giannina Gaslini, Genova, Italy.

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http://dx.doi.org/10.1002/pbc.28783DOI Listing
April 2021

I-Meta-iodobenzylguanidine followed by busulfan and melphalan and autologous stem cell rescue in high-risk neuroblastoma.

Pediatr Blood Cancer 2021 02 24;68(2):e28775. Epub 2020 Oct 24.

Pediatric Oncology Unit, Istituto Giannina Gaslini, Genoa, Italy.

Introduction: Despite the progress in current treatments, the event-free survival of high-risk neuroblastoma (HR-NB) patients does not exceed 40%-50%, and the prognosis of refractory or relapsed patients is poor, still representing a challenge for pediatric oncologist. Therapeutic Iodine-131 meta-iodobenzylguanidine (Th- I-MIBG) is a recognized safe and potentially effective treatment for NB.

Materials: This retrospective study reports the outcomes of 28 MIBG-avid NB patients with advanced disease either refractory or relapsed, which was undertaken from 1996 to 2014. Th- I-MIBG was administered shortly before (median: 17 days) high-dose chemotherapy with busulfan and melphalan (HD-BuMel) and autologous stem cell rescue (ASCR) at the Gaslini Institute in Genoa, with the aim of analyzing the feasibility, safety, and efficacy of this approach.

Results: Engraftment occurred in all patients after a median of 14 (11-29) and 30 days (13-80) from ASCR for neutrophils and platelets, respectively. No treatment-related deaths were observed. The main high-grade (3-4) toxicity observed was oral and gastrointestinal mucositis in 78.6% and 7.1% of patients, respectively, whereas high-grade hepatic toxicity was observed in 10.7%. Two patients developed veno-occlusive-disease (7.1%), completely responsive to defibrotide. Hypothyroidism was the main late complication that occurred in nine patients (31.1%). After Th- MIBG and HD-BuMel, 19 patients (67.8%) showed an improvement in disease status. Over a median follow-up of 15.9 years, the three-year and five-year overall survival (OS) probabilities were 53% (CI 0.33-0.69) and 41% (CI 0.22-0.59), and the three-year and five-year rates of cumulative risk of progression/relapse were 64% (CI 0.47-0.81) and 73% (CI 0.55-0.88), respectively. MYCN amplification emerged as the only risk factor significantly associated with OS (HR, 3.58;P = 0.041).

Conclusion: Th- I-MIBG administered shortly before HD-BuMel is a safe and effective regimen for patients with advanced MIBG-avid NB. These patients should be managed in centers with proven expertise.
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http://dx.doi.org/10.1002/pbc.28775DOI Listing
February 2021

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency.

Blood 2020 12;136(23):2638-2655

Dr von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.
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http://dx.doi.org/10.1182/blood.2020006738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735164PMC
December 2020

Antibacterial prophylaxis of febrile neutropenia is not effective in the pre-engraftment period in pediatric allogeneic hematopoietic stem cell transplantation.

Transpl Infect Dis 2020 10 9;22(5):e13340. Epub 2020 Jun 9.

Infectious Diseases Unit, Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genova, Italy.

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http://dx.doi.org/10.1111/tid.13340DOI Listing
October 2020

Outcome of patients with Fanconi anemia developing myelodysplasia and acute leukemia who received allogeneic hematopoietic stem cell transplantation: A retrospective analysis on behalf of EBMT group.

Am J Hematol 2020 07 21;95(7):809-816. Epub 2020 Apr 21.

Hematopoietic stem cell transplantation Unit, Istituto Giannina Gaslini, Genoa, Italy.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo-HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre-HSCT cytoreductive therapies and related toxicities, disease status pre-HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5-year OS and EFS were 42% (30-53%) and 39% (27-51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48-95] vs 37% [24-50],P = .04), while none of the other variables considered had an impact. Twenty-two patients received pre-HSCT cytoreduction and 9/22 showed a grade 3-4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre-HSCT 48% [20-75%] vs no-toxicity 51% [25-78%],P = .98). The cumulative incidence of day-100 grade II-IV a-GvHD and of 5-year c-GvHD were 38% (26-50%) and 40% (28-52%). Non-relapse-related mortality and incidence of relapse at 5-years were 40% (29-52%) and 21% (11-30%) respectively, without any significant impact of the tested variables. Causes of death were transplant-related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre-HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre-HSCT should be considered if a donor have been secured.
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http://dx.doi.org/10.1002/ajh.25810DOI Listing
July 2020

Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT).

Bone Marrow Transplant 2020 09 19;55(9):1796-1809. Epub 2020 Mar 19.

Paediatric Haematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative procedure in patients with Shwachman-Diamond syndrome (SDS) with bone marrow abnormalities. The results of 74 patients with SDS (6 acute myeloid leukemia, 7 myelodysplastic syndrome, and 61 bone marrow failure) treated with HSCT between 1988 and 2016 are reported. The donor source was: 24% sibling, 8% parent, and 68% unrelated donor. The stem cell source was: 70% bone marrow, 19% peripheral blood stem cells, and 11% cord blood. The conditioning regimen was myeloablative in 54% and reduced intensity in 46%. Neutrophil engraftment was achieved in 84% of patients after a median time of 17.5 days. Graft failure occurred in 15% of HSCTs. Grades I-IV acute and chronic GVHD were observed in 55% and 20% of patients, respectively. After a median follow-up of 7.3 years (95% CI 4.8-10.2), 28 patients died for progression/relapse (7) or toxicity (21). The 5-year overall survival and nonrelapse mortality were 63.3% (95% CI 50.8-73.4) and 19.8% (95% CI 10.8-30.8), respectively. In conclusion, this is the largest series so far reported and confirms that HSCT is a suitable option for patients with SDS. Further efforts are needed to lower transplant-related toxicity and reduce graft failure.
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http://dx.doi.org/10.1038/s41409-020-0863-zDOI Listing
September 2020

Antiemetic prophylaxis in patients undergoing hematopoietic stem cell transplantation: a multicenter survey of the Gruppo Italiano Trapianto Midollo Osseo (GITMO) transplant programs.

Ann Hematol 2020 Apr 8;99(4):867-875. Epub 2020 Feb 8.

SODc Terapie Cellulari e Medicina Trasfusionale, AOU Careggi, Florence, Italy.

A survey within hematopoietic stem cell transplant (HSCT) centers of the Gruppo Italiano Trapianto Midollo Osseo (GITMO) was performed in order to describe current antiemetic prophylaxis in patients undergoing HSCT. The multicenter survey was performed by a questionnaire, covering the main areas on chemotherapy-induced nausea and vomiting (CINV): antiemetic prophylaxis guidelines used, antiemetic prophylaxis in different conditioning regimens, and methods of CINV evaluation. The survey was carried out in November 2016, and it was repeated 6 months after the publication of the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) specific guidelines on antiemetic prophylaxis in HSCT. The results show a remarkable heterogeneity of prophylaxis among the various centers and a significant difference between the guidelines and the clinical practice. In the main conditioning regimens, the combination of a serotonin receptor antagonist (5-HT-RA) with dexamethasone and neurokin receptor antagonist (NK1-RA), as recommended by MASCC/ESMO guidelines, increased from 0 to 15% (before the publication of the guidelines) to 9-30% (after the publication of the guidelines). This study shows a lack of compliance with specific antiemetic guidelines, resulting mainly in under-prophylaxis. Concerted strategies are required to improve the current CINV prophylaxis, to draft shared common guidelines, and to increase the knowledge and the adherence to the current recommendations for CINV prophylaxis in the specific field of HSCT.
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http://dx.doi.org/10.1007/s00277-020-03945-3DOI Listing
April 2020

Occurrence of long-term effects after hematopoietic stem cell transplantation in children affected by acute leukemia receiving either busulfan or total body irradiation: results of an AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) retrospective study.

Bone Marrow Transplant 2020 10 29;55(10):1918-1927. Epub 2020 Jan 29.

Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Torino, Italy.

Patients given allogeneic hematopoietic stem cell transplantation (alloHSCT) present an increased incidence of long-term toxicities that can be attributed to the preparative regimen. We retrospectively analyzed in a population of 670 children receiving allo-HSCT for acute leukemia the occurrence of different late effects in function of the choice made between total body irradiation (TBI) and busulfan, as part of the preparative regimen. In univariable analysis, we found that patients treated with TBI developed cataract in 24% of the cases compared with 4% in patients treated with BU (p = 0.0001) and that the incidence of secondary malignant neoplasia (SMN) was higher in patients treated with TBI (18%) as compared with those prepared to the allograft with a Bu-based regimen (0%) (p = 0.019). Conditioning regimen did not show a statistically significant correlation with the occurrence of all the other investigated late effects. In multivariable analysis, TBI remained associated with the occurrence of cataracts (Relative Risk: 0.33 p = 0.012) and secondary malignancies (Relative Risk 3.96 × 10e-6 p < 0.001); however, other variables, as GvHD and disease type, were also correlated with these long-term sequels, indicating that in our study population the preparative regimen is not the only factor influencing the incidence of these complications.
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http://dx.doi.org/10.1038/s41409-020-0806-8DOI Listing
October 2020

Imatinib melylate as second-line treatment of bronchiolitis obliterans after allogenic hematopoietic stem cell transplantation in children.

Pediatr Pulmonol 2020 03 17;55(3):631-637. Epub 2020 Jan 17.

SCT Unit- Paediatric Haematology, Oncology Department, IRCCS Istituto Giannina Gaslini, Genova, Italy.

Background: The onset of bronchiolitis obliterans (BO) as a pulmonary manifestation of chronic graft vs host disease dramatically changes the prognosis of children undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to evaluate the overall survival (OS) of children with BO treated with imatinib mesylate (IM).

Methods: This study included children who underwent allo-HSCTs between January 2000 and December 2016.

Results: Among 345 patients who underwent HSCTs, 293 were evaluable for BO and 26 (8.9%) developed BO. The cumulative incidence of BO was 4.8% (95% confidence interval [CI], 2.8-7.5) at 1 year and 7.7% (95% CI, 5.1-11.1) at 3 years after transplantation. In the group of HSCTs (n = 67) complicated by chronic GvHD (c-GVHD), the incidence rate of BO was 38.8%. In total, 96.1% of patients with BO had c-GvHD worse than moderate grade, which was present in 70.7% of patients without BO (P = .011). The mortality rates were 46.1% in the BO group and 27.4% in the group without BO. Half of the patients with BO (n = 13) received IM, and the overall response rate was 76.9%. Four years after HSCT, OS was 42.6% (95% CI, 18.2-65.3) in the group without IM and 83.3% (95% CI, 27.3-97.5) in the group with IM.

Conclusions: BO after HSCT in the pediatric population has a high incidence and mortality rate. In terms of overall response and tolerability, this study showed relevant improvements in the prognosis of children with BO after the introduction of IM. Further prospective studies among children are needed to confirm these results.
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http://dx.doi.org/10.1002/ppul.24652DOI Listing
March 2020

Failures of once-a-week trimethoprim-sulfamethoxazole prophylaxis in children undergoing allogeneic hematopoietic stem cell transplant.

Transpl Infect Dis 2020 Feb 27;22(1):e13231. Epub 2019 Dec 27.

Istituto Giannina Gaslini, Ospedale Pediatrico IRCCS, Genova, Italy.

Once-a-week cotrimoxazole is an effective prophylaxis for pneumocystosis during antineoplastic chemotherapy or autologous stem cell transplant. Following allogeneic stem cell transplant, this schedule is at risk of pneumocystosis or neurotoxoplasmosis, as demonstrated by these case reports. Therefore, a 3-times-a-week schedule must be adopted in these patients.
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http://dx.doi.org/10.1111/tid.13231DOI Listing
February 2020

Central nervous system disorders after hematopoietic stem cell transplantation: a prospective study of the Infectious Diseases Working Party of EBMT.

J Neurol 2020 Feb 29;267(2):430-439. Epub 2019 Oct 29.

Department of Pediatric Hematology and Oncology, Collegium Medicum UMK, Bydgoszcz, Poland.

We performed a prospective study to evaluate the types and characteristics of central nervous system (CNS) disorders in patients after hematopoietic stem cell transplantation. The study included 163 episodes of CNS disorders of which 58 (36%) were infections. Proven or probable infections were documented in 34 patients and included fungi (n = 10, 29%), viruses (n = 12, 35%), Toxoplasma spp. (n = 9, 27%) and bacteria (n = 3, 9%). Non-infectious neurological disorders (n = 105, 64%) frequently encompassed metabolic/drug-induced abnormalities (n = 28, 27%) or cerebral vascular events (n = 22, 21%). Median onset times were later for infectious (day + 101) vs non-infectious neurological disorders (day + 50, p = 0.009). An unremarkable cranial CT scan was found in 33% of infection episodes. Absence of cerebrospinal fluid pleocytosis despite a normal or increased peripheral blood white blood cell count occurred in 26% of infections. Day-30 mortality rates were significantly higher for fungal (87%) vs non-fungal infections (40%, p < 0.001). Significantly higher mortality rates were also documented for cerebral vascular events than for other non-infectious disorders (86% vs 34%, p < 0.001). Our prospective study shows that diagnostic findings in CNS infections might differ between hematopoietic stem cell transplant recipients and immunocompetent hosts. Special awareness and timely initiation of adequate diagnostics are crucial to improve the prognosis of these patients.
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http://dx.doi.org/10.1007/s00415-019-09578-5DOI Listing
February 2020

Pneumocystis jirovecii pneumonia prophylaxis in hematopoietic stem cell transplantation, is it acceptable to wait for the engraftment for restarting it?

Transpl Infect Dis 2019 10 21;21(5):e13155. Epub 2019 Aug 21.

IRCCS Istituto Giannina Gaslini, Children's Hospital Genoa, Genoa, Italy.

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http://dx.doi.org/10.1111/tid.13155DOI Listing
October 2019
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