Publications by authors named "Luisa Sisinni"

21 Publications

  • Page 1 of 1

Ruxolitinib for steroid-refractory graft versus host disease in pediatric HSCT: high response rate and manageable toxicity.

Pediatr Hematol Oncol 2021 Mar 4:1-16. Epub 2021 Mar 4.

Translational Research in Pediatric Oncology, Hematopoietic Transplantation & Cell Therapy, Hospital La Paz Institute for Health Research (INGEMM-IdiPAZ), Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.

Ruxolitinib, a selective Janus Kinase (JAK) 1/2 inhibitor, is a promising treatment for the steroid-refractory graft-vs-host disease (GvHD) after hematopoietic stem cell transplantation (HSCT). Most studies have been performed in the adult population showing efficacy against GvHD. In this retrospective study, we evaluated the outcomes of 19 children who received ruxolitinib for refractory acute or chronic GvHD (cGvHD) after HSCT from two Pediatric Hemato-Oncology Departments in Spain between March 2017 and December 2018. Patients received a median number of 4 (IQR 2) previous lines of treatment before starting ruxolitinib. The overall response rate in acute GvHD (aGvHD) and cGvHD was 87% and 91%, respectively. Complete response (CR) was observed in 37% of aGvHD and 8.3% of cGvHD. Remarkably, 43% and 40% of patients with steroid-refractory gastrointestinal aGvHD and lung cGvHD achieved CR. During ruxolitinib treatment, there were 36%, 31%, and 10% infections caused by viruses, bacteria, and fungi, respectively. Overall, four patients interrupted ruxolitinib due to infectious complications, hematological, and liver toxicity. The 2-year overall survival was 71.9% (CI 95% 58.6-85.2). Our experience supports the use of ruxolitinib as an effective treatment for steroid-refractory acute and cGvHD in children with a moderate toxicity profile.
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http://dx.doi.org/10.1080/08880018.2020.1868637DOI Listing
March 2021

Phase 2 Clinical Trial of Infusing Haploidentical K562-mb15-41BBL-Activated and Expanded Natural Killer Cells as Consolidation Therapy for Pediatric Acute Myeloblastic Leukemia.

Clin Lymphoma Myeloma Leuk 2021 Jan 25. Epub 2021 Jan 25.

Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain; Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Madrid, Spain; Pediatric Onco-Hematology Department, La Paz University Hospital, Madrid, Spain; Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain. Electronic address:

Background: Acute myeloid leukemia (AML) accounts for approximately 20% of pediatric leukemia cases; 30% of these patients experience relapse. The antileukemia properties of natural killer (NK) cells and their safety profile have been reported in AML therapy. We proposed a phase 2, open, prospective, multicenter, nonrandomized clinical trial for the adoptive infusion of haploidentical K562-mb15-41BBL-activated and expanded NK (NKAE) cells as a consolidation strategy for children with favorable and intermediate risk AML in first complete remission after chemotherapy (NCT02763475).

Patients And Methods: Before the NKAE cell infusion, patients underwent a lymphodepleting regimen. After the NKAE cell infusion, patients were administered low doses (1 × 10/IU/m) of subcutaneous interleukin-2. The primary study endpoint was AML relapse-free survival. We needed to include 35 patients to demonstrate a 50% reduction in relapses.

Results: Seven patients (median age, 7.4 years; range, 0.78-15.98 years) were administered 13 infusions of NKAE cells, with a median of 36.44 × 10 cells/kg (range, 6.92 × 10 to 193.2 × 10 cells/kg). We observed chimerism in 4 patients (median chimerism, 0.065%; range, 0.05-0.27%). After a median follow-up of 33 months, the disease of 6 patients (85.7%) remained in complete remission. The 3-year overall survival was 83.3% (95% confidence interval, 68.1-98.5), and the cumulative 3-year relapse rate was 28.6% (95% confidence interval, 11.5-45.7). The study was terminated early because of low patient recruitment.

Conclusion: This study emphasizes the difficulties in recruiting patients for cell therapy trials, though NKAE cell infusion is safe and feasible. However, we cannot draw any conclusions regarding efficacy because of the small number of included patients and insufficient biological markers.
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http://dx.doi.org/10.1016/j.clml.2021.01.013DOI Listing
January 2021

Failure of Viral-Specific T Cells Administered in Pre-transplant Settings in Children with Inborn Errors of Immunity.

J Clin Immunol 2021 Jan 18. Epub 2021 Jan 18.

Paediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain.

Purpose: Use of adoptive immunotherapy with virus-specific T cells (VST) in patients with inborn errors of immunity prior to hematopoietic stem cell transplantation (HSCT) has been reported in few patients. We report our experience, reviewing all the cases previously reported.

Methods: We report four children with inborn errors of immunity who received VST infusion in a pre-HSCT setting in two reference centers in Spain and review all inborn errors of immunity cases previously reported.

Results: Taking into account our four cases, nine children have been reported to receive VST prior to HSCT to date: 3 severe combined immunodeficiency, 2 CTPS1 deficiency, 1 dyskeratosis congenital, 1 ORAI1 deficiency, 1 Rothmund-Thomson syndrome, and 1 combined immunodeficiency without confirmed genetic defect. In four patients, immunotherapy resulted in clinical improvement, allowing to proceed to HSCT. In these cases, the infusion was started closely to viral diagnosis [mean time 28 days (IQR; 17-52 days)], and the VST was followed shortly thereafter by HSCT [mean time 28 days (IQR; 10-99 days)]. Viremia was controlled after HSCT in two cases (performed 7 and 36 days after the infusion). Multiple infusions were required in many cases. Five out of nine patients died before receiving HSCT. These patients presented with a prolonged and uncontrolled infection before VST administration [mean time from viral diagnosis to VST infusion was 176 days (IQR; 54-1687)].

Conclusions: In patients with inborn errors of immunity, the efficacy of VST for treating disseminated viral infections in pre-transplant settings seems to have a limited efficacy. However, this therapy could be used in a pre-emptive setting before severe viral disease occurs or closely to HSCT.
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http://dx.doi.org/10.1007/s10875-020-00961-wDOI Listing
January 2021

Haploidentical transplantation in pediatric non-malignant diseases: A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation (GETH).

Eur J Haematol 2021 Feb 17;106(2):196-204. Epub 2020 Nov 17.

La Paz University Hospital, Madrid, Spain.

Objective: Describe the GETH haploidentical stem cell transplantation (haplo-HSCT) activity in non-malignant disease (NMDs).

Methods: We retrospectively analyzed data from children with NMDs who underwent haplo-HSCT.

Results: From January 2001 to December 2016, 26 pediatric patients underwent 31 haplo-HSCT through ex vivo T cell-depleted (TCD) graft platforms or post-transplantation cyclophosphamide (PT-Cy) at 7 Spanish centers. Five cases employed unmanipulated PT-Cy haplo-HSCT, 16 employed highly purified CD34 cells, and 10 employed ex vivo TCD grafts manipulated either with CD3 CD19 depletion, TCRαβ CD19 selection or naive CD45RA T-cell depletion. Peripheral blood stem cells were the sole source for patients following TCD haplo-HSCT, and bone marrow was the source for one PT-Cy haplo-HSCT. The most common indications for transplantation were primary immunodeficiency disorders (PIDs), severe aplastic anemia, osteopetrosis, and thalassemia. The 1-year cumulative incidence of graft failure was 27.4%. The 1-year III-IV acute graft-versus-host disease (GvHD) and 1-year chronic GvHD rates were 34.6% and 16.7%, respectively. The 2-year overall survival was 44.9% for PIDs, and the 2-year graft-versus-host disease-free and relapse-free survival rate was 37.6% for the other NMDs. The transplantation-related mortality at day 100 was 30.8%.

Conclusion: Although these results are discouraging, improvements will come if procedures are centralized in centers of expertise.
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http://dx.doi.org/10.1111/ejh.13536DOI Listing
February 2021

Risk factors and outcome of COVID-19 in patients with hematological malignancies.

Exp Hematol Oncol 2020 25;9:21. Epub 2020 Aug 25.

Hematology División, Institut Català Oncologia-Hospital Duran i Reynals, Barcelona, Spain.

Background: Prognostic factors of poor outcome in patients with hematological malignancies and COVID-19 are poorly defined.

Patients And Methods: This was a Spanish transplant group and cell therapy (GETH) multicenter retrospective observational study, which included a large cohort of blood cancer patients with laboratory-confirmed SARS-CoV-2 infection through PCR assays from March 1st 2020 to May 15th 2020.

Results: We included 367 pediatric and adult patients with hematological malignancies, including recipients of autologous (ASCT) (n = 58) or allogeneic stem cell transplantation (allo-SCT) (n = 65) from 41 hospitals in Spain. Median age of patients was 64 years (range 1-93.8). Recipients of ASCT and allo-SCT showed lower mortality rates (17% and 18%, respectively) compared to non-SCT patients (31%) (p = 0.02). Prognostic factors identified for day 45 overall mortality (OM) by logistic regression multivariate analysis included age > 70 years [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.2-3.8, p = 0.011]; uncontrolled hematological malignancy (OR 2.9, 95% CI 1.6-5.2, p < 0.0001); ECOG 3-4 (OR, 2.56, 95% CI 1.4-4.7, p = 0.003); neutropenia (< 0.5 × 10/L) (OR 2.8, 95% CI 1.3-6.1, p = 0.01); and a C-reactive protein (CRP) > 20 mg/dL (OR 3.3, 95% CI 1.7-6.4, p < 0.0001). In multivariate analysis of 216 patients with very severe COVID-19, treatment with azithromycin or low dose corticosteroids was associated with lower OM (OR 0.42, 95% CI 0.2-0.89 and OR 0.31, 95% CI 0.11-0.87, respectively, p = 0.02) whereas the use of hidroxycloroquine did not show significant improvement in OM (OR 0.64, 95% CI 0.37-1.1, P = 0.1).

Conclusions: In most patients with hematological malignancies COVID-19 mortality was directly driven by older age, disease status, performance status, as well as by immune (neutropenia) parameters and level of inflammation (high CRP). Use of azithromycin and low dose corticosteroids may be of value in very severe COVID-19.
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http://dx.doi.org/10.1186/s40164-020-00177-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445734PMC
August 2020

A case-control study to assess the role of polyomavirus in transplant complications: Where do we stand?

Transpl Infect Dis 2020 Dec 2;22(6):e13432. Epub 2020 Sep 2.

Clinical Pharmacology Department, IdiPaz, School of Medicine, La Paz-Cantoblanco-Carlos III University Hospital, Autonomous University of Madrid, Madrid, Spain.

Purpose: The study's aim was to assess whether polyomavirus DNAemia screening was associated with different outcomes in patients with positive viremia compared with negative viremia.

Methods: Case-control retrospective study of patients with polyomavirus DNAemia (viremia > 1000 copies/mL) matched 1:1 with controls. Control group consists of the patient who received a transplant immediately before or after each identified case and did have nil viremia.

Finding: Ultimately, 120 cases of BK polyomavirus (BKPyV) were detected and matched with 130 controls. Of these, 54 were adult kidney transplant recipients (KTRs), 43 were pediatric KTRs, and 23 were undergoing hemato-oncologic therapy, of which 20 were undergoing hematopoietic stem cell transplantation. The odds ratio (OR) for overall risk of poorer outcomes in cases versus controls was 16.07 (95% CI: 5.55-46.54). The unfavorable outcome of switching the immunosuppressive drug (ISD) (14/40,35%) was no different from that of those treated with reduced ISD doses (31/71, 43.6%, P = .250). Acute rejection or graft-versus-host disease, previous transplant, and intensity of immunosuppression (4 ISDs plus induction or conditioning) were risk factors for BKPyV-DNAemia (OR: 13.96, 95% CI: 11.25-15.18, P < .001; OR: 6.14, 95% CI: 3.91-8.80, P < .001; OR: 5.53, 95% CI: 3.37-7.30, P < .001, respectively).

Conclusions: Despite viremia screening, dose reduction, and change in therapeutic protocol, patients with positive BKPyV-DNAemia present poorer outcomes and unfavorable results.
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http://dx.doi.org/10.1111/tid.13432DOI Listing
December 2020

Blinatumomab and inotuzumab for B cell precursor acute lymphoblastic leukaemia in children: a retrospective study from the Leukemia Working Group of the Spanish Society of Pediatric Hematology and Oncology (SEHOP).

Br J Haematol 2020 09 21;190(5):764-771. Epub 2020 Apr 21.

Pediatric Oncology, Haematology and Stem Cell Transplantation Department, Hospital Niño Jesús, Madrid, Spain.

Blinatumomab and inotuzumab ozogamycin represent promising alternatives to conventional chemotherapy in acute lymphoblastic leukaemia (ALL). We analysed data from 29 children with ALL treated under compassionate use with blinatumomab, inotuzumab or both. The complete remission (CR) rate in a heavily pretreated population with overt relapse was 47·6%. At earlier stages (first/second CR), both antibodies represented a useful tool to reduce minimal residual disease, and/or avoid further toxic chemotherapy until stem cell transplantation. Six patients developed grade 3 reversible non-haematological toxicity. The 12-month overall survival and event-free survival rates were 50·8 ± 26·4% and 38·9 ± 25·3% with blinatumomab, 45·8 ± 26% and 27·5 ± 25% with inotuzumab.
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http://dx.doi.org/10.1111/bjh.16647DOI Listing
September 2020

Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Bone Marrow Transplant 2020 06 6;55(6):1126-1136. Epub 2020 Feb 6.

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University, Frankfurt am Main, Germany.

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.
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http://dx.doi.org/10.1038/s41409-020-0818-4DOI Listing
June 2020

Study protocol for a phase II, multicentre, prospective, non-randomised clinical trial to assess the safety and efficacy of infusing allogeneic activated and expanded natural killer cells as consolidation therapy for paediatric acute myeloblastic leukaemia.

BMJ Open 2020 01 8;10(1):e029642. Epub 2020 Jan 8.

Translational Research Unit in Paediatric Haemato-Oncology, Hematopoietic Stem Cell Transplantation and Cell Therapy, Hospital Universitario La Paz, Madrid, Spain

Introduction: Acute myeloblastic leukaemia (AML) constitutes the second most common haematological malignancy in the paediatric population. Current treatment regimens are based on the administration of polychemotherapy, combining high doses of cytarabine with anthracyclines and topoisomerase inhibitors. Allogeneic haematopoietic stem cell transplantation (HSCT) is an option for high-risk patients with AML (and for intermediate-risk patients if a sibling donor is available). With this strategy, AML survival has increased substantially; however, it has remained stagnant at approximately 60%, with relapse being the principal culprit. The predominant role of the immune system and natural killer (NK) cells in controlling paediatric AML has gained importance within the context of HSCT. In this protocol, we propose incorporating this cell therapy as an adjuvant treatment through the infusion of activated and expanded haploidentical NK (NKAE) cells in paediatric patients with AML who are in cytological remission after completing consolidation therapy, and with no indication for HSCT.

Methods And Analysis: Patients up to 30 years of age, diagnosed with AML, in their first cytological remission, who have completed both the induction and the consolidation phases of chemotherapy and do not meet the criteria for allogeneic HSCT are eligible. The patients will receive two doses of NKAE cells once a week, using a GMP K562-mbIL15-41BBL stimulus from a haploidentical donor and interleukin 2 subcutaneously. The patients will then be followed up for 36 months to assess the primary endpoint, which is the probability of relapse after NK cell infusion.

Ethics And Dissemination: This clinical trial was approved by the Clinical Research Ethics Committee of La Paz University Hospital and The Spanish Agency of Medicines and Medical Devices. Findings will be disseminated through peer-reviewed publications, conference presentations and community reporting.

Trial Registration Number: EudraCT code: 2015-001901-15, ClinicalTrials.gov Identifier: NCT02763475.
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http://dx.doi.org/10.1136/bmjopen-2019-029642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955478PMC
January 2020

Haploidentical transplantation in high-risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH).

Am J Hematol 2020 01 5;95(1):28-37. Epub 2019 Nov 5.

Pediatric Hemato-Oncology, Hospital Niño Jesus, Madrid, Spain.

A total of 192 pediatric patients, median age 8.6 years, with high-risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PT-Cy), or ex vivo T cell-depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT-Cy for graft-vs-host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3-depleted peripheral blood stem cells (PBSCs) by either CD34 selection, CD3 CD19 depletion, TCRαβ CD19 depletion or CD45RA depletion, added to CD34 selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo-HSCT; bone marrow was the source in 9 of 41 patients following PT-CY haplo-HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer-cell immunoglobulin-like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease-free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo-HSCT were effective and could be utilized depending on the comfort level of the center.
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http://dx.doi.org/10.1002/ajh.25661DOI Listing
January 2020

Author Correction: Donor lymphocyte infusions for B-cell malignancies relapse after T-cell replete allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2019 Jul;54(7):1176

Hematology Department, Hospital Universitari Vall d´Hebron, Departament de Medicina, Universitat Autonoma de Barcelona, Barcelona, Spain.

In the original version of this article, author 'Lucia López-Corral' was incorrectly listed as 'Lucia López'. This has now been corrected in both the PDF and HTML versions of the article to 'Lucia López-Corral'.
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http://dx.doi.org/10.1038/s41409-019-0471-yDOI Listing
July 2019

[Subsequent malignancies after long-term follow-up of pediatric hematopoietic stem cell transplantation].

An Pediatr (Barc) 2019 Mar 5;90(3):157-164. Epub 2018 Sep 5.

Pediatric Hematology, Oncology and HSCT Unit, Santa Creu i Sant Pau University Hospital, Barcelona, España.

Introduction: Survival after hematopoietic stem cell transplantation has improved dramatically in recent years. Unfortunately, there is an increased risk of subsequent malignant neoplasms (SMN) in this population and this represents a significant cause of late mortality.

Patients And Methods: In this study, we analyzed the incidence of SMN and the associated risk factors in patients referred at a pediatric age for hematopoietic stem cell transplantation (allogeneic or autologous) in our center.

Results: We observed 19 cases of SMN in a cohort of 371 patients, with a cumulative incidence of 6, 12, and 36% at 15, 20, and 30 years of follow-up, respectively. The solid tumors were the most prevalent malignancies. The risk was significantly higher than expected in the general population for each tumor type and in the different age ranges (p<.0001). Radiotherapy and chronic GvHD were the main risk factors for the development of SMN in our series.

Conclusions: We observed a high incidence of SMN among hematopoietic stem cell transplantation survivors highlighting the need for life-long surveillance.
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http://dx.doi.org/10.1016/j.anpedi.2018.05.023DOI Listing
March 2019

Haematopoietic stem cell transplantation for mucopolysaccharidosis type VII: A case report.

Pediatr Transplant 2018 11 9;22(7):e13278. Epub 2018 Aug 9.

Pediatric Hematology, Oncology and HSCT Unit, Hospital Santa Creu i Sant Pau, Barcelona, Spain.

Mucopolysaccharidosis type VII (MPS VII) is an inherited disease characterized by the cellular accumulation of undegraded GAGs due to the deficiency of the lysosomal enzyme β-glucuronidase. We describe a case of a 2-year-old female affected by a moderate form of MPS VII and submitted twice to HSCT with the aim of stabilizing skeletal problems and preventing neurocognitive alterations. The child underwent a second transplantation due to the rejection of the graft after a reduced-intensity conditioning in the first transplant. A myeloablative regimen allowed to achieve a stable full donor engraftment and normal enzyme levels during the 6 years of follow-up. Clinically, we observed stabilization of skeletal deformities and normal neurocognitive development. This is one of the few reports of mucopolysaccharidosis type VII treated with allogeneic HSCT.
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http://dx.doi.org/10.1111/petr.13278DOI Listing
November 2018

High Incidence of Early Human Herpesvirus-6 Infection in Children Undergoing Haploidentical Manipulated Stem Cell Transplantation for Hematologic Malignancies.

Biol Blood Marrow Transplant 2018 12 29;24(12):2549-2557. Epub 2018 Jul 29.

Pediatric Hematology-Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Human herpesvirus-6 (HHV-6) infection is increasingly recognized among allogeneic hematopoietic stem cell transplantation (HSCT) recipients, with 30% at risk of reactivation in the haploidentical setting. It has been associated with encephalitis, acute graft-versus-host disease, and graft failure. Here we report 2 cohorts of pediatric haploidentical manipulated HSCT in which, despite many differences, HHV-6 reactivation and disease occurred with very high incidence compared with data reported in the literature and represented the main early post-transplant infectious complication compared with other viral, bacterial, or fungal infections. The 2 cohorts were recruited at the pediatric transplant centers of Perugia (n = 13), Barcelona (n = 10), and Madrid (n = 15). All patients received myeloablative conditioning regimens and 2 different types of ex vivo graft manipulation: CD34 selection and regulatory T cell/conventional T cell infusion in 13 patients and CD45RA T cell depletion in 25 patients. Antiviral prophylaxis was acyclovir in 33 and foscarnet in 5 patients. HHV-6 DNAemia was checked by quantitative or qualitative PCR. In vitro experiments demonstrated that donor CD4 T cells are the reservoir of HHV-6 and suggested a role of the graft composition in both transplant settings (rich in CD4 T cells) in the high rate of HHV-6 infections. All patients presented very early HHV-6 DNAemia after transplantation, and although viremic, 9 patients (24%) developed symptomatic limbic encephalitis. All patients responded to antiviral treatment, and none died of infection, although 2 experienced long-term neurologic sequelae (22%). Moreover, 6 patients presented organ involvement in absence of other causes: 1 hepatitis, 1 pneumonia, 2 gastroenteritis, and 2 multiorgan involvement(1 encephalitis, pneumonia, and gastritis; 1 pneumonia and enteritis). Incidences of other viral, bacterial, and fungal diseases were lower in both cohorts. In vitro, HHV-6 was found to infect only CD4 fraction of the graft. Co-culturing CD4 T cells with CD56 natural killer (NK) cells eliminated the virus, demonstrating the main role of NK cells in the antiviral immune response. All 38 pediatric patients undergoing these manipulated haploidentical HSCTs showed HHV-6 reactivation, and 14 of 38 developed HHV-6 disease with similar features in terms of timing, morbidity, response to treatment, and outcome. The graft composition in both transplant platforms, rich in CD4 T cells and poor in NK cells, seems to play a key role. HHV-6 DNAemia surveillance was useful to diagnose and treat preemptively HHV-6 infection.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.033DOI Listing
December 2018

Unexpected High Incidence of Human Herpesvirus-6 Encephalitis after Naive T Cell-Depleted Graft of Haploidentical Stem Cell Transplantation in Pediatric Patients.

Biol Blood Marrow Transplant 2018 11 19;24(11):2316-2323. Epub 2018 Jul 19.

Pediatric Hemato-Oncology, La Paz University Hospital, Madrid, Spain.

The CD45RA T cell depletion (TCD) method has been used to deplete naive T cells, preventing graft-versus-host disease (GVHD) but preserving memory cells, providing immediate functional T cells with anti-infection, antileukemia, and antirejection effects. We describe a series of 25 consecutive high-risk patients with leukemia who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with CD45RA TCD. Each patient received 2 cell products: 1 created by CD34 positive selection and the other through CD45RA depletion from the CD34 negative fraction by a CliniMACS device. CD45RA-depleted haplo-HSCT was well tolerated, with rapid engraftment and low risk of severe acute GVHD and chronic GVHD. Although this treatment achieved a good control of viral reactivations, such as cytomegalovirus and adenovirus, we observed an unexpectedly high rate of limbic encephalitis due to human herpesvirus-6 (HHV-6; 8 cases). Characteristically, the infection appeared early in almost all patients, just after the engraftment. Although no patient died from encephalitis, 1 patient showed neuropsychological sequelae, and another experienced secondary graft failure just after the HHV-6 reactivation.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.016DOI Listing
November 2018

Analysis of relapse after transplantation in acute leukemia: A comparative on second allogeneic hematopoietic cell transplantation and donor lymphocyte infusions.

Exp Hematol 2018 06 8;62:24-32. Epub 2018 Mar 8.

Hematology Department, Hospital Universitario Vall d'Hebron (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain.

Relapse of acute leukemia (AL) after allogeneic hematopoietic cell transplantation (Allo-HCT) entails a dismal prognosis. In this scenario, donor lymphocyte infusions (DLIs) and second Allo-HCT are two major approaches. We compared outcomes of AL patients treated for relapse with DLI or second Allo-HCT after receiving debulking therapy. In total, 46 patients were included in the study; 30 (65%) had acute myeloid leukemia and 16 (35%) had acute lymphoblastic leukemia. The median age was 38 years (range 4-66). Twenty-seven patients received a second Allo-HCT and 19 patients received DLI. The median follow-up of the cohort was 273 days (range 9-7013). Overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and cumulative incidence (CI) of relapse were calculated from DLI or second Allo-HCT date. In univariate analysis, second Allo-HCT was associated with higher OS (p = 0.021) and a trend to higher DFS (p = 0.097) and CI of relapse (p = 0.094) on univariate analysis. However, multivariate analysis showed comparable outcomes between DLI and second Allo-HCT, with the time interval to relapse before DLI or second Allo-HCT the only statistically significant factor with an impact on OS and DFS. Within the DLI cohort, T-cell-depleted Allo-HCT was associated with higher OS (p = 0.003) and DFS (p < 0.001) and lower CI of relapse (p = 0.002) than T-cell-replete Allo-HCT. Overall, in this cohort of AL patients, second Allo-HCT and DLI associated similar outcomes. As in other relapse studies, the length of remission (time to relapse) was identified as a factor with statistical impact on survival. Further studies are warranted.
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http://dx.doi.org/10.1016/j.exphem.2018.03.002DOI Listing
June 2018

[Reduced-intensity conditioning haematopoietic stem cell transplantation in genetic diseases: Experience of the Spanish Working Group for Bone Marrow Transplantation in Children].

An Pediatr (Barc) 2018 Apr 8;88(4):196-203. Epub 2017 Jul 8.

Unidad Pediátrica de Trasplante Hematopoyético, Hospital Santa Creu i Sant Pau, Universidad Autónoma, Barcelona, España.

Introduction: Haematopoietic stem cell transplantation (HSCT) involves implanting cellular elements capable of generating a new and healthy haematopoietic system. Reduced intensity conditioning (RIC) consists of an immunosuppressive treatment to facilitate a progressive implant with lower morbidity. This type of conditioning can also lead to myelosuppression, which is potentially reversible over time. Reduced intensity conditioning enables HSCT to be performed on patients with genetic diseases for whom added comorbidity is undesirable due to the high doses of chemotherapy that accompanies conventional myeloablative regimens.

Patients And Methods: An analysis was performed on the outcomes of 68 paediatric patients with genetic diseases who underwent HSCT with RIC between 2005 and 2013 in the of Paediatric Haematopoietic Stem Cell Transplantation Units that are part of the Spanish Working Group for Bone Marrow Transplantation in Children. A multicentre study was conducted including 68 patients, of whom 43 had Primary Immunodeficiency, 21 with congenital haematological diseases, and 4 with metabolic diseases.

Results: Fifty (73.5%) of the 68 patients were still alive. The Overall Survival (OS) at nine years was 0.74. Twenty-three (33.8%) had some event during the course of the HSCT, with an event-free survival rate of 0.66. The OS in patients with haematological diseases was 0.81, being 0.7 in primary immunodeficiencies, and 0.4 in metabolic diseases. No significant difference was observed between the 3 groups of diseases. As regards the source of haematopoietic progenitors, there was an OS rate of 0.74 in patients transplanted with peripheral blood, 0.70 with bone marrow, and 0.70 and with cord blood, with no statistically significant differences.

Conclusions: Favourable results have been obtained in HSCT with reduced intensity conditioning in genetic diseases. It should be noted that the risks and benefits of the RIC in patients with metabolic diseases need to be assessed on an individual basis.
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http://dx.doi.org/10.1016/j.anpedi.2017.02.015DOI Listing
April 2018

Vesical Artery Embolization in Haemorrhagic Cystitis in Children.

Cardiovasc Intervent Radiol 2016 Jul 5;39(7):1066-9. Epub 2016 Feb 5.

Hospital Clinic, Villarroel Street, 170, 08036, Barcelona, Spain.

Haemorrhagic cystitis is an uncommon and, in its severe form, potentially life-threatening complication of haematopoietic stem cell transplantation or cancer therapy in children. The severe form involves macroscopic haematuria with blood clots, urinary obstruction and/or renal impairment. There are many therapeutic options to treat acute haemorrhage, but only recombinant factor VII has a high level of clinical evidence in children. Supraselective vesical artery embolization (SVAE) is an increasingly used therapeutic procedure for controlling haemorrhage in adults, but is less commonly used in children. This might be due to several factors, such as the invasive nature of the procedure, lack of appropriate medical experience and possible long-term side effects. We present three cases of children successfully treated by means of effective SVAE.
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http://dx.doi.org/10.1007/s00270-016-1300-yDOI Listing
July 2016