Cell Transplantation In Children Research Articles

Stable to improved cardiac and pulmonary function in children with high-risk sickle cell disease following haploidentical stem cell transplantation.

Children with sickle cell disease (SCD) are at high-risk of progressive, chronic pulmonary and cardiac dysfunction. In this prospective multicenter Phase II trial of myeloimmunoablative conditioning followed by haploidentical stem cell transplantation in children with high-risk SCD, 19 patients, 2.0-21.0 years of age, were enrolled with one or more of the following: history of (1) overt stroke; (2) silent stroke; (3) elevated transcranial Doppler velocity; (4) multiple vaso-occlusive crises; and/or (5) two or more acute chest syndromes and received haploidentical transplants from 18 parental donors. Cardiac and pulmonary centralized cores were established. Pulmonary function results were expressed as percent of the median of healthy reference cohorts, matched for age, sex, height and race. At 2 years, pulmonary functions including forced expiratory volume (FEV), FEV1/ forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity of lung for carbon monoxide (DLCO) were stable to improved compared to baseline values. Importantly, specific airway conductance was significantly improved at 2 years (p < 0.004). Left ventricular systolic function (fractional shortening) and tricuspid regurgitant velocity were stable at 2 years. These results demonstrate that haploidentical stem cell transplantation can stabilize or improve cardiopulmonary function in patients with SCD.

The Effects of Conditioning Regimen on Thyroid Function After Hematopoietic Stem Cell Transplantation in Children: 2-Year Short Term Follow Up

Background: Long term effect of conditioning regimen such as Total body irradiation (TBI) and chemotherapy has been studied. However short term effect of conditioning regimen on endocrinologic system was not well known. Purpose. Our study aimed to evaluate the effect of conditioning regimen on thyroid function in children who had HSCT after 2 years. Methods:. Date was obtained from retrospective review of medical records who treated malignant hematologic disease and transplanted hematopoietic stem cell in Seoul St. Mary’s hospital from January 1, 2010 to August 31, 2018. Among 563 patients who underwent HSCT for about 9 years, we studied 150 patients who conforming to inclusion criteria of this study. Thyroid function was tested before HSCT and follow 12 and 24 months. Anthropometric date, duration of chemotherapy, history of relapse, graft versus host disease (GVHD) were also analyzed. Results: In patient’s characteristics, median age at HSCT was 10.49 (0.89 - 19.29) years. Out of 150 patients, male was 92 and female was 58. Acute lymphoid leukemia (ALL) was 74, acute myeloid leukemia (AML) was 76. Among them, busulfan based conditioning was done in 53 patients, TBI based conditioning regimen used in 72 and 25 patients had done TBI with busulfan based conditioning regimen. Fifteen patients (12.5%) had thyroid dysfunction after 2 years of HSCT (4 euthyroid sick syndrome, 11 subclinical hypothyroidism and 1 high T4 syndrome). Incidence of thyroid dysfunction by conditioning regimen was different at 2 years after HSCT, higher in TBI with busulfan based group (p = 0.033). In univariate regression analysis, using conditioning regimen, by TBI with busulfan was risk factor of thyroid dysfunction at 2 years after HSCT. Conclusions: TBI with busulfan based group showed higher incidence of thyroid dysfunction and conditioning regimen was risk factor of thyroid dysfunction at 2 years after HSCT.

Defibrotide in preventing veno-occlusive disease after hematopoietic stem cell transplantation in children with osteopetrosis

Defibrotide in preventing veno-occlusive disease after hematopoietic stem cell transplantation in children with osteopetrosis

Allogeneic hematopoietic stem cell transplantation in children with lymphoblastic lymphoma

Lymphoblastic lymphoma (LBL) in children is curable in most cases, but there is still a significant proportion of patients in whom standard therapy is ineffective. Thus, patients develop a relapse or a primary refractory disease in about 10% of cases (R/R). In this case, the main treatment method is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The choice in favor of transplantation is predominantly based on the experience in adult patients. A small number of pediatric patients accounts for the limited data in pediatrics. The prognosis of these patients is always extremely poor. It has been shown that the survival of patients after allo-HSCT is higher only if remission is achieved prior to the transplantation. In order to provide more evidence in support of allo-HSCT, randomized clinical trials are needed. However, such studies in the field of allo-HSCT are quite difficult to conduct, and this necessitates the search for alternative methods of evidence-based medicine in this area. Probably, the achievement of high survival rates could be considered a sufficient argument in favor of this method. This study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint-Petersburg State Medical University of the Ministry of Healthcare of Russia. In this work, we summarize the experience in allo-HSCT in children with R/R LBL obtained at the R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation, I.P. Pavlov First Saint-Petersburg State Medical University. This work is one of the few ones devoted exclusively to the role of alloHSCT in the treatment of pediatric R/R LBL. From 2006 to 2020, at the R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation, I.P. Pavlov First Saint-Petersburg State Medical University, allo-HSCT was performed in 13 children and adolescents with R/R LBL (2 patients underwent 2 transplantations). Repeated transplantations were performed due to progression and primary graft failure. The median number of prior lines of therapy was 2.5 (2–4). Remission prior to alloHSCT was observed in 7 cases. The graft sources were a fully HLA-matched related donor (n = 3), a fully HLA-matched unrelated donor (n = 4), and a haploidentical donor (n = 8). The following schedules were used as a conditioning regimen: fludarabine 150 mg/m2 + busulfan 8–14 mg/kg (n = 8), fludarabine 150 mg/m2 + melphalan 140 mg/m2 (n = 5), fludarabine 150 mg/m2 + treosulfan 30 mg/m2 (n = 2). In most cases, the prevention of “graft versus host” disease (GVHD) was based on post-transplant cyclophosphamide (n = 11). Cyclophosphamide alone was used in fully matched related transplantation (n = 2), in combination with tacrolimus and cellsept – in unrelated transplantation (n = 1), and in combination with sirolimus and tacrolimus – in haploidentical transplantation (n = 8). A combination of ATGAM, methotrexate and cyclosporin A was used three times in alloHSCT from an unrelated donor for the prevention of GVHD. In one allo-HSCT from a fully matched related donor, cyclosporin A alone was used for the prevention of GVHD. The graft sources were bone marrow (n = 9) and peripheral blood stem cells (n = 4). The median CD34+ cells/kg was 3.8 (1.1–10.0). At the median follow-up of 651 (106–3034) days, the 3-year event-free survival rate was 52% (95% CI: 25–74), the incidence of relapse/progression was 48% (95% CI: 26–76). Five out of thirteen patients died during the study period. The cause of death was the underlying disease in all cases. The cumulative incidence of acute and chronic GVHD was 28% (95% CI: 11–58%) and 24% (95% CI: 5–48), respectively. This work is one of the largest in terms of the number of transplanted children with R/R LBL. Our results are superior to those obtained in case of using only chemotherapy in comparison with the historical control and are comparable with the few previously published data on allo-HSCT in children. In this study, we included patients who underwent allo-HSCT. Among them, there were also children out of remission of LBL which implies that there was no selection of patients, and thus our study settings were close to the so-called real clinical settings. The drawbacks of this work include the following: the study was carried out at a single transplant center, there was no comparison group, the number of patients was low. Nevertheless, considering the complexity of conducting randomized trials in the field of allo-HSCT, the presented data serve as an important confirmation of the effectiveness of transplantation in R/R LBL.

Cyclosporine A-related neurotoxicity after haploidentical hematopoietic stem cell transplantation in children with hematopathy

BackgroundTo evaluate cyclosporine A (CSA)-related neurotoxicity after haploidentical hematopoietic stem cell transplantation (HID-HSCT) in children with hematopathy.MethodsThis retrospective case series study included children with hematopathy who underwent HID-HSCT at Fujian Medical University Union Hospital between February 2013 and January 2017.ResultsFifty-one children (39 males) were included in the study with a median age of 8 (range, 1.1–18) years. Seven patients (13.7%) developed CSA-related neurotoxicity after a median 38 (range, − 3 to 161) days from HID-HSCT. Hypertension (5/7, 71%) was the most common prodrome. Brain magnetic resonance imaging showed posterior reversible encephalopathy syndrome in six patients and atypical abnormalities in one patient. One patient died from grade IV graft-versus-host disease (GvHD) on day + 160, and six patients were alive at the last follow-up. Four patients (71.4%) achieved complete remission, while two patients developed secondary epilepsy and exhibited persistent MRI and electroencephalogram abnormalities at the 5-year follow-up. Hypertension after CSA was more common in patients with CSA-related neurotoxicity than in those without (71% vs. 11%, P = 0.002). Five-year overall survival did not differ significantly between patients with CSA-related neurotoxicity (85.7 ± 13.2%) and those without (65.8 ± 7.2%).ConclusionsThe incidence of CSA-related neurotoxicity in children with hematopathy undergoing HID-HSCT is relatively high.

Use of eltrombopag for the treatment of poor graft function after hematopoietic stem cell transplantation in children.

The main objective of this study was to determine whether Eltrombopag, a synthetic thrombopoietin receptor agonist, could improve peripheral blood counts in the three hematopoietic lineages and achieve transfusion independence in children with poor graft function (PGF) after allogenic hematopoietic stem cell transplantation (HSCT). Retrospective study of patients under 18years who developed PGF post-HSCT in a large tertiary institution between January 2013 and March 2019. Out of 198 allogeneic HSCT, five patients met PGF criteria and were treated with eltrombopag. Median time from HSCT to eltrombopag initiation was 120days. The median starting dose was 50mg/day and the maximum dose reached was 75mg/day. Median treatment duration was 9months. Three patients achieved complete response and one partial response. The median dose among responders was 75mg/day and the median time to response 8weeks. Responses were sustained in three patients and two required a booster dose of CD34+ -selected cells from the original donor. None of the patients had to stop treatment due to adverse effects. The use of eltrombopag in children with PGF achieved responses in 80% of cases and demonstrated to be an effective and safe therapeutic option in pediatric patients with PGF.

HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia

AbstractWe report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell–depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.

Is Busulfan Clearance Different in Patients With Sickle Cell Disease? Let's Clear Up That Case With Some Controls.

In busulfan-based conditioning regimen for hematopoietic stem cell transplantation in children, accurate a priori determination of the first dose is important because of its narrow therapeutic window. Sickle cell disease (SCD) influences pharmacokinetics of the commonly used drugs by affecting organs responsible for drug metabolism and elimination. This pharmacokinetics study assesses the influence of SCD on the metabolic pathway of busulfan that is mainly metabolized in the liver. In this retrospective cross-sectional case-control study, 16 patients with SCD were matched to 50 patients without SCD on known busulfan clearance's covariates (glutathione-S-transferase alpha1 polymorphisms, age, weight). Clearance of the first dose of busulfan was not significantly different independently of genetic or anthropometric factors in patients with or without SCD.

Metabolic syndrome and risk factors after hematopoietic stem cell transplantation in children and adolescents.

The early and late complications after hematopoietic stem cell transplantation (HSCT) determine the patients' prognosis and life quality. We aim to determine the metabolic syndrome development frequency after HSCT in children to find out the risk factors and compare them with healthy adolescents. Thirty-six children who underwent HSCT at least two years ago were analyzed prospectively and cross-sectionally. Our study included 18 healthy children between the ages of 11 and 17 as a control group. All of the cases were assessed in terms of metabolic syndrome (MS) through the use of Modified WHO Criteria. The patients' median age was 10.6 (5.1-17) years, the median time of follow-up after HCST was 4.1 (2-13.5) years and 70% were male. Two cases were diagnosed with MS (5.6%). When considered in terms of the sub-components of MS, 2 cases (5.6%) were found to have obesity, 17 cases (47%) abnormal glucose tolerance, 11 cases (30.7%) dyslipidemia, and 3 cases (8.6%) hypertension. The MS rate was not different when compared with the 11-17 year-old healthy control group (0 vs. 11%, p=0.48). Myeloablative conditioning regimen (65 vs. 20%) and the increased age at which HSCT was performed were considered to be risk factors in terms of insulin resistance (p=0.025 and 0.002). Age and conditioning regimens were found to be the risk factors for insulin resistance development. The long-term follow-up of the cases who had undergone HSCT in childhood in terms of MS and its sub-components is important in order to increase life quality.

Brentuximab Vedotin as Consolidation Therapy After Autologous Stem Cell Transplantation in Children and Adolescents (

We describe 6 pediatric patients (12 to 18 y) with relapsed or refractory Hodgkin lymphoma treated with consolidative Brentuximab vedotin (Bv) following reinduction chemotherapy and autologous stem cell transplantation. The progression-free survival after autologous stem cell transplantation was 12, 18, 22, 24, 30, and 30 months. Most patients tolerated Bv well although 2 patients developed grade 3 neuropathy that prevent them from completing the scheduled 16 doses of Bv. Consolidative Bv in children and adolescents, as currently recommended for adult patients with early relapsed or refractory Hodgkin lymphoma, is feasible but with some significant toxicities.

Eltrombopag for treatment of thrombocytopenia after allogeneic hematopoietic cell transplantation in children: Single-centre experience.

Delayed recovery of thrombocytopenia is a well-known complication after allogeneic HSCT. Eltrombopag (ELT), a thrombopoietin receptor agonist (TRAs), induces platelet maturation and release. Mostly conducted in adults, some of the previous studies have shown that ELT seems to enhance platelet recovery for post-allogeneic HSCT thrombocytopenia, appears efficacious, and offers transfusion independence. To evaluate the safety and efficacy of ELT in pediatric patients with prolonged isolated thrombocytopenia (PIT) or secondary failure of platelet recovery (SFPR) after alloHSCT. Retrospective analysis of childhood patients who received treatment with ELT for persistent thrombocytopenia after alloHSCT between May 2016 and August 2019. We evaluated the safety and efficacy of ELT in 18 childhood patients with PIT or SFPR after alloHSCT. Eltrombopag (50mg/d) treatment was started in all patients, above 6years of age and 20kg weight, who had thrombocytopenia despite neutrophil engraftment on the 30th day of HSCT. Our objective was to decrease the need for platelet transfusion and have a platelet count of more than 50000/µL. The overall response rate was 77.7%. The median time to achieve a platelet level above 30000/µL and 50000/µL was 21 and 44days, respectively. In four patients, platelet count never reached 30000/mm3 . In two patients, the treatment was discontinued due to grade 3 hepatotoxicity. Our study supports the efficacy and relative safety of ELT use for the treatment of PIT and SFPR seen after alloHSCT in children.

Long-Term Follow-up of High-Dose Chemotherapy with Autologous Stem Cell Transplantation in Children and Young Adults with Metastatic or Relapsed Ewing Sarcoma: A Single-Institution Experience

Forty-seven patients with metastatic disease at diagnosis or recurrent Ewing sarcoma (EWS) received high-dose chemotherapy (HDC) followed by tandem (n=20, from February 13, 1997, to October 24, 2002) or single (n=27, from October 1, 2004, to September 5, 2018) autologous hematopoietic stem cell transplantation (ASCT). To our knowledge, this is the largest single-institution study with sustained long-term follow-up exceeding 10 years. All patients who underwent single ASCT received a novel conditioning regimen with busulfan, melphalan, and topotecan. The overall survival (OS) and disease-free survival (DFS) were 46% and 37% at 10 years and 42% and 37% at 15 years, respectively. Disease status at transplant and the time to disease relapse prior to ASCT were identified as important prognostic factors in OS, DFS, and risk of relapse. At 10 years, patients who underwent transplantation in first complete response (1CR) had an excellent outcome (OS 78%), patients in 1CR/second complete response (2CR)/first partial response (1PR) had an OS of 66%, and patients at third or more complete response, second or more partial response, or advanced disease had an OS of 26%. Ten-year OS for patients without a history of relapse, with late relapse (≥2 years from diagnosis), or with early relapse (<2 years from diagnosis) was 75%, 50%, and 18%, respectively. Selected patients in 1CR, 2CR, 1PR, and with late relapse had excellent, sustained 10- and 15-year OS and DFS.

Melphalan, Etoposide, and Carboplatin Megatherapy with Autologous Stem Cell Transplantation in Children with Relapsing or Therapy-Resistant Extracranial Germ-Cell Tumors-A Retrospective Analysis.

Simple SummaryGerm cell tumors (GCTs) are malignancies derived from germ cells that originate in gonads or extragonadal localizations. They are considered highly curable in both children and adults even if distant metastases are present, but therapy-resistant or relapsing patients have a worse prognosis. The aim of our retrospective study was to analyze the outcome of 18 children with GCT treated with melphalan–etoposide–carboplatin high-dose chemotherapy and autologous stem cell transplantation. To date, this is one of the largest reported pediatric cohorts of GCT patients treated with megatherapy. We observed high survival rates—a five-year overall survival of 76%, and event-free survival of 70.8% without therapy-associated mortality. We concluded that this megatherapy protocol is feasible in heavily pretreated children, but the issue of precise indications for high dose chemotherapy (HDCT) is evident and must be answered in a well-designed controlled study to avoid unnecessary overtreatment.Pediatric germ cell tumors (GCTs) are a group of chemosensitive malignancies with a 90% curability rate. We report a series of children with relapsing or therapy-resistant GCT treated with melphalan–etoposide–carboplatin high-dose chemotherapy (HDCT) and autologous stem cell transplantation. This consisted of 18 children, either with GCTs after relapse (nine patients) or with an unsatisfactory response to first-line chemotherapy (nine patients), who underwent HDCT. The HDCT regimens MEC1 (carboplatin 1500 mg/m2, etoposide 1800 mg/m2, and melphalan 140 mg/m2) and MEC2 (carboplatin 800 mg/m2, etoposide 800 mg/m2, and melphalan 140 mg/m2) were each used in nine patients. The median observation time was 81 months, the 5-year overall survival (OS) was 76%, and the event-free survival (EFS) was 70.8%. Non-relapse mortality was 0%, and four patients died after HDCT due to progression of the malignancy. No difference in OS or EFS was noted between the MEC1 and MEC2 protocols. The 5-year OS and 5-year EFS were higher in children treated with autologous stem cell transplantation before the age of four years. The presence of metastatic disease or time of HDCT consolidation during first/subsequent line chemotherapy did not affect patient survival. The melphalan–etoposide–carboplatin protocol is feasible in pediatric GCT, but is associated with potentially life-threatening complications. In conclusion, the use of HDCT must be examined in well-designed clinical trials, and the identification of patients who can benefit from this approach is critical to avoid overtreatment.

Marginal Benefit/Disadvantage of Granulocyte Colony-Stimulating Factor Therapy After Autologous Blood Stem Cell Transplantation in Children: Results of a Prospective Randomized Trial

AbstractIn this prospective trial, a total of 74 children who were scheduled to undergo high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) were prospectively randomized at diagnosis to evaluate the effectiveness of exogenous granulocyte colony-stimulating factor (G-CSF) treatment in accelerating hematopoietic recovery after PBSCT. The diagnosis included acute lymphoblastic leukemia (ALL) (n = 27), neuroblastoma (n = 29), and miscellaneous solid tumors (n = 18). Eligibility criteria included (1) primary PBSCT, (2) chemotherapy-responsive disease, and (3) collected cell number >1 × 105 colony-forming unit–granulocyte-macrophage (CFU-GM)/kg and >1 × 106CD34+ cells/kg patient's body weight. After applying the above criteria, 11 patients were excluded due to disease progression before PBSCT (n = 6) or a low number of harvested cells (n = 5), leaving 63 patients for analysis; 32 patients in the treatment group (300 μg/m2 of G-CSF intravenously over 1 hour from day 1 of PBSCT) and 31 in the control group without treatment. Two distinct disease-oriented high-dose regimens without total body irradiation consisted of the MCVAC regimen using ranimustine (MCNU, 450 mg/m2), cytosine arabinoside (16 g/m2), etoposide (1.6 g/m2), and cyclophosphamide (100 mg/kg) for patients with ALL, and the Hi-MEC regimen using melphalan (180 mg/m2), etoposide (1.6 g/m2), and carboplatinum (1.6 g/m2) for those with solid tumors. Five patients (two in the treatment group and three in the control group) were subsequently removed due to protocol violations. All patients survived PBSCT. The median numbers of transfused mononuclear cells (MNC), CD34+ cells, and CFU-GM were, respectively, 4.5 (range, 1 to 19) × 108/kg, 8.0 (1.1 to 25) × 106/kg, and 3.7 (1.2 to 23) × 105/kg in the treatment group (n = 30) and 2.9 (0.8 to 21) × 108/kg, 6.3 (1.1 to 34) × 106/kg, and 5.5 (1.3 to 37) × 105/kg, respectively, in the control group (n = 28), with no significant difference. After PBSCT, the time to achieve an absolute neutrophil count (ANC) of >0.5 × 109/L in the treatment group was less than that in the control group (median, 11 v 12 days; the log-rank test, P = .046), although the last day of red blood cell (RBC) transfusion (day 11 v day 10) and the duration of febrile days (>38°C) after PBSCT (4 v 4 days) were identical in both groups. However, platelet recovery to >20 × 109/L was significantly longer in treatment group than control group (26 v 16 days; P = .009) and >50 × 109/L tended to take longer in the treatment group (29v 26 days; P = .126), with significantly more platelet transfusion-dependent days (27 v 13 days;t-test, P = .037). When patients were divided into two different disease cohorts, ALL patients showed no difference in engraftment kinetics between the G-CSF treatment and control groups, while differences were seen in those with solid tumors. We concluded that the marginal clinical benefit of 1 day earlier recovery of granulocytes could be offset by the delayed recovery of platelets. We recommend that the routine application of costly G-CSF therapy in children undergoing PBSCT should be seriously reconsidered.

Infectious complications after allogeneic hematopoietic stem cell transplantation in children in a bone marrow transplant unit in Colombia.

There is a relative lack of information about infections occurring in children following allogeneic hematopoietic stem cell transplants (allo-HSCT) in developing countries. Herein, we describe the incidence rates of different infections according to the transplant period and baseline condition in Colombia. In a retrospective cohort study of all children who underwent allo-HSCTs from 2012 to 2017 in a hospital in Cali, Colombia, we reviewed medical records from the first post-transplant day until day+365 to describe microbiologically confirmed incidence rates of infections and deaths during three post-transplant periods and according to baseline condition. Most allo-HSCT (n=144, 96%) were followed by infections over the following year, mostly due to bacteria and cytomegalovirus (4.3 and 3.3 per 1000 patient-days, respectively). Children were at the highest risk for infection in the first 30days post-HSTC, but mortality was highest after 100days. Overall, high mortality (n=44, 31.7%) was associated with infections, especially from extensively drug-resistant bacteria, adenovirus, and aspergillosis. Infection rates were similar independent of the baseline condition. Almost all children in this cohort developed infections post allo-HSCT. Describing the distribution of infections throughout the first post allo-HSCT year allows clinicians to narrow the differential diagnosis of infections according to the post-transplant period. This is especially useful when prioritizing interventions in children receiving HSCT in stringent healthcare systems in developing countries.

Outcome of Hematopoietic Stem Cell Transplantation in Children with Primary Hemophagocytic Lymphohistiocytosis: A Single Institution Experience Using Reduced Intensity Conditioning

Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for primary hemophagocytic lymphohistiocytosis (HLH). Conventional myeloablative conditioning regimen using busulfan, cyclophosphamide with or without etoposide was associated with high rate of transplant-related mortality (Horne et al. BJH 2005). Reduced intensity conditioning (RIC) is used in HLH to minimize transplant-related toxicities. The use of alemtuzumab, fludarabine, and melphalan in HLH was associated with low mortality; however, mixed donor chimerism and graft failure were frequent (Allen et al. Blood 2018). A recent report in 25 HLH patients who underwent HSCT from HLA matched donors using targeted busulfan (45-65 mg/L X h), fludarabine, and serotherapy resulted in adequate stable donor chimerism, no graft rejection, and no mortality (Felber et al. Blood Adv. 2020). In this study, we reviewed the outcome of 16 HLH patients who underwent HSCT from HLA matched donors using RIC. All patients were initially treated using HLH-2004 protocol. They subsequently underwent HSCT from 10/10 HLA matched related or unrelated donor using RIC regimens. We initially used AFM conditioning regimen that included alemtuzumab (1 mg/kg), fludarabine (150 mg/m2), and melphalan (140 mg/m2) with or without thiotepa (10 mg/kg). GVHD prophylaxis included cyclosporine (CSA) and steroids. Given the high rate of low donor chimerism with AFM regimen, we subsequently used BF conditioning regimen that included busulfan (weight-based dosing for total of 16 doses) and fludarabine (160 mg/m2). Therapeutic drug monitoring of busulfan was performed. Thymoglobulin (10 mg/kg) was added in matched unrelated donor (MUD). GVHD prophylaxis included CSA and steroids in matched related donors (MRD) and CSA and methotrexate in MUD. Bone marrow was the stem cell source in all patients except one who underwent second transplant using peripheral blood stem cells. Supportive care was consistent among all patients. Defibrotide prophylaxis was administered to prevent sinusoidal obstruction syndrome (SOS). Donor chimerism &amp;lt;5% from whole blood or &amp;lt;20% in T-cell, graft failure, and death from any cause were considered as events. A total of 16 HSCT transplants were performed, 5 received AFM regimen and 11 received BF regimen. Patient and transplant characteristics are shown in Table. All patients had successful neutrophil and platelet engraftments. Among the five patients who underwent AFM conditioning, one patient with SH2D1A mutation is 8 years post transplant with stable full donor chimerism and another patient with PRF1 mutation who received AFM with thiotepa has stable sufficient donor chimerism 3 years post transplant. Both patients did not require donor leukocyte infusions (DLI). The remaining 3 patients had declining donor chimerism beyond the first year of transplant despite the frequent use of DLI, one of them had disease reactivation and underwent second HSCT using BF regimen. Event free survival (EFS) at 3 years was 60% and overall survival (OS) was 100%. Among the 11 patients who underwent BF regimen, 7 were transplanted using MRD and 4 MUD. The median cumulative area under the curve of busulfan was 64 mg/L X h (range, 56-73). Median donor myeloid chimerism was 97% (range, 83-100) and median T-cell chimerism was 78% (range, 40-93). One patient who underwent MUD had grade III acute GVHD and none had chronic GVHD. Two patients had mild SOS. There were no events among BF group with median follow up duration of 393 days (151-2080). The use of BF regimen in HLH was associated with excellent outcome and stable donor chimerism with no graft failure in comparison to AFM regimen. Longer follow up is needed to confirm our findings. Disclosures No relevant conflicts of interest to declare.

Outcome of Non-hematological Autoimmunity After Hematopoietic Cell Transplantation in Children with Primary Immunodeficiency.

Knowledge of post-hematopoietic cell transplantation (HCT) non-hematological autoimmune disease (AD) is far from satisfactory. This multicenter retrospective study focuses on incidence, risk factors, and outcomes of post-HCT AD in 596 children with primary immunodeficiency (PID) who were transplanted from 2009 to 2018. The indications of HCT were severe combined immunodeficiency (SCID, n = 158, 27%) and non-SCID PID (n = 438, 73%). The median age at HCT was 2.3years (range, 0.04 to 18.3years). The 5-year overall survival for the entire cohort was 79% (95% cumulative incidence (CIN), 74-83%). The median follow-up of surviving patients was 4.3years (0.08 to 14.7years). The CIN of post-HCT AD was 3% (2-5%) at 1year post-HCT, 7% (5-11%) at 5years post-HCT, and 11% (7-17%) at 8years post-HCT. The median onset of post-HCT AD was 2.2years (0.12 to 9.6years). Autoimmune thyroid disorder (n = 19, 62%) was the most common post-HCT AD, followed by neuromuscular disorders (n = 7, 22%) and rheumatological manifestations (n = 5, 16%). All patients but one required treatment for post-HCT AD. After multivariate analysis, age at transplant (p = 0.01) and T cell-depleted graft (p < 0.001) were significant predictors of post-HCT AD. None of the T cell-depleted graft recipients developed post-HCT AD. Patients with a lower CD3+ count at 6months post-HCT had a significant higher incidence of post-HCT AD compared to disease controls. Graft-versus-host disease, viral infection, and donor chimerism had no association with post-HCT AD. Post-HCT AD occurred in 11% at 8years post-HCT and its occurrence was associated with older age at HCT and unmanipulated graft.

Human leukocyte antigen disparities reduce relapse after hematopoietic stem cell transplantation in children with juvenile myelomonocytic leukemia: A single-center retrospective study from China.

HSCT is the only proven curative therapy for JMML. Matching donor and recipient HLA alleles is considered optimal to reduce the risk of GVHD after HSCT but is not always possible. Only a limited number of studies have compared the influence of HLA disparities on HSCT outcomes for patients with JMML. We conducted a retrospective study among 47 children with JMML who received related or unrelated unmanipulated HSCT (March 2010-October 2018). Among our participants, 27 (57.4%) donor-recipient pairs had 0-1 HLA disparities (Group 1: HLA-matched or ≤1 allele/antigen mismatch donor) and 20 (42.6%) had ≥2 HLA disparities (Group 2: 2-3 mismatched/haploidentical donors). The median follow-up period was 26.0months (range: 1-105months), and the 5-year probabilities of DFS and RI for the whole cohort were 54.6±7.7% and 34.8±15.0%, respectively. Compared to Group 1, Group 2 patients had a significantly lower RI (5.3±10.5% vs 55.5±20.9%, P˂.001), though similar rates of grade II-IV acute GVHD (60.0±22.4% vs 33.3±18.2%, P=.08), grade III-IV acute GVHD (25.0±19.5% vs 7.4±10.1%, P=.08), chronic GVHD (30.0±20.9% vs 34.9±18.8%, P=.85), NRM (20.0±18.0% vs 3.9±7.7%, P=.07), and DFS (74.4±9.9% vs 41.3±10.0%, P=.08). Disease relapse remains the major cause of treatment failure in JMML patients, especially in patients receiving HLA-matched and limited HLA-mismatched HSCT. Our findings suggest that donor-recipient HLA disparities may improve the outcome of HSCT in children with JMML.

Iron overload after allogeneic stem cell transplantation in children with acute lymphoblastic leukemia.

Red blood cell transfusions are an essential part of supporting care in leukemia treatment. We examined the prevalence of iron overload and its effects on organ function and childhood growth in pediatric patients after allogeneic HSCT for acute lymphoblastic leukemia. Twenty-three patients were included (median age 12.6, range 7.5-21.4years). Body iron load was determined using laboratory tests, hepatic and cardiac MRI, and by calculating iron received from transfusions. We performed multivariate analysis to determine association of body iron load with liver enzymes, cardiac function, insulin resistance, and growth. Median plasma ferritin was 344 (range 40-3235) ng/mL and exceeded 1000ng/mL in three patients (13%). In MRI, 11 patients (48%) had hepatic iron overload and 1 patient (4%) myocardial iron overload. In cardiac MRI, 8 patients (35%) had significant but subclinical decrease in ejection fraction (median z-score -1.7, range -3.1-0.14), but cardiac function did not associate with iron status. Alanine transaminase associated with transfused iron per time unit (P=.001) after the median follow-up of 4.5years. No correlation was found between iron load and growth or insulin resistance. Iron overload is common in children transplanted for ALL, but iron overload associated organ dysfunction is not present at early age. We recommend evaluation of iron load for all patients at least once during follow-up after transplantation.

The challenges presented by haematopoietic stem cell transplantation in children with primary immunodeficiency and Covid-19 and the ‘new normal’: are remote video consultations here to stay

The challenges presented by haematopoietic stem cell transplantation in children with primary immunodeficiency and Covid-19 and the ‘new normal’: are remote video consultations here to stay