Abstract Objective The selection of graft‐vs. ‐host disease (GvHD) prophylaxis is vital for the success of hematopoetic stem cell transplantation (HSCT), and calcineurin inhibitors (CNI) have been used for decades as the backbone of GvHD prophylaxis. The aim of this study is to analyze the results of switching cyclosporine (CSA) to tacrolimus because of acute GvHD, engraftment syndrome (ES), persistent low level of CSA, or various CSA‐associated adverse events in the first 100 days of pediatric HSCT. Materials and Methods This is a retrospective analysis of 192 patients who underwent allogeneic hematopoietic stem cell transplantation at Medicalpark Göztepe and Antalya Hospitals between April 2014 and May 2019 had therapy switched from CSA to tacrolimus‐based immunosuppression within 100 days of transplant. Results The reasons for conversion to tacrolimus were low level of CSA ( n = 70), aGvHD ( n = 63), CSA‐associated neurotoxicity ( n = 15), CSA‐associated nephrotoxicity ( n = 10), hypertension ( n = 10), allergic reactions ( n = 9), ES ( n = 7), CSA‐associated hepatotoxicity ( n = 5), and vomiting ( n = 3). The median day after transplant for conversion to tacrolimus for all patients was day 20 (range 0‐100 days). Response rates to conversion were 38% for GvHD, 86% for neurotoxicity, 50% for nephrotoxicity, 60% for hepatotoxicity, 80% for hypertension, 66% for vomiting, and 57% for ES. Twenty‐nine patients (15%) experienced tacrolimus‐associated toxicities after therapy conversion to tacrolimus. Neurotoxicity emerged as posterior reversible encephalopathy syndrome (PRES), which was the most common toxicity observed after conversion (18/29 patients). Conclusion Our data support the quick conversion to tacrolimus in the condition of persistent low CSA levels with acceptable efficacy and safety. Although both drugs are CNI and share a very similar mechanism of action, the conversion could be preferred especially in specific organ toxicities with special attention for neurotoxicity after conversion.
Background: Total body irradiation (TBI) is the cornerstone of conditioning regimens in pediatric hematopoietic stem cell transplantation for acute lymphoblastic leukemia. As the late effects and survival comparison between TBI and chemotherapy were well analyzed before, in this study, we aim to focus on the first 100 days and early complications of transplantation. Methods: This retrospective study involves 72 pediatric patients (0 to 18 y) underwent first hematopoietic stem cell transplantation for acute lymphoblastic leukemia between October 2015 and May 2019. Patients are divided into 2 groups regarding conditioning regimens. Conditionings includes either TBI 1200 cGy/6 fractions/3 days and etoposide phosphate or busulfan, fludarabine, and thiotepa. Busulfan was administered IV and according to body weight. Results: The incidences of acute graft versus host disease grade 2 to 4, veno-occlusive disease, capillary leakage syndrome, thrombotic microangiopathy, blood stream infection, hemorrhagic cystitis and posterior reversible encephalopathy syndrome before day 100 were similar for both conditioning regimens; however, patients received TBI-based conditioning had significantly longer neutrophil engraftment time (17.5 vs. 13 d, P =0.001) and tended to have more engraftment syndrome (ES) (45.5% for TBI vs. 24.0% for chemotherapy, P =0.069). Multivariate analysis showed that TBI-based conditioning was associated with a longer neutrophil engraftment time (hazard ratio [HR]=1.20, P =0.006), more cytomegalovirus (CMV) reactivation (HR=3.65, P =0.038) and more ES (HR=3.18, P =0.078). Conclusions: Our findings support chemotherapy-based regimens with early neutrophil engraftment, less ES and CMV reactivation compared with TBI. Although there is no impact on survival rates, increased incidence of ES and CMV reactivation should be considered in TBI-based regimens.
Background: Data on the outcome and risk factors of pediatric patients with SARS-CoV-2 infection (COVID-19) following hematopoietic stem cell transplantation (HSCT) are limited. Objectives: We aimed to describe risk factors for a severe course and mortality. Method: In this nationwide study, data were collected retrospectively from 28 transplant centers. Results: One hundred ninety-six children [(63.8% male; median age 8.75 (IQR, 4.86-14.30)] who received allogeneic (n: 184, 93.9%) or autologous (n: 12, 6.1%) HSCT were included. The median time from HSCT to SARS-CoV-2 infection was 207.5 days (IQR, 110.2-207.5). The most common clinical manifestation was fever (58.2%), followed by cough (33.7%); 43 cases (21.9%) were asymptomatic. Lower respiratory tract disease (LRTD) and multisystem inflammatory syndrome in children (MIS-C) developed in 58 (29.6%) and 8 (4.1%) patients, respectively. Twenty-six patients (13.3%) required ICU admission. Nine patients died at a median of 17 days (min-max 1-33) after COVID-19 diagnosis, 6 of whom died due to the disease, with a COVID-19 lethality rate of 3.1%. The 6-week overall survival was 95.4% (95% CI 92.5-98.3). Multivariate analysis found that HSCT with a mismatched donor (OR, 8.98, p: 0.039) and LRTD (OR, 61.55, p: 0.001) were independent risk factors for ICU admission; MIS-C (OR, 9.55, p: 0.044) and lymphopenia (OR, 4.01, p: 0.030) at diagnosis were risk factors for mortality. Conclusion: Overall mortality was lower in children than in adult counterparts, and HSCT with a mismatched donor, lymphopenia, LRTD, MIS-C and ICU admission were important risk factors for adverse outcomes.
The use of unmanipulated haploidentical hematopoietic stem cell transplantations (haplo-HSCT) with post-transplant cyclophosphamide (PTCY) in children has emerged as an acceptable alternative to the patients without a matched donor. However, the timing of calcineurin inhibitors (CNIs) used in combination with PTCY is increasingly becoming a topic of controversy.We evaluated 49 children with acute leukemia who underwent unmanipulated haplo-HSCT with PTCY according to the initiation day of CNIs (pre- or post-cyclophosphamide [CY]).There were no significant differences in the overall survival analysis between the 2 groups. The cumulative incidence of relapse at 2 years was 21.2% in the pre-CY group and 38.9% in the post-CY group (p = 0.33). Cytokine release syndrome (CRS) was observed more frequently in the post-CY group (p = 0.04). The overall survival and event-free survival at 2 years in patients with and without CRS in the pre-CY group were 42.9% versus 87.5% (p = 0.04) and 38.1% versus 87.5% (p = 0.04), respectively.Our study shows that the argument for starting CNI administration after CY is tenuous, and the rationale for not starting CNIs before CY needs to be reconsidered.
Germline pathogenic variants (PVs) in CBL is found in 15% of juvenile myelomonocytic leukemia (JMML) cases. Here we report siblings with CBL variations presenting a heterogenous JMML clinic and outcome. The index case was diagnosed at the age of seven, whereas the younger brother was 10 months old and the youngest was one month old. The hematopoietic stem cell transplantation was successful for the index and the youngest brother with event free survival, but the middle brother showed severe graft versus host disease. This study shows the heterogeneity of JMML and how the outcome might differ even within the family.
Abstract The use of unmanipulated haploidentical stem cell transplantations (haplo-HSCT) with post-transplant cyclophosphamide (PTCY) in children has emerged as an acceptable alternative to the patients without a matched donor. However, the timing of calcineurin inhibitors (CNI) used in combination with PTCY is increasingly becoming a topic of controversy. We evaluated 49 children with acute leukemia who underwent unmanipulated haplo-HSCT with PTCY according to the initiation day of CNIs (pre- or post-CY). There were no significant differences in the overall survival analysis between the two groups. The cumulative incidence of relapse at 2 years was 21.2% in the pre-CY group and 38.9% in the post-CY group (p = 0.33). Cytokine release syndrome (CRS) was observed more frequently in the post-CY group. Our study shows that the argument for starting CNI administration after CY is tenuous, and the rationale for not starting CNI before CY needs to be reconsidered.
Amaç: Aralık 2019'dan beri, Dünya Sağlık Örgütü (DSÖ) tarafından koronavirüs hastalığı-2019 (COVID-19) olarak adlandırılan COVID-19 pandemisi tüm dünyayı etkilediği gibi hematolojik uygulamaları da etkilemektedir.COVID-19'un yaşlılarda, altta yatan kronik hastalığı olanlarda
Data on the risk factors and outcomes for pediatric patients with SARS-CoV-2 infection (COVID-19) following hematopoietic stem cell transplantation (HSCT) are limited. The study aimed to analyze the clinical signs, risk factors, and outcomes for ICU admission and mortality in a large pediatric cohort who underwent allogeneic HSCT prior to COVID-19 infection. In this nationwide study, we retrospectively reviewed the data of 184 pediatric HSCT recipients who had COVID-19 between March 2020 and August 2022. The median time from HSCT to COVID-19 infection was 209.0 days (IQR, 111.7-340.8; range, 0-3845 days). The most common clinical manifestation was fever (58.7%). While most patients (78.8%) had asymptomatic/mild disease, the disease severity was moderate in 9.2% and severe and critical in 4.4% and 7.6%, respectively. The overall mortality was 10.9% (n: 20). Deaths were attributable to COVID-19 in nine (4.9%) patients. Multivariate analysis revealed that lower respiratory tract disease (LRTD) (OR, 23.20, p: .001) and lymphopenia at diagnosis (OR, 5.21, p: .006) were risk factors for ICU admission and that HSCT from a mismatched donor (OR, 54.04, p: .028), multisystem inflammatory syndrome in children (MIS-C) (OR, 31.07, p: .003), and LRTD (OR, 10.11, p: .035) were associated with a higher risk for COVID-19-related mortality. While COVID-19 is mostly asymptomatic or mild in pediatric transplant recipients, it can cause ICU admission in those with LRTD or lymphopenia at diagnosis and may be more fatal in those who are transplanted from a mismatched donor and those who develop MIS-C or LRTD.
Background: Posterior reversible encephalopathy syndrome (PRES) is a reversible clinical-neuroradiological complication seen after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Aims: This study aims to predict the risk factors that cause PRES in pediatric patients undergoing allo-HSCT and to evaluate the management of PRES. Methods: Forty-four patients were diagnosed with PRES out of 641 patients who underwent hematopoietic stem cell transplantation in Göztepe Medical Park Hospital Pediatric Bone Marrow Transplantation Unit, between April 2014 and November 2020, were evaluated retrospectively. Results: Characteristics of transplantation were presented in Table-1. The median PRES day of the patients was found to be 40 (1-363 days), and PRES occurred in the first 100 days in 84.4% of the cases.Thirty-three patients (75%) were using steroids at the time of PRES diagnosis, and concomitant hypertension was detected in 29 of these patients. Forty-three patients were using calcineurin inhibitors (CNI) as immunosuppressive therapy at the time of PRES. The median plasma cyclosporine (CSA) level measured closest to the time of PRES was detected 191 (65-650) ng/ml, and the median tacrolimus level was 15 (2.6-30) ng/ml. Antiepileptic, antihypertensive, and supportive therapy were initiated just after PRES. Thirteen patients (28.8%) were followed up in the intensive care unit. CNI was discontinued in 40 patients and instead of CNI, sirolimus was started in 8 patients, mycophenolate mofetil (MMF) in 22 patients, and ruxolitinib in 4 patients. In 2 of the 3 patients whose CNI was not discontinued, another type of CNI was used and the seizure did not recur. In one patient, the preparation was interrupted because the blood level was excessively high, and when the blood level was restored, the same preparation was continued, and seizures did not recur. Twenty-three patients (52.2%) had graft versus host disease (GvHD) at the time of PRES. Twelve patients (27.2%) who had no sign of GvHD at the time of PRES developed GvHD in the follow-up after the treatment alteration, and 5 of these patients died due to severe GvHD during the follow-up. When CNI treatments were discontinued in 7 patients with low-grade GvHD at the time of PRES, their GvHD stages increased and 4 patients died due to severe GVHD. Three patients who were followed up with severe GvHD during PRES died due to complications of GvHD. Image:Summary/Conclusion: As a result of this study, it is seen that the concomitant use of steroids with calcineurin inhibitors may increase the possibility of PRES. Therefore, the possibility of PRES development should be considered in cases where steroid addition is considered for the treatment of GvHD. The median level of calcineurin inhibitors measured during PRES is within the upper limits of normal and PRES findings can be seen even at low grades, suggesting that PRES may develop independently of the drug level. In addition, it has been observed that discontinuation of CNI in patients who develop PRES may lead to deterioration in GvHD findings and increase mortality. Therefore, in patients with high-grade GvHD, reintroduction of calcineurin inhibitors may be considered after PRES has been stabilized.
