Hematologic Stem Cell Transplantation Research Articles

Educational outcomes school year nine in children treated for acute lymphoblastic leukemia: A nationwide registry-based study from Sweden.

Acute lymphoblastic leukemia (ALL) constitutes approximately 25% of pediatric cancers, and with contemporary protocols, the 5-year survival rate is over 90%. Despite improved survival, neurocognitive impairments from treatment raise concerns. This registry study aimed to explore the impact of ALL treatment on educational outcomes from school year nine in Swedish children. A population-based cohort of 503 children diagnosed with ALL from 1990 to 2010 was identified from the Swedish Childhood Cancer Registry and matched with five controls each. Assessed variables were delayed graduation, high school eligibility, total merit value, school grades in Swedish, English, mathematics, and physical education, and results in national tests. Analyses were performed between cases and controls and by sex, age at diagnosis, and risk group. Our results showed that, compared to controls, cases had higher odds for delayed graduation, poorer results in physical education, and higher rates of absence in national tests in English and mathematics. Children in the standard-risk group (treated with first-line chemotherapy only) exhibited similar results to matched controls whereas children in the high-risk group (treated with cranial irradiation, hematological stem cell transplantation, or/and for ALL relapse and thus likely received also radiotherapy) had lower total merit value compared to controls. We conclude that Swedish children diagnosed with ALL between the years 1990-2010 mainly exhibited comparable educational outcomes to controls, although children in the high-risk group had lower results. These findings highlight the importance of evaluating especially children with high-risk ALL in order to identify those requiring educational support and for designing targeted interventions.

Impact of bone marrow fibrosis on outcomes of allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia

Bone marrow fibrosis (BMF) of unknown etiology was common in hematological malignancies, but its prognostic value for acute myeloid leukemia (AML) is unclear. We interrogated data from 532 newly diagnosed subjects with AML receiving allogeneic hematological stem cell transplantation to evaluate the prognostic impact of BMF on transplant outcomes. Using the European consensus on the grading of BMF at diagnosis, 255 (48%) subjects were BMF-0, 209 (39%), BMF-1 and 68 (13%), BMF-2-3. Subjects with BMF-2-3 had poor overall survival (P < 0.001), disease-free survival (P < 0.001) and a higher incidence of relapse (CIR, P < 0.001). Multi-variable analyses in subjects achieving pre-transplant complete remission showed BMF-2-3 was an independent risk factor for CIR (Hazard Ratio [HR] = 2.17, (95% CI, 1.11, 4,24); P = 0.02). Furthermore, BMF-2-3 group showed delayed neutrophil and platelet engraftment and delayed B cell recovery post-transplantation. These findings demonstrate the significance of BMF in transplant outcomes and attract more attention to AML with BMF.

Immunotherapy in first line treatment of adult acute lymphoblastic leukemia.

The use of immunotherapy in recent years has changed the paradigm of treatment in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), improving outcomes in the relapsed/refractory setting. New strategies are incorporating immunotherapy into front-line regimens to reduce the toxicity of chemotherapy, prolong survival and increase the possibility of treating older patients. The aim of this review was to describe the new strategies, which have incorporated these drugs into front-line regimens for BCP-ALL patients. Recent studies have demonstrated that immunotherapy can be included in front-line induction, consolidation and/or maintenance regimens for the treatment of BCP-ALL patients by its addition to chemotherapy, by substituting some chemotherapy cycles or even including immunotherapy in chemotherapy-free strategies. The implications of these relevant findings will allow treating older patients, reducing the toxicity of chemotherapy and increasing patient outcomes. In addition, these findings have raised the possibility of avoiding the need for hematologic stem cell transplant in some selected patients.

Impact of hydroxyurea on follicle density in patients with sickle cell disease

AbstractThe impact of hydroxyurea (HU) on the ovarian reserve of female patients with sickle cell disease (SCD) remains poorly elucidated. Only direct histological analysis of ovarian follicle density can effectively evaluate HU’s effect on ovarian reserve. By analyzing digitized slides of ovarian tissue from girls and young women with SCD who underwent ovarian tissue cryopreservation (OTC) before hematological stem cell transplantation, we meticulously counted follicles and categorized them based on their growth stage. We then calculated the densities of different follicle types and assessed their correlation with patient characteristics, clinical manifestations, and treatments extracted from medical records. Seventy-six patients with SCD participated in the study, with a median age at OTC of 10.2 years (interquartile range [IQR], 7.5-14.6), and 50 (65.8%) were prepubertal. Of these, 35 patients (46.1%) had received HU, with a median daily dosage of 23.0 mg/kg (IQR, 20.0-25.0) and median exposure time of 44 months (IQR, 24.0-54.0). Primordial follicle density was comparable between the HU and non-HU groups (5.8 follicles per mm2 [IQR, 1.0-13.3] vs 4.2 follicles per mm2 [IQR, 1.1-14.4], respectively; P = .95). However, in the HU group, after adjusting for age, the density of growing follicles was marginally lower than that in the non-HU group (P = .09). Notably, other parameters such as vaso-occlusive crisis did not affect follicular density. In conclusion, exposure to HU did not demonstrate a reduction in ovarian reserve in girls or women with SCD. Therefore, fertility preservation measures before initiating HU treatment do not seem necessary.

Filtered handheld far-ultraviolet disinfection device in reducing environmental pathogens from high-touch clinical surfaces

Background: Healthcare-acquired infections (HAIs) continue to be a major challenge. In fact, an increased risk of HAIs has been linked to high-touch surfaces contaminated with multidrug-resistant organisms (MDROs), and enhanced environmental disinfection is linked to reduced HAI rates. Recently, more focus has been placed on emerging disinfection technologies, such as UV light-producing portable device that emits light at a wavelength of 222 nm, which has previously demonstrated germicidal capabilities at short contact times. In this study, we aim i) to evaluate the efficacy of a filtered far-UV-C handheld device (FFUHH) to reduce bacterial loads on high-touch surfaces in clinical workrooms in a cancer center, and ii) to isolate, identify and establish a genetic relationship between these environmental clinically significant pathogens and the ones recovered from patients. Methods: Samples were collected weekly on a rotating schedule over a 24-week period from five high-touch items (dictation device, mouse, armchair, desk, and keyboard) in multiple clinical work rooms on hematologic malignancy and stem cell transplant units. Contact plates for colony count and swabs were collected pre- and post-intervention with the FFUHH on standardized adjacent areas respectively for each surface. The swabs were enriched and cultured on selective media to isolate clinically significant pathogens. Whole genome sequencing (WGS) was then performed on environmental pathogens validated by MALDI-TOF as well as clinical samples collected from patients in the same unit around the time of environmental sample collection. Results: A total of 440 plates, 220 pre- and 220 post-interventions, were collected and analyzed. The highest mean colony count pre-treatment was detected from the armchairs and the lowest for the keyboards. The mean reduction of colony forming units (CFUs) ranged between 53% for the keyboard and 83% for the mouse. The reduction was statistically significant across all surfaces with P values &lt; 0.05, except for the keyboard (Figure 1). We isolated many pathogens of the human microbiota identified by MALDI-TOF such as Micrococcus luteus, S. capitis as well as methicillin-resistant S. epidermidis, S. haemolyticus and S. hominis. We also identified several Candida parapsilosis, Pseudomonas stutzeri, one Listeria grayi and one Acinetobacter baumanni. Finally, WSG allowed us to further characterize an environmental multi-drug resistant S. epidermidis ST5 strain associated with patient bacteremia, and ST16 strains detected on surfaces both pre- and post-FFUHH treatment. Conclusion: The FFUHH effectively reduced the microbial burden on high-touch surfaces in clinical workrooms on hematologic malignancy and stem cell units.

Epidemiology and risk factors of community-acquired pneumonia in patients with different causes of immunosuppression

Immunosuppression constitutes a significant risk for community-acquired pneumonia (CAP). Nevertheless, specific causes of immunosuppression and their relevance for incidence, etiology and prognosis of CAP are insufficiently investigated.We conducted a population-based cohort study within a statutory health insurance in Germany from 2015 to 2018. CAP was retrieved by ICD-10-GM codes. Episodes of immunosuppression were identified by coded conditions (hematologic neoplasms, stem cell or organ transplantation, neutropenia, HIV, primary immunosuppressive syndromes) or treatments (immunosuppressants, antineoplastic drugs, systemic steroids). Endpoints were defined as occurrence of CAP (primary), hospitalization, 30-day mortality and CAP associated with rare pathogens. Our analysis utilized the Andersen-Gill model adjusted for sex, age, level of long-term care, vaccination status, community type and comorbidities.942,008 individuals with 54,781 CAPs were included (hospitalization 55%, 30-day mortality 14.5%). 6% of individuals showed at least one episode of immunosuppression during the study period with systemic steroids (39.8%) and hematologic neoplasms (26.7%) being most common. Immunosuppression was recorded in 7.7% of CAPs. Besides classical risk factors such as age and level of long-term care, immunosuppressed patients were most prone to CAP (HR 2.4[2.3–2.5]) and consecutive death (HR 1.9[1.8–2.1]). Organ and stem cell transplantation (HR 3.2[2.6–4.0] and 2.8[2.1–3.7], respectively), HIV (HR 3.2[1.9–5.4]) and systemic steroids (> 20 mg prednisone daily dose equivalent (HR 2.7[2.4–3.1])) showed the highest risk for contracting CAP. CAP by rare pathogens was strongly associated with immunosuppression (HR 17.1[12.0–24.5]), especially HIV (HR 34.1[7.6–153]) and systemic steroids (HR 8.2[4.6–14.8]).Our study elucidates the relevance of particular immunosuppressive conditions including systemic steroids for occurrence and prognosis of CAP.

Central Line Associated Bloodstream Infections Outside the Intensive Care Unit: A 2-Year Analysis

Objective: There is limited data on the rates of central line-associated bloodstream infections (CLABSI) in non-intensive care units (ICU). Our aim was to determine the rates and features of CLABSI in non-ICU units. Method: CLABSI surveillance is performed according to CDC criteria in Internal Medicine Nephrology, Pediatric/Adult Hematology, Oncology and hematopoietic stem cell transplant (HSCT) units. Hospital infections control committee surveillance data was used. Results: Totally, 70028 patient days(pd) and 22358 catheter days, 101 infections were detected in 94 patients. The CLABSI rate was 1.44/1000 pd, the incidence density was 4.2/1000 catheter days, and the device utilization rate was 0.32. The highest infection rate was observed in the adult HSCT unit (15.18/1000 pd). 56.4% of the patients were male (n=53) and the mean age of the patients was 32±2.5 years. The mean length of hospitalization was 27.7±2.5 days. Half of the patients (n=47) had permanent central lines. Hematologic cancer was found in 54.7% and hemodialysis in 19.2%. 21.8% of infections were polymicrobial. Of the 125 microorganisms isolated, 61.6% were Gram negative, 20.8% were fungi and 17.6% were Gram positive. The most frequent pathogen was E.coli (13.6%) followed by and K.pneumoniae (13.6%), Staphylococcus aureus (8%) and C.parapsilosis (7.2%). Crude mortality was 36.2%. Colistin and amikacin were the most effective antibiotics in E.coli and K.pneumoniae, oxacillin resistance was 60% in S. aureus. In Candida species, fluconazole resistance was 15.8%. Conclusion: CLABSI can also be seen outside intensive care units and surveillance in these units is necessary for infection control.

Jaundice That Has Persisted for 5 Days

Hepatitis B virus (HBV) reactivation associated with various therapeutic interventions is a significant cause of morbidity and mortality among patients with current or resolved HBV infection. Since no curative treatment for HBV infection is currently available, a large number of individuals in the general population are at risk for HBV reactivation. Populations vulnerable to HBV reactivation include those currently infected with HBV or those who have had past exposure to the virus. The potential consequences of HBV reactivation are particularly concerning when these populations undergo anti-cancer chemotherapy, immunosuppressive or immunomodulatory therapies for managing various malignancies, rheumatologic diseases, inflammatory bowel disease, or undergo solid-organ or hematologic stem cell transplantation. This article aims to increase awareness of HBV reactivation and to elucidate the mechanisms and risks associated with HBV reactivation in various clinical settings.

Multicenter Retrospective Study of Invasive Fusariosis in Intensive Care Units, France.

Invasive fusariosis can be life-threatening, especially in immunocompromised patients who require intensive care unit (ICU) admission. We conducted a multicenter retrospective study to describe clinical and biologic characteristics, patient outcomes, and factors associated with death and response to antifungal therapy. We identified 55 patients with invasive fusariosis from 16 ICUs in France during 2002----2020. The mortality rate was high (56%). Fusariosis-related pneumonia occurred in 76% of patients, often leading to acute respiratory failure. Factors associated with death included elevated sequential organ failure assessment score at ICU admission or history of allogeneic hematopoietic stem cell transplantation or hematologic malignancies. Neither voriconazole treatment nor disseminated fusariosis were strongly associated with response to therapy. Invasive fusariosis can lead to multiorgan failure and is associated with high mortality rates in ICUs. Clinicians should closely monitor ICU patients with a history of hematologic malignancies or stem cell transplantation because of higher risk for death.

CYP3A5 influences oral tacrolimus pharmacokinetics and timing of acute kidney injury following allogeneic hematopoietic stem cell transplantation.

Introduction: Polymorphisms in genes responsible for the metabolism and transport of tacrolimus have been demonstrated to influence clinical outcomes for patients following allogeneic hematologic stem cell transplant (allo-HSCT). However, the clinical impact of germline polymorphisms specifically for oral formulations of tacrolimus is not fully described. Methods: To investigate the clinical impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on oral tacrolimus pharmacokinetics and clinical outcomes, we prospectively enrolled 103 adult patients receiving oral tacrolimus for the prevention of graft-versus-host disease (GVHD) following allo-HSCT. Patients were followed in the inpatient and outpatient phase of care for the first 100 days of tacrolimus therapy. Patients were genotyped for CYP3A5 *3 (rs776746), CYP3A4 *1B (rs2740574), ABCB1 exon 12 (rs1128503), ABCB1 exon 21 (rs2032582), ABCB1 exon 26 (rs1045642). Results: Expression of CYP3A5 *1 was highly correlated with tacrolimus pharmacokinetics in the inpatient phase of care (p < 0.001) and throughout the entirety of the study period (p < 0.001). Additionally, Expression of CYP3A5 *1 was associated with decreased risk of developing AKI as an inpatient (p = 0.06). Variants in ABCB1 were not associated with tacrolimus pharmacokinetics in this study. We were unable to discern an independent effect of CYP3A4 *1B or *22 in this population. Conclusion: Expression of CYP3A5 *1 is highly influential on the pharmacokinetics and clinical outcomes for patients receiving oral tacrolimus as GVHD prophylaxis following allo-HSCT.

A Single-Center Study of the Utility of Bronchoalveolar Lavage in Critically Ill Patients With Haematological Malignancy or Stem Cell Transplants.

The aim of this study was to evaluate the yield of bronchoscopy-guided bronchoalveolar lavage (BAL) and decisions on management of antimicrobials in critically ill patients with hematological malignancy and/or hematological stem cell transplant (HSCT). The safety and tolerance of bronchoscopy were also reported. A retrospective cohort study was conducted by reviewing health charts of all adult patients with a hematological malignancy and/or an HSCT who were admitted to the intensive care unit and underwent bronchoscopy and BAL over four years from April 2016 to April 2020 at King Abdulaziz Medical City, Riyadh. Results: The cohort included 75 critically ill patients. Of these 75 patients, 53 (70.7%) had HSCT (allogenic 66%, autologous 32.1%, haplogenic 3.8%). Computed tomography of the chest was abnormal in all patients. Predominant findings included airspace abnormalities, ground glass opacities, and others. The positive yield was found to be 20% for bacterial, 22% for viral, 21% for fungal, and other organisms were identified in 2%. Although cytology was not performed in 18 patients, malignant cells were identified on BAL in two patients. While the overall mortality of the cohort was high (46.7%), the vast majority (94.7%) tolerated bronchoscopy and BAL without any complications. However, three patients (4%) developed a pneumothorax and one patient bled and developed the acute respiratory distress syndrome post bronchoscopy. BAL can identify and detect microorganisms directly influencing the clinical care of patients who have received non-invasive diagnostic tests that yielded negative culture results. Bronchoscopy and BAL are generally safe and well tolerated by critically ill patients with hematological malignancy or HSCT.

Hematological Involvement in Childhood Langerhans Cell Histiocytosis: A Cohort Study of 303 Patients

Introduction: Hematological involvement (HI) is a life-threatening involvement of Langerhans cell histiocytosis (LCH). Since 1975, its definition is based on the Lahey criteria: Anemia (Hb &amp;lt;10 g/dL and &amp;lt;9 g/dL in infants) and/or thrombocytopenia (platelet count &amp;lt;100x10 9/l). Methods: Among 2,234 patients &amp;lt; 18 years enrolled in the French histiocytosis registry (cutoff date May 2023), 303 patients presented HI. We differentiated mild HI (MHI) (Hb &amp;gt; 7 g/dl and Platelets &amp;gt; 20x10 9/l) from severe HI (SHI) (Hb ≤ 7 g/dl and Platelets ≤ 20x10 9/l) by using usual cutoffs for transfusion requirements. Results: Median age at diagnosis was one year and sex was male in 49%. The median follow-up in the 258 survivors was 10.9 years, while death occurred after a median of 0.9 years in the 45 patients who died (Figure 1A). Only 3 patients died later than two years of initial diagnosis. The HI was mild in 150 cases and severe in 153 cases. BRAF v600E was found in 88 among the 101 patients for which mutation analysis was documented. Patients with SHI had significantly more lung involvement (35 % vs 19 %), more hepatic involvement (72 % vs 21 %), and more skin involvement (85 % vs 61 %). Morphological bone marrow infiltration by CD1a positive cells could not differentiate between SHI and MHI and bone marrow features were hardly informative. Signs of myelofibrosis were documented in 9 patients mostly later in the disease course. Lastly, 44 macrophage activation syndromes were observed exclusively in SHI. For 11 of those patients panel analyses of hemophagocytic lymphohistiocytosis genes did not show any bi-allelic pathogenic variants. 20 patients did not receive any therapy, including one with SHI and 19 with MHI. An intensive approach with hematologic stem cell transplantation (HSCT) (n=11) and 2-Cda-Cytarabine (2-Cda-AraC) (n=44) was proposed almost only for SHI. MAPK-inhibition was used in 40 patients. Three deaths were observed among the MHI and 42 among the SHI. From 1983 to 1998 mortality was about 50% and 30 of 63 patients died. With the establishment of the second-line treatment by 2-Cda-AraC mortality decreased drastically and from 1998 to 2014 only 13 of 194 patients died. From 2014 on patients received exclusively MAPK-inhibition as second line treatment and 2 of 46 patients died (one without therapy, one at the initiation). The overall survival is depicted in figure 1A. Neurodegenerative (ND) complications were observed in 32 patients (10.5%) with a median delay of 4.8 years after initial LCH diagnosis and incidence of ND was independent of the MHI or SHI group (Figure 1B). Conclusion: In Langerhans cell histiocytosis, the classic definition of hematological involvement by the Lahey criteria should be reconsidered. HI may be limited to severe HI that included almost all medical complications and warrants innovative approaches, while mild HI can be managed by the classic therapeutical approach. Even if progress has been achieved in the treatment of LCH patients with HI with more than 95% achieving short-term control, long term neurodegeneration remains a challenge in this group of patients, which warrants further research. Figure 1: A) Kaplan-Meier curve of cumulative incidence of death for all the 303 patients, regardless of therapy. B) Risk of clinical neurodegenerative symptoms in the same cohort (considering death as a censor).

Virtual Reality-Assisted Exercise Therapy during Inpatient Treatment after Intensive Chemotherapy for Acute Myeloid Leukemia (AML) and after Autologous or Allogeneic Stem Cell Transplantation

Background and Objectives Medical advances in treatment of hematologic malignancies have led to improved survival. However, aggressive treatments come with the potential of significant side effects that can affect quality-adjusted life years. During treatment, physical activities are markedly reduced and immobility and psychologic burden, especially during long isolation processes, result in fatigue and decline of quality of life as well as loss of cognitive function. Physiotherapy and exercise therapy positively impact muscle strength, quality of life, cognitive functioning and fatigue, but sufficient implementation of training in the inpatient setting is often limited by shortage in human resources. The aim of this study was to assess the feasibility of a virtual reality (VR) based exercise program during inpatient stay of patients undergoing intensive treatment for hematologic malignancies, including autologous and allogeneic hematologic stem cell transplantation (HSCT). Method Patients aged 18 or above, admitted to the hematology ward for HSCT or intensive chemotherapy for acute leukemia were included. As this was a feasibility trial, there was no randomization. After consent, patients were asked to use the VR training device on a daily basis for the length of their stay, accompanied by medical personal. The training program consisted of customized VR-applications addressing movement, concentration and alertness as well as relaxation. An individual program was developed for every patient at the beginning of treatment and continuously readjusted according to individual needs and preferences. Patients who did not want to or were not able to use the VR device were asked to participate in the control group and received the standard-of-care treatment consisting of once daily physiotherapy. As objectives, quality of life, fatigue, strength and cognitive function were assessed once weekly until discharge as well as two weeks post discharge in both groups. The time of usage was recorded by the VR device. A structured interview was conducted after discharge to evaluate the patients' perspective on the intervention. Results Over a three-months period, a total of 10 patients were enrolled in the study, seven patients with intervention, three patients in the control group. The usage was feasible and well tolerated. No unpleasant side effects such as dizziness, nausea or fatigue were reported. Mean time of usage varied between patients (132.6±68.6 minutes, min 12.4, max 463.5 minutes) on 31±28.2% of hospitalization days. Patients in the intervention group achieved a higher overall score in EORTC QLQ-C30 after discharge (s). Moreover, the use of VR was associated with a trend towards improved mean symptom burden (60 vs 43.3 pts), cognitive function (83.3 vs. 16.7pts) and physical strength (63.3 vs 26.7pts) post discharge (significance was not calculated due to the small number of cases). VR occupation time was markedly affected by age and general condition during treatment. The patients perception of the intervention was positive. Conclusions The results show that the use of a VR based exercise program during inpatient stay of patients receiving intensive treatment for hematologic malignancies is feasible and safe, and can improve QoL. Because of the small number of subjects and distinctive differences in time of usage we can only recognize a trend towards positive effects so far. In view of these promising results a larger prospective, randomized trial has been designed.

CCL1 As a Biomarker of Engraftment Syndrome of Hematological Stem Cell Transplantation

BACKGROUND Many complications occur in the practice of hematopoietic stem cell transplantation, especially those presenting with fever, which can be caused by infection as well as engraftment syndrome (ES), which is difficult to distinguish. The mechanism of ES is unknown, and no characteristic biomarkers have been identified. METHODS We attempted to identify cytokines specific to the engraftment syndrome by cytokine array analysis of sera from 7 patients who underwent HSCT at our institution from January 2019 to March 2022 and who developed fever between 1 week before and the day of engraftment. Cases in which pathogens were detected in blood culture at the time of fever were diagnosed as infections, and cases in which blood culture was negative or clinically treated as engraftment syndrome or fever associated with engraftment were diagnosed as engraftment syndrome. Cases that did not present with fever from infusion to engraftment were used as negative controls. RESULTS. Three of the seven patients had fever due to infection and four had fever due to engraftment syndrome. Median age was 41 (21-62) years, 5 males and 2 females. Four patients had acute leukemia, one had chronic myelomonocytic leukemia, and two had nonhematologic tumors. The donors were blood related in 3 cases, unrelated in 3 cases, and cord blood in 2 cases. Pretreatment was myeloablative (MAC) in 2 patients and reduced intensity pretreatment (RIC) in 5 patients. Cytokine arrays identified five cytokines that were elevated in the ES group. Of these, cytokine The cytokine CCL1 (I-309) tended to be elevated in the ES group (p=0.06). The validity of CCL1 with respect to the diagnosis of fever of engraftment was examined using sera from another 16 hematopoietic stem cell transplant cases performed at the same period, and the results showed that CCL1 was only mildly elevated in cases diagnosed with infection, regardless of the elevated values of fever and inflammatory response, but tended to be elevated in fever of engraftment (area under ROC curve: 0.74 (95% confidence interval 0.422-1)). CONCLUSIONS. CCL1 was identified as a cytokine specific for ES, indicating that CCL1 may be useful in differentiating ES from infection. CCL1 is mainly secreted by T lymphocytes and its oversecretion during the hematopoietic recovery process may be involved in immune activation and the engraftment syndrome.

Simultaneously measure the concentrations of busulfan and phenytoin in human plasma using an HPLC-MS/MS method: Application to the TDM for children underwent hematological stem cell transplantation

AbstractIn this work, a simple and rapid high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to carry out the simultaneous measurement of busulfan (BU) and phenytoin (PHT) in the plasma of children. In this method, plasma sample could be prepared by one-step protein precipitation using 1 mL of methanol/water (1:1, v/v). After centrifugation (14,500 rpm, 5 min, 4 °C), 10 μL of the supernatant was injected into a Hypersil Gold C18 column (150 × 2.1 mm, 5 μm, Thermo Fisher Scientific) for separation by gradient elution. Quantification was carried out using multiple reactions monitoring (MRM) under positive scan mode. In the method verification, the calibration curves of BU and PHT showed satisfactory linearity (r &gt; 0.99) at the concentration ranging from 0.02 to 20 μg mL−1. The accuracy and precision were tested at four concentration levels (including the LLOQ level) with the relative error (RE) ranging from −0.80% to 11.45% and coefficient of variation (CV) between 0.93% and 7.74%. There was no pronounced matrix effect to interfere with the quantitative analysis. Compared to determine BU and PHT using two individual methods, less pre-treatment process, labor and blood sample volume are required in this proposed method. Finally, this method was successfully applied to the therapeutic drug monitoring of BU and PHT for children underwent hematological stem cell transplantation.

Seizures in children undergoing stem cell transplantation.

Neurological complications (NCs) are of major concern following hematological stem cell transplantation (HSCT), most of which present with seizures. We performed a retrospective study (2002-2018) of patients undergoing HSCT in order to analyze the incidence and aetiologies related to seizures. Of 155 children undergoing HSCT, 27 (17.4%) developed seizures at some point in 2 years of follow-up. The most frequent etiologies were central nervous system (CNS) infection (n = 10), drug toxicity (n = 8), and vascular disease (n = 5). A statistically significant association was found between seizure and the HSCT type (lower risk for a related identical donor, p = .010), prophylactic or therapeutic mycophenolate use (p = .043 and .046, respectively), steroid use (p = .023), selective CD45RA+ depletion (p = .002), pre-engraftment syndrome (p = .007), and chronic graft-versus-host disease (GVHD) severity (p = .030). Seizures predicted evolution to life-threatening complications and admission to intensive care (p < .001) and higher mortality (p = .023). A statistically significant association was also found between seizures and sequelae in survivors (p = .029). Children who developed seizures had a higher risk of CNS infection and vascular disease (odds ratio 37.25 [95% CI: 7.45-186.05] and 12.95 [95% CI 2.24-74.80], respectively). Neurological complications highly impact survival and outcomes and need to be addressed when facing an HSCT procedure.

Comparison of outcomes for patients with acute myeloid leukemia undergoing haploidentical stem cell transplantation in first and second complete remission.

There was no consensus on whether prognostic advantages existed when transplant conducted at first complete remission (CR1) stage than at second complete remission (CR2) stage for patients with AML who received haploidentical hematological stem cell transplantation (haplo-HSCT). In 768 consecutive AML patients who received haplo-HSCT from January 2014 to December 2017, a 1:2 ratio matched-pair analysis was performed, 69 patients who in CR2 group and 138 CR1 patients were enrolled. Hematopoietic recovery, graft versus host disease (GVHD), relapse, transplant related mortality (TRM), disease-free survival (DFS) and overall survival (OS) were compared in two groups, and further evaluated in low-, intermediate-, and high-risk subgroups. The cumulative incidences of 30-day myeloid recovery and 90-day platelet recovery were comparable in CR1 and CR2 groups. The cumulative incidences of grade II-IV and grade III-IV aGVHD were not significantly different. The cumulative incidences of relapse at 3-year and 5-year in these two groups were 12.4% versus 11.6% (P = 0.880) and 12.4% versus 17.5% (P = 0.322). The cumulative incidences of TRM at 3-year and 5-year were both 10.9% versus 23.2% (P = 0.019). The probability of DFS at 3-year and 5-year were 76.7% versus 65.2% (P = 0.029) and 76.7% versus 59.3% (P = 0.009). The probability of OS at 3-year and 5-year were 81.8% versus 68.1% (P = 0.026) and 76.7% versus 59.3% (P = 0.026). In the intermediate-risk group, TRM was lower in CR1 group, DFS and OS of CR1 group were superior to CR2 group. In conclusion, haplo-HSCT at CR1 stage was of better prognosis for intermediate-risk AML patients than at CR2 stage.

#6294 UTILITY OF KIDNEY BIOPSY AND SPECTRUM OF BIOPSY PROVEN KIDNEY DISEASES IN PATIENTS WITH MALIGNANCY: A RETROSPECTIVE SINGLE-CENTER EXPERIENCE

Abstract Background and Aims Kidney biopsy may improve diagnostic accuracy and aid in the management of cancer patients with kidney diseases. However, literature on the utility of kidney biopsy in cancer patients and survivors is lacking. We aimed to evaluate the clinical characteristics of cancer patients who underwent kidney biopsy, as well as the histological spectrum of biopsy proven kidney diseases in this cohort. Method This was a single-center retrospective study of all patients who had native kidney biopsies at the Singapore General Hospital between 1st October 2015 to 31st December 2022. Demographic, clinical, laboratory and histological data were retrieved from electronic medical records to identify patients with solid-organ or hematological malignancies who underwent kidney biopsy. Results Out of 1208 patients who underwent kidney biopsy between 1st October 2015 to 31st December 2022, 116 (9.6%) patients had diagnoses of solid-organ or hematological malignancies. Approximately two-thirds (79/116; 68.1%) had solid-organ malignancies, of which 21.5% had metastatic disease at time of biopsy. Approximately one-third (36/116; 31.0%) had hematological malignancies, of which 10 (8.6%) had a hematological stem-cell transplant (HSCT). One (0.9%) patient had both solid-organ and hematological malignancies. Sixty-eight (58.6%) patients were in remission at time of biopsy, comprising of 52 (44.8%) and 16 (13.8%) patients with solid -organ and hematological malignancies, respectively. Median age at biopsy was 65.7 years (IQR 56.5, 71.4) and majority was female (61/116; 52.6%). Comorbidities of hypertension, type 2 diabetes mellitus, autoimmunity, and liver transplant were found in 36.2% (42/116), 23.3% (27/116), 8.6% (10/116) and 1.7% (2/116) patients respectively. Median serum creatinine at time of biopsy was 152.0μmol/L (IQR 101.8, 220.5). Micro-hematuria was present in approximately two-thirds (68.1%) of patients. Nephrotic range proteinuria and nephrotic syndrome were observed in one-quarter (25.9%) and one-third (31.0%) of the patients, respectively. Approximately half (49.1%) of the patients had acute kidney injury at time of biopsy, while one-fifth (19.8%) had progressive chronic kidney disease. A wide spectrum of histological diagnoses was observed. Glomerulonephritides, tubulointerstitial inflammation and/or glomerular endothelial injuries were diagnosed in 60.8% (48/79) of solid-organ and 80.6% (29/37) of hematological malignancies. Amongst patients with active solid-organ malignancies (n = 20), acute tubulointerstitial nephritis (ATIN) (5/20, 25.0%), IgA nephropathy (3/20; 15.0%) and lupus nephritis (3/20; 15.0%) were the most common primary diagnoses. Amongst patients with active hematological malignancies (n = 17), dysproteinemic kidney disease and/or leukemic infiltration was most frequently diagnosed (6/17; 35.9%). Compared to remission status, active malignancy was not associated with an increased likelihood of an overall diagnosis of glomerulonephritides, tubulointerstitial inflammation and/or glomerular endothelial injuries (p = 0.16). Specifically, the incidence of membranous nephropathy was similar in patients with active malignancy and those in remission (p = 0.42). Amongst patients with HSCT, thrombotic microangiopathy (40.0%) was observed most frequently. Overall, onco-therapeutics-related kidney injuries were present in 13 (11.2%) patients, of which ATIN (38.4%) was most commonly encountered, followed by glomerular endothelial injury (30.7%). Conclusion Kidney biopsy provides valuable diagnostic information amongst cancer patients. While a broad spectrum of histological diagnoses can be observed, glomerular diseases and onco-therapeutics-related kidney injuries remain the most common.

Busulfan versus treosulfan conditioning for acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis.

e19032 Background: Busulfan containing myeloablative conditioning regimens are widely used before allogeneic hematological stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Treosulfan-based conditioning regimens are a potential alternative with potent myelotoxic immunosuppressive characteristics and favorable extramedullary toxicity profile compared to busulfan. In order to determine the optimal conditioning regimen, we conducted a systematic review and meta-analysis to compare the efficacy and safety outcomes of busulfan and treosulfan based conditioning regimens in patients with AML/MDS. Methods: A retrospective systematic literature search was undertaken on PubMed, Cochrane, Embase and Clinicaltrials.gov, using MeSH terms and relevant keywords for AML, MDS, busulfan and treosulfan, to retrieve studies published prior to February 5, 2023. Efficacy outcomes were overall survival (OS), disease-free survival (DFS), and relapse. Safety outcomes included non-relapse mortality (NRM), acute (a) and chronic (c) graft-versus-host disease (GvHD). The random-effects model with the Mantel-Haenszel method was used to pool risk ratios (RR) for dichotomous variables in Revman version 5.4. Results: The initial search retrieved 1094 articles. After removal of duplicates, reviews and non-relevant articles, data was extracted from seven different studies. Busulfan and treosulfan were employed in 4706 and 1979 patients, respectively. The median age ranged from 55 to 61 years, and the median follow-up ranged from 14 to 58 months. The treosulfan and busulfan doses administered ranged from 10-42 g/m2 and 0.8-12.8 mg/kg, respectively. Treosulfan was superior to busulfan in terms of OS (RR 1.39, 95% CI 1.15-1.68, p-value 0.0007, I2 58%), DFS (RR 1.39, 95% CI 1.10-1.75, p-value 0.006, I2 60%) and NRM (RR 0.95, 95% CI 0.90-1.00, p-value 0.05, I2 67%). The two regimens were comparable in terms of relapse (RR 0.96, 95% CI 0.89-1.04, p-value 0.33, I2 76%), aGvHD (RR 1.00, 95% CI 0.65-1.54, p-value 1.00, I2 94%) and cGvHD (RR 1.00, 95% CI 0.95-1.05, p-value 0.92, I2 0%). Conclusions: Treosulfan was superior in terms of OS, EFS and NRM, whereas both regimens were comparable in terms of relapse, aGvHD and cGvHD. Treosulfan may be more favorable compared to busulfan as conditioning in AML/MDS. Large scale prospective studies are needed to confirm the most suitable option.

One fits all: a highly sensitive combined ddPCR/pyrosequencing system for the quantification of microchimerism after hematopoietic and solid organ transplantation.

A combined digital droplet PCR (ddPCR)/pyrosequencing assay system was developed that demonstrated advantages applicable to multiple qualitative and quantitative molecular genetic diagnostic applications. Data for characterizing this combined approach for hematologic stem cell transplantation (HSCT) and allele quantification from graft-derived cell-free (cf) DNA in solid organ transplantation (SOT) is presented. ddPCR and pyrosequencing assays targeting 32 SNPs/markers were established. ddPCR results from 72 gDNAs of 55 patients after allogeneic HSCT and 107 plasma-cfDNAs of 25 liver transplant recipients were compared with established methods/markers, i.e.short-tandem-repeat PCR and ALT, respectively. The ddPCR results were in good agreement with the established marker. The limit of detection was 0.02 % minor allele fraction. The relationship between ddPCR andSTR-PCR was linear with R2=0.98 allowing to transfer previously established clinical STR-PCR cut-offs to ddPCR; 50-fold higher sensitivity and a variation coefficient of <2 % enable the use of low DNA concentrations (e.g. pre-sorted cells). ddPCR detected liver allograft injury at least as sensitive as ALT suggesting that ddPCR is a reliable method to monitor the transplant integrity, especially when other biomarkers are lacking (e.g. kidney). Combining pyrosequencing for genotyping and ddPCR for minor allele quantification enhances sensitivity and precision for the patient after HSCT and SOT. Theassay is designed for maximum flexibility. It is expected to be suitable for other applications (sample tracking, prenatal diagnostics, etc.).