The role of immune reconstitution in relapse after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Leukemia relapse following stem cell transplantation remains a significant barrier to long-term remission. Timely and balanced immune recovery after transplantation is crucial for preventing leukemia relapse. AREAS COVERED: After an extensive literature search of PubMed and Web of Science through October 2023, we provide an overview of the dynamics of immune reconstitution and its role in controlling leukemia relapse. We also discuss strategies to promote immune reconstitution and reduce disease recurrence following allogeneic hematopoietic stem cell transplantation. EXPERT OPINION: Immune reconstitution after transplantation has substantial potential to prevent relapse and might predict disease recurrence and prognosis. High dimensional cytometry, multi-omics, and T cell repertoire analysis allow for a more comprehensive and detailed understanding of the immune system's dynamics post-transplantation, and contribute to the identification of rare immune cell subsets or potential biomarkers associated with successful immune reconstitution or increased risk of complications. Strategies to enhance the immune system, such as adoptive immunotherapy and cytokine-based therapy, have great potential for reducing leukemia relapse after transplantation. Future research directions should focus on refining patient selection for these therapies, implementing appropriate and timely treatment, investigating combination approaches to maximize therapeutic outcomes, and achieving a robust graft-versus-leukemia (GVL) effect while minimizing graft-versus-host disease (GVHD) for optimal results.

Obesity, bone marrow adiposity, and leukemia: Time to act.

Obesity has taken the face of a pandemic with less direct concern among the general population and scientific community. However, obesity is considered a low-grade systemic inflammation that impacts multiple organs. Chronic inflammation is also associated with different solid and blood cancers. In addition, emerging evidence demonstrates that individuals with obesity are at higher risk of developing blood cancers and have poorer clinical outcomes than individuals in a normal weight range. The bone marrow is critical for hematopoiesis, lymphopoiesis, and myelopoiesis. Therefore, it is vital to understand the mechanisms by which obesity-associated changes in BM adiposity impact leukemia development. BM adipocytes are critical to maintain homeostasis via different means, including immune regulation. However, obesity increases BM adiposity and creates a pro-inflammatory environment to upregulate clonal hematopoiesis and a leukemia-supportive environment. Obesity further alters lymphopoiesis and myelopoiesis via different mechanisms, which dysregulate myeloid and lymphoid immune cell functions mentioned in the text under different sequentially discussed sections. The altered immune cell function during obesity alters hematological malignancies and leukemia susceptibility. Therefore, obesity-induced altered BM adiposity, immune cell generation, and function impact an individual's predisposition and severity of leukemia, which should be considered a critical factor in leukemia patients.

Residential exposure to magnetic fields from transformer stations and risk of childhood leukemia.

BACKGROUND: Several studies have documented an increased risk of leukemia among children exposed to magnetic fields from high-voltage power lines, with some evidence of dose-response relation. However, findings in some studies have been inconsistent, and data on the effects of different sources of exposure are lacking. In this study, we evaluated the relation of childhood leukemia risk to exposure to magnetic fields from transformer stations. METHODS: We conducted a population-based case-control study in a pediatric population of two Northern Italian provinces of Modena and Reggio Emilia. We included 182 registry-identified childhood leukemia cases diagnosed during 1998-2019 and 726 population controls matched on sex, year of birth, and province of residence. We assessed exposure by calculating distance from childhood residence to the nearest transformer station within a geographical information system, computing disease odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, adjusting for potential confounders. We evaluated exposure using two buffers (15 m and 25 m radius) and assessed two case groups: leukemia (all subtypes) and acute lymphoblastic leukemia (ALL). RESULTS: Residing within 15 m of a transformer station (vs. ≥15 m) was not appreciably associated with risk of leukemia (all subtypes) or ALL. We found similar results using a less stringent exposure buffer (25 m). Among children aged ≥5 years, the adjusted ORs were 1.3 (95% CI 0.1-12.8) for leukemia and 1.3 (95% CI 0.1-12.4) for ALL using the 15 m buffer, while they were 1.7 (95% CI 0.4-7.0) for leukemia and 0.6 (95% CI 0.1-4.8) for ALL using the 25 m buffer. CONCLUSIONS: While we found no overall association between residential proximity to transformer stations and childhood leukemia, there was some evidence for elevated risk of childhood leukemia among children aged ≥5 years. Precision was limited by the low numbers of exposed children.

Shedding light on the side effects of immunotherapies used for leukemia: an updated review of the literature.

INTRODUCTION: Leukemia is an abnormal clonal development of leukemic cells originating from the bone marrow, which is widely known for its significant prevalence and mortality rate. Chemotherapy, surgery, radiation, and combination therapies have been its routine therapeutic methods; however, the advent of cancer immunotherapy is known as revolutionary for its higher efficacy and lesser toxicity. AREAS COVERED: Immunotherapy boosts the body's immune system by using components from other living organisms. Although immunotherapy seems to be safer than chemotherapy, many studies have noticed different immune-related side effects in various body systems (e.g. cardiovascular, neurologic) which we have reviewed in this investigation as the main goal. We tried to describe immunotherapy-related side effects in human body systems in detail. EXPERT OPINION: Being aware of these side effects leads to better clinical decision-making for each individual, and a one-step-ahead management in case of occurrence. We also briefly discussed the role of immunotherapy in treating leukemia as one of the most prevalent cancers in children and tried to emphasize that it is crucial to monitor adverse events as they may remain obscure until adolescence.

Electromagnetic Radiation Exposure and Childhood Leukemia: Meta-Analysis and Systematic Review.

Objective: Leukemia is the most prevalent cancer among children and adolescents. This study investigated the potential association between exposure to magnetic fields and the risk of pediatric leukemia. Methods: We conducted a comprehensive search of electronic databases, including Scopus, EMBASE, Cochrane, Web of Science, and Medline, up to December 15, 2022, to identify relevant studies examining the link between childhood leukemia and magnetic field exposure. Results: The first meta-analysis revealed a statistically significant inverse association between pediatric leukemia and magnetic field strengths ranging from 0.4 µT to 0.2 µT, suggesting a reduced risk associated with this range. The second meta-analysis focused on wiring configuration codes and observed a potential link between residential magnetic field exposure and childhood leukemia. Pooled relative risk estimates were 1.52 (95% CI = 1.05-2.04, P = .021) and 1.58 (95% CI = 1.15-2.23, P = .006) for exposure to 24-hour magnetic field measurements, suggesting a possible causal relationship. In the third meta-analysis, the odds ratios for the exposure groups of 0.1 to 0.2 µT, 0.2 to 0.3 µT, 0.3 to 0.4 µT, and 0.4 µT above 0.2 µT were 1.09 (95% confidence interval = 0.82 to 1.43 µT), 1.14 (95% confidence interval = 0.68 to 1.92 µT), and 1.45 (95% confidence interval = 0.87 to 2.37 µT), respectively. In contrast to the findings of the three meta-analyses, there was no evidence of a statistically significant connection between exposure to 0.2 µT and the risk of juvenile leukemia. A further result showed no discernible difference between the two groups of children who lived less than 100 meters from the source of magnetic fields and those who lived closer (OR = 1.33; 95% CI = 0.98-1.73 µT). Conclusions: The collective results of three meta-analyses, encompassing magnetic field strengths ranging from 0.1 µT to 2.38 µT, underscore a statistically significant association between the intensity of magnetic fields and the occurrence of childhood leukemia. However, one specific analysis concluded that no apparent relationship exists between exposure to 0.1 µT and an elevated risk of leukemia development in children.

Residential exposure to magnetic fields from high-voltage power lines and risk of childhood leukemia.

BACKGROUND: Several studies have suggested an excess risk of leukemia among children living close to high-voltage power lines and exposed to magnetic fields. However, not all studies have yielded consistent results, and many studies may have been susceptible to confounding and exposure misclassification. METHODS: We conducted a case-control study to investigate the risk of leukemia associated with magnetic field exposure from high-voltage power lines. Eligible participants were children aged 0-15 years residing in the Northern Italian provinces of Modena and Reggio Emilia. We included all 182 registry-identified childhood leukemia cases diagnosed in 1998-2019, and 726 age-, sex- and province-matched population controls. We assessed exposure by calculating distance from house to nearest power line and magnetic field intensity modelling at the subjects' residence. We used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for potential confounders (distance from nearest petrol station and fuel supply within the 1000 m-buffer, traffic-related particulate and benzene concentrations, presence of indoor transformers, percentage of urban area and arable crops). RESULTS: In multivariable analyses, the OR comparing children living <100 m from high-voltage power-lines with children living ≥400 m from power-lines was 2.0 (95% CI 0.8-5.0). Results did not differ substantially by age at disease diagnosis, disease subtype, or when exposure was based on modeled magnetic field intensity, though estimates were imprecise. Spline regression analysis showed an excess risk for both overall leukemia and acute lymphoblastic leukemia among children with residential distances <100 m from power lines, with a monotonic inverse association below this cutpoint. CONCLUSIONS: In this Italian population, close proximity to high-voltage power lines was associated with an excess risk of childhood leukemia.

Accumulation of T-cell-suppressive PD-L1high extracellular vesicles is associated with GvHD and might impact GvL efficacy.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment option for a number of hemato-oncological disorders. In fact, allo-HSCT is considered as one of the most successful immunotherapies as its clinical efficacy is based on the donor T-cells' capacity to control residual disease. This process is known as the graft-versus-leukemia (GvL) reaction. However, alloreactive T-cells can also recognize the host as foreign and trigger a systemic potentially life-threatening inflammatory disorder termed graft-versus-host disease (GvHD). A better understanding of the underlying mechanisms that lead to GvHD or disease relapse could help us to improve efficacy and safety of allo-HSCT. In recent years, extracellular vesicles (EVs) have emerged as critical components of intercellular crosstalk. Cancer-associated EVs that express the immune checkpoint molecule programmed death-ligand 1 (PD-L1) can suppress T-cell responses and thus contribute to immune escape. At the same time, it has been observed that inflammation triggers PD-L1 expression as part of a negative feedback network.Here, we investigated whether circulating EVs following allo-HSCT express PD-L1 and tested their efficacy to suppress the ability of (autologous) T-cells to effectively target AML blasts. Finally, we assessed the link between PD-L1 levels on EVs to (T-)cell reconstitution, GvHD, and disease relapse.We were able to detect PD-L1+ EVs that reached a peak PD-L1 expression at 6 weeks post allo-HSCT. Development of acute GvHD was linked to the emergence of PD-L1high EVs following allo-HSCT. Moreover, PD-L1 levels correlated positively with GvHD grade and declined (only) on successful therapeutic intervention. T-cell-inhibitory capacity was higher in PD-L1high EVs as compared with their PD-L1low counterparts and could be antagonized using PD-L1/PD-1 blocking antibodies. Abundance of T-cell-suppressive PD-L1high EVs appears to also impact GvL efficacy as patients were at higher risk for relapse. Finally, patients of PD-L1high cohort displayed a reduced overall survival.Taken together, we show that PD-L1-expressing EVs are present following allo-HSCT. PD-L1 levels on EVs correlate with their ability to suppress T-cells and the occurrence of GvHD. The latter observation may indicate a negative feedback mechanism to control inflammatory (GvHD) activity. This intrinsic immunosuppression could subsequently promote disease relapse.

The stem cell-specific long non-coding RNAs in leukemia

Leukemia is defined as a heterogeneous group of hematological cancers whose prevalence is on the rise worldwide. Despite the large body of studies, the etiology of leukemia has not been fully elucidated. Leukemia stem cells (LSCs) are a subpopulation of cancer cells that sustain the growth of the leukemic clone and are the main culprit for the maintenance of the neoplasm. In contrast to most leukemia cells, LSCs are resistant to chemo- and radiotherapy. Several recent studies demonstrated the altered expression profile of long non-coding RNAs (lncRNAs) in LSCs and shed light on the role of lncRNAs in the survival, proliferation, and differentiation of LSCs. LncRNAs are transcripts longer than 200 nucleotides that are implicated in several cellular and molecular processes such as gene expression, apoptosis, and carcinogenesis. Likewise, lncRNAs have shown a prognostic marker in leukemia patients and represent novel treatment options. Herein, we review the current knowledge concerning lncRNAs’ implication in the pathogenesis of LSCs and discuss their prognostic, diagnostic, and therapeutic potential (AU)

Risk factors for tumors or leukemia development in the first two years of life.

OBJECTIVES: The objective of this study was to determine the incidence of neoplastic diseases and associated risk factors in the early stages of life. METHODS: Data were retrospectively assessed in 730,000 live births between 2000 and 2019. The occurrence of tumors was monitored in the neonatal, infant (1-12 months), and toddler (13-24 months) periods. Risk factors were divided into demographic, internal, and environmental factors. The control group consisted of subjects in the same age category without oncological diseases. RESULTS: A total of 452 neoplastic diseases were diagnosed in the study sample. In total, 24% (110/452) manifested during the neonatal period, 45% (203/452) in infants, and 31% (139/452) at the age of 13-24 months. Any genetic disease (OR 26.68; 95% CI 7.64-93.12) and medications used by the mother (OR 3.07; 95% CI 1.32-7.15) were identified as risk factors. Without adjustment for all factors, asphyxia in the first minute, a younger age of the mother, lower pregnancy, and the presence of a congenital defect manifested themselves as risk factors. CONCLUSIONS: The highest risk factors for the development of early childhood tumors were identified as with medications used by the mother before or during pregnancy and genetic diseases.

Label-free testing strategy to evaluate packed red blood cell quality before transfusion to leukemia patients.

Patients worldwide require therapeutic transfusions of packed red blood cells (pRBCs), which is applied to the high-risk patients who need periodic transfusions due to leukemia, lymphoma, myeloma and other blood diseases or disorders. Contrary to the general hospital population where the transfusions are carried out mainly for healthy trauma patients, in case of high-risk patients the proper quality of pRBCs is crucial. This leads to an increased demand for efficient technology providing information on the pRBCs alterations deteriorating their quality. Here we present the design of an innovative, label-free, noninvasive, rapid Raman spectroscopy-based method for pRBCs quality evaluation, starting with the description of sample measurement and data analysis, through correlation of spectroscopic results with reference techniques' outcomes, and finishing with methodology verification and its application in clinical conditions. We have shown that Raman spectra collected from the pRBCs supernatant mixture with a proper chemometric analysis conducted for a minimum one ratio of integral intensities of the chosen Raman marker bands within the spectrum allow evaluation of the pRBC quality in a rapid, noninvasive, and free-label manner, without unsealing the pRBCs bag. Subsequently, spectroscopic data were compared with predefined reference values, either from pRBCs expiration or those defining the pRBCs quality, allowing to assess their utility for transfusion to patients with acute myeloid leukemia (AML) and lymphoblastic leukemia (ALL).

An updated lymphohematopoietic and bladder cancers risk evaluation for occupational and environmental exposures to 1,3-butadiene.

EPA designated 1,3-butadiene (BD) as a high priority chemical in December 2019 and is presently performing an evaluation under the Toxic Substances Control Act (TSCA). EPA's cancer dose-response assessment for BD was published in 2002 and was primarily based on a study on workers exposed to BD in the North American synthetic Styrene-Butadiene Rubber (SBR) Industry developed by the University of Alabama at Birmingham (UAB). EPA relied upon a Poisson regression of leukemia mortality data from this cohort (hereinafter referred to as the SBR study) to estimate the cancer potency of BD. At the time, the SBR cohort included more than 15,000 male workers that were followed up through 1991. The SBR cohort has undergone multiple updates over the past two decades. Most recently, Sathiakumar et al. (2021a, b) published an update, with 18 more years of follow up in addition to approximately 5,000 female workers and updated exposure concentration estimates. Recent EPA assessments (e.g., for ethylene oxide, USEPA 2016) based on epidemiological studies use Cox proportional hazards models because they offer better control of the effect of age in cancer development and are less restrictive than Poisson regression models. Here, we develop exposure-response models using standard Cox proportional hazards regression. We explore the relationship between six endpoints (all leukemia, lymphoid leukemia, myeloid leukemia, multiple myeloma, non-Hodgkin's lymphoma, and bladder cancer) and exposures to BD using the most recent exposure metrics and the most recent update of the SBR study. After adjusting for statistically significant covariates, an upper 95% confidence level on the cancer potency based on leukemia derived herein is 0.000086 per ppm, which is approximately 1,000-fold less than EPA's (2002) estimate of 0.08 per ppm and about 10-fold less than TCEQ's (2008) estimate of 0.0011 per ppm.

Multiple air pollutants exposure and leukaemia incidence in Tehran, Iran from 2010 to 2016: a retrospective cohort study.

OBJECTIVE: Leukaemia is one of the most common cancers and may be associated with exposure to environmental carcinogens, especially outdoor air pollutants. The objective of this study was to investigate the association of ambient air pollution and leukaemia in Tehran, Iran. DESIGN: In this retrospective cohort study, data about the residential district of leukaemia cases diagnosed from 2010 to 2016 were inquired from the Ministry of Health cancer database. Data from a previous study were used to determine long-term average exposure to different air pollutants in 22 districts of Tehran. Latent profile analysis (LPA) was used to classify pollutants in two exposure profiles. The association between air pollutants and leukaemia incidence was analysed by negative binomial regression. SETTING: Twenty-two districts of Tehran megacity. PARTICIPANTS: Patients with leukaemia. OUTCOME MEASURES: The outcome variables were incidence rate ratios (IRR) of acute myeloid and lymphoid leukaemia across the districts of Tehran. RESULTS: The districts with higher concentrations for all pollutants were near the city centre. The IRR was positive but non-significant for most of the air pollutants. However, annual mean NOx was directly and significantly associated with total leukaemia incidence in the fully adjusted model (IRR (95% CI): 1.03 (1.003 to 1.06) per 10 ppb increase). Based on LPA, districts with a higher multiple air-pollutants profile were also associated with higher leukaemia incidence (IRR (95% CI): 1.003 (0.99 to 1.007) per 1 ppb increase). CONCLUSIONS: Our study shows that districts with higher air pollution (nitrogen oxides and multipollutants) have higher incidence rates of leukaemia in Tehran, Iran. This study warrants conducting further research with individual human data and better control of confounding.

Exploring Blue Spaces' Effects on Childhood Leukaemia Incidence: A Population-Based Case-Control Study in Spain.

BACKGROUND: Blue spaces have been a key part of human evolution, providing resources and helping economies develop. To date, no studies have been carried out to explore how they may be linked to paediatric oncological diseases. OBJECTIVES: To explore the possible relationship of residential proximity to natural and urban blue spaces on childhood leukaemia. METHODS: A population-based case-control study was conducted in four regions of Spain across the period 2000-2018. A total of 936 incident cases and 5616 controls were included, individually matched by sex, year of birth and place of residence. An exposure proxy with four distances (250 m, 500 m, 750 m, and 1 km) to blue spaces was built using the geographical coordinates of the participants' home residences. Odds ratios (ORs) and 95% confidence intervals (95%CIs) for blue-space exposure were calculated for overall childhood leukaemia, and the acute lymphoblastic (ALL) and acute myeloblastic leukaemia (AML) subtypes, with adjustment for socio-demographic and environmental covariates. RESULTS: A decrease in overall childhood leukaemia and ALL-subtype incidence was found as we came nearer to children's places of residence, showing, for the study as a whole, a reduced incidence at 250 m (odds ratio (OR) = 0.77; 95%CI = 0.60-0.97), 500 m (OR = 0.78; 95%CI = 0.65-0.93), 750 m (OR = 0.80; 95%CI = 0.69-0.93), and 1000 m (OR = 0.84; 95%CI = 0.72-0.97). AML model results showed an increasing incidence at closest to subjects' homes (OR at 250m = 1.06; 95%CI=0.63-1.71). CONCLUSIONS: Our results suggest a possible association between lower childhood leukaemia incidence and blue-space proximity. This study is a first approach to blue spaces' possible effects on childhood leukaemia incidence; consequently, it is necessary to continue studying these spaces-while taking into account more individualised data and other possible environmental risk factors.

Comparison of Pulmonary Toxicity after Total Body Irradiation- and Busulfan-Based Myeloablative Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients.

Pulmonary toxicity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for childhood leukemia and myelodysplastic syndrome (MDS), along with the impact of different myeloablative conditioning regimens, remain incompletely described. Here we compared the acute and long-term incidence of pulmonary toxicity (PT) after total body irradiation (TBI)- and busulfan-based myeloablative conditioning. We conducted this retrospective cohort study of 311 consecutive pediatric patients with leukemia or MDS who underwent allo-HSCT at Dana-Farber Cancer Institute/Boston Children's Hospital between 2008 and 2018. PT was graded using Common Terminology Criteria for Adverse Events version 5.0. The primary objective was to compare the cumulative incidence of grade ≥3 and grade 5 PT after TBI-based and busulfan-based myeloablative conditioning using Gray's test. Secondary objectives were to determine factors associated with PT and overall survival (OS) using competing risk analysis and Cox regression analyses, respectively. There was no significant difference between the TBI-conditioned group (n = 227) and the busulfan-conditioned group (n = 84) in the incidence of grade ≥3 PT (29.2% versus 34.7% at 2 years; P = .26) or grade 5 pulmonary toxicity (6.2% versus 6.1% at 2 years; P = .47). Age (hazard ratio [HR], 1.70, 95% confidence interval [CI], 1.11 to 2.59; P = .01), grade ≥2 PT prior to allo-HSCT or preexisting pulmonary conditions (HR, 1.84, 95% CI, 1.24 to 2.72; P < .01), acute graft-versus-host disease (GVHD) (HR, 2.50; 95% CI, 1.51 to 4.14; P < .01), and chronic GVHD (HR, 2.61; 95% CI, 1.26 to 5.42; P = .01) were associated with grade ≥3 PT on multivariable analysis. Grade ≥3 PT was associated with worse OS (81.1% versus 61.5% at 2 years; P < .01). In pediatric allo-HSCT recipients, rates of PT were similar in recipients of TBI-based and recipients of busulfan-based myeloablative conditioning regimens. Age, the presence of PT or preexisting pulmonary conditions prior to transplantation, and the development of either acute or chronic GVHD were associated with grade ≥3 PT post-transplantation. Furthermore, the occurrence of grade 3-4 PT post-transplantation was associated with inferior OS.

Health effects of exposure to indoor volatile organic compounds from 1980 to 2017: A systematic review and meta-analysis.

Exposure to volatile organic compounds (VOCs) indoors is thought to be associated with several adverse health effects. However, we still lack concentration-response (C-R) relationships between VOC levels in civil buildings and various health outcomes. For this paper, we conducted a systematic review and meta-analysis of observational studies to summarize related associations and C-R relationships. Four databases were searched to collect all relevant studies published between January 1980 and December 2017. A total of 39 studies were identified in the systematic review, and 32 of these were included in the meta-analysis. We found that the pooled relative risk (RR) for leukemia was 1.03 (95% CI: 1.01-1.05) per 1 µg/m3 increase of benzene and 1.25 (95%CI: 1.14-1.37) per 0.1 µg/m3 increase of butadiene. The pooled RRs for asthma were 1.08 (95% CI: 1.02-1.14), 1.02 (95% CI: 1.00-1.04), and 1.04 (95% CI: 1.02-1.06) per 1 µg/m3 increase of benzene, toluene, and p-dichlorobenzene, respectively. The pooled RR for low birth weight was 1.12 (95% CI: 1.05-1.19) per 1 µg/m3 increase of benzene. Our findings provide robust evidence for associations between benzene and leukemia, asthma, and low birth weight, as well as for health effects of some other VOCs.

Assessment of Patient-Specific Human Leukocyte Antigen Genomic Loss at Relapse After Antithymocyte Globulin-Based T-Cell-Replete Haploidentical Hematopoietic Stem Cell Transplant.

Importance: Patient-specific human leukocyte antigen (HLA) genomic loss (HLA loss) is one of the reputed mechanisms of leukemia immune escape and relapse after haploidentical hematopoietic stem cell transplant (HSCT). However, clinical characteristics and prognosis of this distinct relapse type in the setting of haploidentical HSCT based on antithymocyte globulin (ATG) T-cell-replete conditioning are still unknown, especially for patients with lymphoid leukemia. Objective: To identify the incidence of and patient characteristics associated with HLA loss at hematologic cancer relapse after ATG-based haploidentical HSCT and to assess overall survival after HLA loss at relapse. Design, Setting, and Participants: This retrospective and multicenter case series study used data from medical records to identify patients who experienced relapse of hematologic cancer after receipt of ATG-based haploidentical HSCT. The study included 788 consecutive patients aged 8 to 70 years with lymphoid or myeloid leukemia who received ATG T-cell-replete haploidentical HSCT at the Zhejiang Cooperative Group for Blood and Marrow Transplantation between May 1, 2012, and May 31, 2021. Exposures: Relapse after ATG-based haploidentical HSCT. Main Outcomes and Measures: Incidence, risk factors, and postrelapse overall survival among patients with HLA loss at hematologic cancer relapse after receipt of haploidentical HSCT. Logistic regression analysis was used to identify characteristics associated with the likelihood of HLA loss, and Kaplan-Meier and Cox regression analyses were performed to evaluate postrelapse survival. Results: A total of 788 patients who received haploidentical HSCT for hematologic cancer were identified, 180 of whom experienced relapse after HSCT. Of those, 106 evaluable patients (median age, 30.9 years [range, 8.3-64.6 years]; 54 female [50.9%] and 52 male [49.1%]) were screened for HLA loss, which was detected in 54 patients (50.9%). Patients with HLA loss experienced relapse later than those without HLA loss (lymphoid group: median, 323 days [range, 98-2056 days] vs 151 days [range, 57-2544 days]; P = .01; myeloid group: median, 321 days [range, 55-1574 days] vs 223 days [range, 68-546 days]; P = .03). Among patients with lymphoid leukemia, those with minimal residual disease positivity before hematologic relapse (odds ratio [OR], 28.47; 95% CI, 1.99-407.98; P = .01), those with chronic graft-vs-host disease (OR, 27.68; 95% CI, 1.40-546.88; P = .03), and those with more than 180 days between HSCT and relapse (OR, 6.91; 95% CI, 1.32-36.22; P = .02) were more likely to lose unshared HLA at relapse, whereas male patients (OR, 0.03; 95% CI, 0.003-0.32; P = .04) were more likely to preserve their HLA genome at relapse. Patients with myeloid leukemia had different factors associated with HLA loss, including underweight status (OR, 0.10; 95% CI, 0.02-0.60; P = .01) and acute graft-vs-host disease (OR, 4.84; 95% CI, 1.14-20.53; P = .03). The receipt of preemptive donor lymphocyte infusion among patients with minimal residual disease recurrence did not postpone hematologic cancer relapse in those with HLA loss (median, 322 days [range, 204-1030 days]) compared with no receipt of donor lymphocyte infusion (median, 340 days [range, 215 days to not available]; P > .99). Conclusions and Relevance: In this study, HLA loss at leukemia relapse occurred frequently after receipt of ATG-based haploidentical HSCT. The identification of risk factors associated with HLA loss would help to prompt screening, avoid potentially harmful infusions of donor T cells, and develop alternative therapeutic strategies.

Cardiac Disorders Associated with Cellular Therapy and Novel Agents for Acute Leukemia.

BACKGROUND: Several novel strategies have emerged in the last decade as potential therapies for patients with chemorefractory lymphoproliferative diseases and acute leukemia. While these treatments include exciting drugs that dramatically change the landscape of treatment, the organ-toxicity profile associated with these therapies may be significant. This article focuses on cardiac disorders associated with chimeric antigen receptor T-cell (CAR-T) therapy, as well as with novel regimens for acute leukemia.

Organochlorine pesticides, oxidative stress biomarkers, and leukemia: a case-control study.

Exposure to pesticides has been linked to an elevated risk of leukemia. The present research aimed to evaluate the relationship between organochlorine (OC) pesticides and biomarkers of oxidative stress in patients with leukemia. This work was conducted on 109 patients with leukemia and 109 healthy controls. The serum concentrations of seven derivatives of OCs including alpha-hexachlorocyclohexane (HCH), beta-HCH, gamma-HCH, 2,4-dichlorodiphenyltrichloroethane (DDT), 4,4-DDT, 2,4-dichlorodiphenyldichloroethylene (DDE), and 4,4-DDE along with acetylcholinesterase (AChE), glutathione peroxidase (GPx), superoxide dismutase (SOD), paraoxonase-1 (PON1), and catalase (CAT) activities as well as total antioxidant capacity (TAC), nitric oxide (NO), protein carbonyl (PC), and malondialdehyde (MDA) levels were measured in all the subjects. Levels of OCs were remarkably higher in patients with leukemia compared with the controls (p<0.05). In addition, levels of SOD, AChE, GPx, PON1, and TAC were remarkably lower in patients with leukemia compared with controls (p<0.05). In contrast, MDA, NO, and PC concentrations were higher in patients with leukemia than in the controls (p<0.05). Moreover, the serum level of 4,4-DDE was negatively associated with GPx activity (p=0.038). Our findings suggest that OCs may play a role in the development of leukemia by disrupting the oxidant/antioxidant balance.

Association Between Neonatal Phototherapy Exposure and Childhood Neoplasm.

OBJECTIVE: To study the association between phototherapy for the treatment of neonatal jaundice and the risk of childhood neoplasms. STUDY DESIGN: This population-based retrospective cohort study included all infants born at ≥32 weeks of gestation at a single medical center between 1988 and 2018. The incidence of neoplastic diseases was compared between infants exposed to phototherapy and those unexposed. Kaplan-Meier curves and log-rank tests were used for cumulative incidence comparison, and multivariable Cox and Weibull survival analysis were used to adjust for confounding or clinically significant variables. RESULTS: The study population included 342 172 infants, of whom 18 797 (5.5%) were exposed to phototherapy. The median duration of follow-up was 9.5 years (range, birth to 18 years). Phototherapy was associated with a significantly increased risk for childhood malignancies and benign tumors (preterm birth and maternal age-adjusted hazard ratio, 1.89 [95% CI, 1.35-2.67] for malignancies and 1.27 [95% CI, 1.02-1.57] for benign tumors) Specifically, phototherapy was associated with hematopoietic cancers and leukemia (hazard ratio, 2.29 [95% CI, 1.48-3.54; P < .01] for hematopoietic cancers and 2.51 [95% CI, 1.52-4.14; P < .001] for leukemia), but not with solid tumors and lymphoma. CONCLUSIONS: Phototherapy may be associated with a slightly increased childhood risk of neoplasm. It is important to strictly follow phototherapy treatment guidelines to minimize unnecessary exposure.

Increased visceral fat distribution and body composition impact cytokine release syndrome onset and severity after CD19 chimeric antigen receptor T-cell therapy in advanced B-cell malignancies.

Chimeric antigen receptor T-cell (CAR-T) therapy is associated with a distinct toxicity profile that includes cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is characterized by the release of pro-inflammatory cytokines such as interleukin 6 (IL-6) and is closely linked to CAR-T expansion and bystander cells like monocytes/macrophages. In other hyperinflammatory states, obesity contributes to inflammatory cascades and acts as a risk factor for disease severity. We aimed to study the influence of anthropometric and body composition (BC) measurements on CAR-T-related immunotoxicity in 64 patients receiving CD19-directed CAR-T for relapsed/refractory Bcell malignancies. Patients with grade ≥2 CRS presented with a significantly higher median body mass index (BMI), waist circumference, waist-to-height ratio (WtHR) and visceral adipose tissue (VAT). These parameters were also found to be associated with an earlier CRS onset. Other adipose deposits and muscle mass did not differ between patients with grade 0-1 CRS versus grade ≥2 CRS. Moreover, BC parameters did not influence ICANS severity or onset. In a multivariate binary logistic regression incorporating known risk factors of immunotoxicity, the factors BMI, waist circumference, WtHR and VAT increased the probability of grade ≥2 CRS. Receiver operating characteristic analyses were utilized to determine optimal discriminatory thresholds for these parameters. Patients above these thresholds displayed markedly increased peak IL-6 levels. Our data imply that increased body composition and VAT in particular represent an additional risk factor for severe and early CRS. These findings carry implications for risk-stratification prior to CD19 CAR-T and may be integrated into established risk models.