Efficacy and Safety in Early application of Ruxolinitib for high-risk: Acute lymphoblastic leukemia to prevent GVHD and recurrence after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been identified as the potentially curative treatment for high-risk acute lymphoblastic leukemia (ALL) in adult patients. However, relapse of the disease and/or development of graft-versus-host disease (GVHD) remain to be the most common barriers for successful allo-HSCT. Preclinical studies showed that ruxolitinib, a Janus tyrosine kinase (Jak)1 and Jak2 inhibitor, has a selective anti-GVHD effects while preserving a potent graft-versus-leukemia (GVL) effect. Our study aimed to investigate the efficacy and safety in early application of ruxolitinib for the high-risk ALL patients to prevent GVHD. METHODS: There were eight patients undergoing allo-HSCT at the Bone Marrow Transplantation Center of the Third Xiangya Hospital of Central South University between April 2020 and April 2021. Ruxolitinib (5-10 mg twice daily) was administered early (median time: 45 days) after stem cell infusion. RESULTS: After a median follow-up of 14 months (range from 8 to 18 months), the ALL disease relapse occurred in two cases. Among all eight patients, two of them developed grade I/II acute (a) GVHD, while no patient developed grade III/IV aGVHD, and one patient developed chronic (c) GVHD. As for the virus activation, no patient developed EBV activation or EBV related lymphoproliferative disease, and three patients developed CMV activation. Our results suggest that the early application of ruxolitinib could safely and effectively prevent the occurrence of GVHD after allo-HSCT for the high-risk ALL patients. However, it may have a limited effect on preventing the recurrence of high-risk ALL and thus may require additional therapy with other anti-relapse drugs. CONCLUSIONS: Our preliminary observations suggest that an early application of ruxolitinib can safely and effectively prevent the occurrence of GVHD after allo-HSCT for the high-risk ALL patients. However, ruxolitinib may have a limited effect on preventing the ALL recurrence of high-risk patients.

Pre- and Postnatal Exposures to Tobacco Smoking and Survival of Childhood Acute Lymphoblastic and Myeloid Leukemias in California, United States.

BACKGROUND: Tobacco smoke adversely affects the prognosis of adult cancers including myeloid leukemia, but less is known in children. METHODS: We evaluated whether pre- and postnatal exposures to tobacco smoke decrease 5-year survival of 1,235 childhood acute lymphoblastic leukemia (ALL) and 188 childhood acute myeloid leukemia (AML) cases derived from a population-based case-control study in California. Cases were diagnosed between 1995 and 2015 (median follow-up time of 13.2 years overall). We obtained data on tobacco smoking (before conception, during pregnancy, after birth), parental education and income, clinical features, and vital status through 2020. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for mortality associated with smoking, adjusting for sociodemographic characteristics and risk group (ALL only). RESULTS: About 23% of mothers and 39% of fathers reported smoking and 130 children with ALL and 52 with AML died within 5 years. For AML, increased risks of death were observed among children whose fathers smoked before conception compared with nonsmoking fathers [HR = 1.41; 95% confidence interval (CI), 0.95-3.44 and 3.47; 95% CI, 1.37-8.81, respectively for <20 vs. ≥20 cigarettes per day; Ptrend = 0.01]. HR for child's passive smoking was 1.74, 95% CI, 0.81-3.73. Paternal preconception smoking may also reduce 5-year survival among ALL with favorable prognostic molecular subtypes (high hyperdiploidy and absence of IKZF1 gene deletion), although the associations did not reach statistical significance (Pheterogeneity = 0.07). CONCLUSIONS: Paternal preconception smoking decreased 5-year survival of childhood AML. IMPACT: Knowledge of exposure to tobacco smoking should be integrated in the treatment plan of childhood leukemias.

Adverse events and efficacy of second-round CAR-T cell therapy in relapsed pediatric B-ALL.

OBJECTIVE: Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment approach for pediatric patients suffering from relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, there was a paucity of data on the challenges associated with second-round CAR-T therapy in this population. METHODS: Medical records of nine pediatric patients who received second-round CAR-T therapy in a single center from June 2019 to May 2023 were analyzed. Throughout the course of the clinical trial, we evaluated adverse events including CRS, CRES, infections, hematologic toxicity, and organ injury, as well as CAR-T responses. RESULTS: Except for one patient who chose CART therapy due to testicular relapse, the remaining patients had indications for CAR-T therapy due to relapse with bone marrow alone or combined with other site. There were no difference between the transfusion dose of CART1 and CART2. No differences of incidence and grade of CRS was found between the first-round CAR-T therapy (CART1) and second-round CAR-T therapy (CART2). Additionally, we found that the incidence of CRES was higher for CART1(3/9,33.3%) than CART2(1/9,11.1%). Our findings revealed that there were no differences of IL-2, IL-4, IL-6, IL-10, IFN-γ, and TNF-α between CART1 and CART2, but the peak level of IL-17A was significantly higher in patients receiving CART1 compared to those receiving CART2 (p = .011). Early and late infection rates after CART1 were higher than CART2. Based on the dynamic changes of ANC, hemoglobin and platelet, ANC, and platelet were reduced obviously post CART. It seems that the incidences of severe thrombocytopenia and severe anemia were higher in the CART1 group compared to CART2. The MRD-negative CR rates for CART1 and CART2 are 100% and 44.4%, respectively (p = .029). All patients experienced events (relapse, chemotherapy, transplantation, or death) after receiving CART2, including one died, three discharged automatically, and the remaining five patients survived. CONCLUSION: Although the remission rate of CART2 is not as high as the CART1 due to the severity of the disease, its safety regarding CRS, CRES, infections, and organ injury is still excellent. Therefore, CART2 remains a viable option for treating pediatric relapsed B-ALL.

Low rate of nonrelapse mortality in under-4-year-olds with ALL given chemotherapeutic conditioning for HSCT: a phase 3 FORUM study.

ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). For young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of 2 TBI-free conditioning regimens in children aged <4 years with ALL. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children received transplantation and were observed for ≥6 months (median follow-up: 3 years). The 3-year OS was 0.63 (95% confidence interval [95% CI], 0.52-0.72) and 0.76 (95% CI, 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (P = .075), respectively. Three-year EFS was 0.52 (95% CI, 0.41-0.61) and 0.51 (95% CI, 0.39-0.62), respectively (P = .794). Cumulative incidence of nonrelapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI, 0.02-0.12) vs 0.03 (95% CI: <0.01-0.09) (P = .406) and 0.42 (95% CI, 0.31-0.52) vs 0.45 (95% CI, 0.34-0.56) (P = .920), respectively. Grade >1 acute graft-versus-host disease (GVHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% of those receiving Flu/Thio/Treo (P = .049), whereas grade 3/4 occurred in 10% and 9%, respectively (P = .813). The 3-year incidence of chronic GVHD was 0.07 (95% CI, 0.03-0.13) vs 0.05 (95% CI, 0.02-0.11), respectively (P = .518). In conclusion, both chemotherapeutic conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure. This trial was registered at www.clinicaltrials.gov as #NCT01949129.

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.

THE STRUCTURE OF THE INCIDENCE OF ONCOHEMATOLOGICAL DISEASES IN ECOLOGICALLY DISADVANTAGED REGIONS OF THE DNIPROPETROVSK REGION FOR THE PERIOD 2006-2017. / СТРУКТУРА ЗАХВОРЮВАНОСТІ НА ОНКОГЕМАТОЛОГІЧНІ ХВОРОБИ В ЕКОЛОГІЧНО НЕБЛАГОПОЛУЧНИХ РЕГІОНАХ ДНІПРОПЕТРОВСЬКОЇ ОБЛАСТІ ЗА ПЕРІОД 2006­2017 РОКІВ).

OBJECTIVE: to conduct a comparative analysis of the incidence of malignant oncohematological diseases structure among the population of the 4 most ecologically disadvantaged cities of the Dnipropetrovsk region, taking into account the possible influence of various adverse environmental factors (radiation and chemical pollution of air, water and soil) for the period 2006-2017. MATERIALS AND METHODS: 1948 cases of acute myeloblastic and lymphoblastic leukemia, chronic myeloid and lymphocytic leukemia in residents of 4 cities of the Dnipropetrovsk region were analyzed, taking into account the possible influence of adverse environmental factors (radiation, air pollution, etc.). We used clinical and hematological data per patient and statistic information on these diseasis incidence in the region. RESULTS: An analysis of the oncohematological patients incidence structure, namely: acute lymphoblastic (C91.0) and myeloblastic leukemia (C92.0), chronic lymphocytic (C91.1) and myeloid (C92.1) leukemia, over 12 years in environmentally disadvantaged cities of Dnipropetrovsk region have been conducted. A comparative analysis of the incidence of these diseases among the population of 4 cities of the Dnipropetrovsk region was carried out, taking into account the possible influence of adverse environmental factors (radiation, air pollution, etc.). An excess of the incidence rates of the above-mentioned oncohematological diseases for the period 2006-2017 was revealed in the cities of Dnipro, Kryvyi Rih, Kamianske and Zhovti Vody, where environmental factors significantly affect the increase in morbidity due to pollution mainly by radioactive and chemical substances.

Lessons from mouse models in the impact of risk factors on the genesis of childhood B-cell leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) stands as the primary contributor to childhood cancer-related mortality on a global scale. The development of the most conventional forms of this disease has been proposed to be conducted by two different steps influenced by different types of risk factors. The first step is led by a genetic insult that is presumably acquired before birth that transforms a healthy cell into a preleukemic one, which is maintained untransformed until the second step takes place. This necessary next step to leukemia development will be triggered by different risk factors to which children are exposed after birth. Murine models that recap the stepwise progression of B-ALL have been instrumental in identifying environmental and genetic factors that contribute to disease risk. Recent evidence from these models has demonstrated that specific environmental risk factors, such as common infections or gut microbiome dysbiosis, induce immune stress, driving the transformation of preleukemic cells, and harboring genetic alterations, into fully transformed leukemic cells. Such models serve as valuable tools for investigating the mechanisms underlying preleukemic events and can aid in the development of preventive approaches for leukemia in child. Here, we discuss the existing knowledge, learned from mouse models, of the impact of genetic and environmental risk factors on childhood B-ALL evolution and how B-ALL prevention could be reached by interfering with preleukemic cells.

Microbiota, Diet and Acute Leukaemia: Tips and Tricks on Their Possible Connections.

Acute leukaemia is probably one of the most recurrent cancers in children and younger adults, with an incidence of acute lymphoblastic leukaemia in 80% of cases and an incidence of acute myeloid leukaemia in 15% of cases. Yet, while incidence is common in children and adolescents, acute leukaemia is a rare disease whose aetiology still requires further analysis. Many studies have investigated the aetiology of acute leukaemia, reporting that the formation of gut microbiota may be modified by the start and development of many diseases. Considering that in patients affected by acute lymphoblastic leukaemia, there is an inherent disequilibrium in the gut microbiota before treatment compared with healthy patients, increasing evidence shows how dysbiosis of the gut microbiota provokes an inflammatory immune response, contributing to the development of cancer. Our analysis suggeststhe key role of gut microbiota in the modulation of the efficacy of leukaemia treatment as well as in the progress of many cancers, such as acute leukaemia. Therefore, in this paper, we present an examination of information found in literature regarding the role of dietary factors and gut microbiota alterations in the development of leukaemia and suggest possible future preventive and therapeutic strategies.

Risk factors for overweight and obesity after childhood acute lymphoblastic leukemia in North America and Switzerland: A comparison of two cohort studies.

BACKGROUND: After childhood acute lymphoblastic leukemia (ALL), sequelae include overweight and obesity, yet with conflicting evidence. We compared the prevalence of overweight and obesity between ≥5-year ALL survivors from the North American Childhood Cancer Survivor Study (CCSS) and the Swiss Childhood Cancer Survivor Study (SCCSS) and described risk factors. METHODS: We included adult childhood ALL survivors diagnosed between 1976 and 1999. We matched CCSS participants (3:1) to SCCSS participants by sex and attained age. We calculated body mass index (BMI) from self-reported height and weight for 1287 CCSS and 429 SCCSS participants; we then compared those with siblings (2034) in North America and Switzerland (678) siblings. We assessed risk factors for overweight (BMI 25-29.9 kg/m2 ) and obesity (≥30 kg/m2 ) using multinomial regression. RESULTS: We found overweight and obesity significantly more common among survivors in North America when compared with survivors in Switzerland [overweight: 30%, 95% confidence interval (CI): 27-32 vs. 24%, 21-29; obesity: 29%, 27-32 vs. 7%, 5-10] and siblings (overweight: 30%, 27-32 vs. 25%, 22-29; obesity: 24%, 22-26 vs. 6%, 4-8). Survivors in North America [odds ratio (OR) = 1.24, 1.01-1.53] and Switzerland (1.27, 0.74-2.21) were slightly more often obese than siblings. Among survivors, risk factors for obesity included residency in North America (5.8, 3.7-9.0); male (1.7, 1.3-2.3); attained age (≥45 years: 5.1, 2.4-10.8); Non-Hispanic Black (3.4, 1.6-7.0); low household income (2.3, 1.4-3.5); young age at diagnosis (1.6, 1.1-2.2). Cranial radiotherapy ≥18 Gray was only a risk factor for overweight (1.4, 1.0-1.8); steroids were not associated with overweight or obesity. Interaction tests found no evidence of difference in risk factors between cohorts. CONCLUSIONS: Although treatment-related risk for overweight and obesity were similar between regions, higher prevalence among survivors in North America identifies important sociodemographic drivers for informing health policy and targeted intervention trials.

Hyper-CVAD versus dose-adjusted EPOCH as initial treatment for adults with acute lymphoblastic leukemia.

OBJECTIVES: We recently performed a single-arm phase II trial of DA-EPOCH in adults with acute lymphoblastic leukemia (ALL). We sought to compare these results to those with standard Hyper-CVAD. METHODS: We created a retrospective matched cohort of patients who received Hyper-CVAD (n = 69) at our center and otherwise met eligibility criteria for the DA-EPOCH trial (n = 53). RESULTS: Our outcomes support the use of Hyper-CVAD over DA-EPOCH in Ph- disease for both overall survival (OS; HR 0.18, p = .004) and event-free survival (EFS; HR 0.51, p = .06). In contrast, outcomes were similar in Ph+ disease (OS HR 0.97, p = .96; EFS HR 0.65, p = .21). Rates of morphologic remission and measurable residual-disease negativity were similar between the regimens. Hyper-CVAD was associated with significantly more febrile neutropenia (OR 1.9, p = .03) and a greater incidence of Grade 4 or 5 adverse events (20% vs. 6%). Average transfusions per cycle of both red blood cells (p < .001) and platelets (p < .001) were five-fold higher with Hyper-CVAD. CONCLUSIONS: Our findings support continued use of Hyper-CVAD for Ph- ALL but suggest that DA-EPOCH may be a reasonable alternative for Ph+ ALL. These data also highlight a potential role for DA-EPOCH in resource-limited settings or when more intense therapy is not feasible.

Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: A Children's Oncology Group study (AINV18P1).

BACKGROUND: Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. PROCEDURE: The Children's Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug re-induction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1-3) and subsequently combined with re-induction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort. RESULTS: Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m2 /dose orally for 21 days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. CONCLUSIONS: Palbociclib in combination with re-induction chemotherapy was well tolerated with a RP2D of 50 mg/m2 /day for 21 days. Complete responses were observed among heavily pretreated patients.

Novel strategies to prevent and overcome relapse after allogeneic hematopoietic cell transplantation in acute lymphoblastic leukemia.

The outcome of B-cell acute lymphoblastic leukemia (B-ALL) has improved over time with the incorporation of multi-agent chemotherapy in the treatment landscape as well as the recent approval of immunotherapeutic agents allowing a larger proportion of patients to undergo allogeneic hematopoietic cell transplantation (allo-HCT) which is still considered a potential curative approach. However, relapse post-transplant is still occurring and constitutes a common cause of treatment failure in B-ALL. The present review aims to discuss the novel strategies and therapies used to prevent and overcome relapse post allo-HCT in patients with ALL, focusing on the role of tyrosine kinase inhibitors in Philadelphia chromosome positive B-ALL, the role of innovative agents such as blinatumomab and inotuzumab ozogamicin, and finally the role of cellular therapy.

Total marrow lymphoid irradiation and cyclophosphamide is associated with low toxicity and good outcomes in patients undergoing hematopoietic stem cell transplantation for acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crises - A phase I study.

INTRODUCTION: Total marrow lymphoid irradiation (TMLI) can deliver higher doses of irradiation without increasing toxicity compared to Total body irradiation (TBI). METHODS: Twenty adult patients undergoing hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia with lymphoid blast crises (CML-LBC) received TMLI and cyclophosphamide for conditioning. Ten patients each received 13.5 or 15 Gy of TMLI. The graft source was peripheral blood stem cells in all, and donors included matched related (n = 15), haplo-identical (n = 3) or matched unrelated donors (n = 2). RESULTS: The median cell dose infused was 9 × 106 CD34/kg (range 4.8-12.4). Engraftment occurred in all (100%) at a median of 15 days (range: 14-17). Toxicity was low with hemorrhagic cystitis seen in two but no sinusoidal obstruction syndrome. Acute GVHD occurred in 40% while chronic GVHD was seen in 70.5%. Viral infections were seen in 55% while blood stream bacterial infections occurred in 20% and invasive fungal disease (IFD) in 10%. The Day 100 non-relapse mortality (NRM) was 10%. At a median follow up of 25 months (range 2-48), two patients have relapsed. Overall survival at 2 years is 80% while the disease-free survival is 75%. CONCLUSIONS: The combination of TMLI and cyclophosphamide for myeloablative conditioning is associated with low toxicity and favorable early outcomes in patients undergoing HSCT for ALL and CML-LBC.

Residential proximity to petrol stations and risk of childhood leukemia.

Petrol stations emit benzene and other contaminants that have been associated with an increased risk of childhood leukemia. We carried out a population-based case-control study in two provinces in Northern Italy. We enrolled 182 cases of childhood leukemia diagnosed during 1998-2019 and 726 age- and sex-matched population controls. We geocoded the addresses of child residences and 790 petrol stations located in the study area. We estimated leukemia risk according to distance from petrol stations within a 1000 m buffer and amount of supplied fuel within a buffer of 250 m from the child's residence. We used conditional logistic regression models to approximate risk ratios (RRs) and 95% confidence intervals (CIs) for associations of interest, adjusted for potential confounders. We also modeled non-linear associations using restricted cubic splines. In secondary analyses, we restricted to acute lymphoblastic leukemia (ALL) cases and stratifed by age (<5 and ≥5 years). Compared with children who lived≥1000 m from a petrol station, the RR was 2.2 (95% CI 0.5-9.4) for children living<50 m from nearest petrol station. Associations were stronger for the ALL subtype (RR=2.9, 95% CI 0.6-13.4) and among older children (age≥5 years: RR=4.4, 95% CI 0.6-34.1; age<5 years: RR=1.6, 95% CI 0.1-19.4). Risk of leukemia was also greater (RR=1.6, 95% CI 0.7-3.3) among the most exposed participants when assigning exposure categories based on petrol stations located within 250 m of the child's residence and total amount of gasoline delivered by the stations. Overall, residence within close proximity to a petrol station, especially one with more intense refueling activity, was associated with an increased risk of childhood leukemia, though associations were imprecise.

Ph-like acute lymphoblastic leukemia in adults: understanding pathogenesis, improving outcomes, and future directions for therapy.

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subgroup of B cell ALL with distinct genotypes, unified by gene expression profile similar to Ph-positive ALL, but lacking the BCR::ABL1 fusion. Ph-like ALL patients respond inadequately to conventional chemotherapy with higher rates of induction failure, persistent measurable residual disease, and lower survival rates compared to other B cell ALL subtypes. Considering Ph-like ALL's chemo-refractory nature, there is an interest in pursuing innovative therapeutic approaches to treat, including the combination of tyrosine kinase inhibitors with frontline regimens, and early introduction of novel antibody-drug conjugates and immunotherapies. Accurate diagnosis and disease-risk stratification are key to increase access for high-risk patients to allogeneic hematopoietic cell transplantation in their first complete remission. In this review, we will discuss our current knowledge of pathogenesis of Ph-like ALL, diagnostic strategies, as well as emerging data on new and current treatment strategies for this disease.

Glyphosate in house dust and risk of childhood acute lymphoblastic leukemia in California.

BACKGROUND: Residential use of pesticides has been associated with increased risk of childhood acute lymphoblastic leukemia (ALL). We evaluated determinants of glyphosate concentrations in house dust and estimated ALL risk in the California Childhood Leukemia Study (CCLS). METHODS: The CCLS is a population-based case-control study of childhood leukemia in California. Among those < 8-years (no move since diagnosis/reference date), we collected dust (2001-2007) from the room where the child spent the most time while awake and measured > 40 pesticides. Three-to-eight years later, we collected a second sample from non-movers. We used Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry to measure glyphosate (µg/g dust) for 181 ALL cases and 225 controls and for 45 households with a second dust sample. We used multivariable Tobit regression to evaluate determinants of glyphosate concentrations. Odds ratios (ORs) and 95 % confidence intervals (CI) were calculated for ALL and quartiles of the concentration (first samples) using unconditional logistic regression. We computed the within- and between-home variance and intraclass correlation coefficient (ICC). RESULTS: Glyphosate was frequently detected (cases: 98 %; controls: 99 %). Higher concentrations were associated with occupational pesticide exposure, nearby agricultural use, treatment for lawn weeds and bees/wasps, and sampling season. Increasing concentrations were not associated with ALL risk (adjusted ORQ4vsQ1 = 0.8, CI: 0.4-1.4). We observed similar null associations for boys and girls, Hispanics and non-Hispanic whites, and among those who resided in their home since birth (76 cases/117 controls) or age two (130 cases/176 controls). The ICC was 0.32 indicating high within-home temporal variability during the years of our study. CONCLUSIONS: We observed higher concentrations in homes associated with expected predictors of exposure but no association with childhood ALL risk. Due to continuing use, potential exposure to young children is high. It will be important to evaluate risk in future studies with multiple dust measurements or biomarkers of exposure.

Prognosis of patients with acute lymphoblastic leukaemia relapsing after allogeneic stem cell transplantation.

The outcomes of patients with acute lymphoblastic leukaemia (ALL) presenting relapse after allogeneic stem cell transplant (allo-SCT) are poor, with few data available in this setting. OBJECTIVE AND METHODS: To evaluate the outcomes of patients with ALL presenting relapsed after allo-SCT, we performed a retrospective study including 132 from 11 centres in Spain. RESULTS: Therapeutic strategies consisted of palliative treatment (n = 22), chemotherapy (n = 82), tyrosine kinase inhibitors (n = 26), immunotherapy with inotuzumab and/or blinatumumab (n = 19), donor lymphocyte infusions (n = 29 pts), second allo-SCT (n = 37) and CAR T therapy (n = 14). The probability of overall survival (OS) at 1 and 5 years after relapse was 44% (95% confidence interval [CI]: 36%; 52%) and 19% (95% CI: 11%; 27%). In the 37 patients undergoing a second allo-SCT, the 5-year estimated OS probability was 40% [22%; 58%]. Younger age, recent allo-SCT, late relapse, 1st complete remission at 1st allo-SCT and chronic graft-versus-host disease confirmed their positive impact on survival in the multivariable analysis. CONCLUSION: Despite the poor prognosis of patients with ALL presenting relapse after a first allo-SCT, some can be satisfactorily rescued and a second allo-SCT still remains a valid option for selected patients. Moreover, emerging therapies really might improve ALL patients outcome when relapsing after an allo-SCT.

Outdoor artificial light at night, air pollution, and risk of childhood acute lymphoblastic leukemia in the California Linkage Study of Early-Onset Cancers.

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children (age 0-14 years); however, the etiology remains incompletely understood. Several environmental exposures have been linked to risk of childhood ALL, including air pollution. Closely related to air pollution and human development is artificial light at night (ALAN), which is believed to disrupt circadian rhythm and impact health. We sought to evaluate outdoor ALAN and air pollution on risk of childhood ALL. The California Linkage Study of Early-Onset Cancers is a large population-based case-control in California that identifies and links cancer diagnoses from the California Cancer Registry to birth records. For each case, 50 controls with the same year of birth were obtained from birth records. A total of 2,782 ALL cases and 139,100 controls were identified during 2000-2015. ALAN was assessed with the New World Atlas of Artificial Night Sky Brightness and air pollution with an ensemble-based air pollution model of particulate matter smaller than 2.5 microns (PM2.5). After adjusting for known and suspected risk factors, the highest tertile of ALAN was associated with an increased risk of ALL in Hispanic children (odds ratio [OR] = 1.15, 95% confidence interval [CI] 1.01-1.32). There also appeared to be a borderline association between PM2.5 level and risk of ALL among non-Hispanic White children (OR per 10 µg/m3 = 1.24, 95% CI 0.98-1.56). We observed elevated risk of ALL in Hispanic children residing in areas of greater ALAN. Further work is needed to understand the role of ALAN and air pollution in the etiology of childhood ALL in different racial/ethnic groups.

Severe Recurrent Nocturnal Hypoglycemia During Chemotherapy With 6-mercaptopurine in 2 Children With Acute Lymphoblastic Leukemia.

Mercaptopurine (6MP) and methotrexate are the cornerstones of maintenance therapy in pediatric patients with acute lymphoblastic leukemia. However, although bone marrow suppression and liver dysfunction are common side effects of these antimetabolites, 6MP-induced hypoglycemia during the maintenance phase is rare. Guidelines and international protocols are well established for the management of bone marrow suppression and liver dysfunction, but promptly identifying 6MP-induced hypoglycemia is the key to its control. Here we report 2 cases of leukemia that developed hypoglycemia during the maintenance phase. Both patients were boys younger than 6 years of age and both suffered symptomatic morning hypoglycemia induced by 6MP (which was diagnosed after excluding all other possible causes). Successful management included changing the time of 6MP administration from evening to morning. Other management options are also discussed.