Post-induction Phase Research Articles

Non-Alcoholic Fatty Liver Disease in Children with Acute Lymphoblastic Leukemia

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a major health concern and is predicted to become the leading cause of end-stage liver disease in the coming decades. Few studies examined the frequency of NAFLD in childhood acute lymphoblastic leukemia (ALL). Aim To assess the prevalence of NAFLD in children with ALL at various phases of treatment. The study also investigates the impact of different treatment regimens and other risk factors on NAFLD development in this population. Methods This cross-sectional study with prospective follow up for the newly diagnosed group of patients included 60 children with ALL recruited from the Pediatric Oncology Unit at Ain Shams University Children’s Hospital. We collected data including sociodemographic data, age at diagnosis of ALL, diagnosis and risk stratification, treatment regimens, as well as 24-hour dietary recall. All patients were assessed for anthropometric measurements, body composition analysis, abdominal examination, laboratory investigations including liver function tests and lipid profile in addition to abdominal ultrasound. Results The mean age of the studied patients was 8.9 years. Among all studied groups, 56% of the post- induction group, 10% of patients during the maintenance phase and 25% post-completion of therapy had NAFLD. Regarding protocol of therapy in all patients who received chemotherapy, (100%) of patients who had received total XV-HR as a protocol of therapy had NAFLD with p-value = 0.023, on the other hand there was no difference found between patients with and without NAFLDregarding total XV-LR and total XV-SR protocols with p value 0.436 and 0.933 respectively. Among all studied groups, patients with NAFLD had higher median energy level (3272 kcal/d in NAFLD vs 1834 kcal/d in non-NAFLD, p = 0.021), higher median fat intake (87 g/d for NAFLD vs 49 g/d for non-NAFLD, p = 0.046), higher median carbohydrate intake (486 g/d for NAFLD vs 274 g/d for non NAFLD, p = 0.016) and higher median fructose containing beverages (2 per month for NAFLD group versus 0 per month for non-NAFLD group p = 0.041). Additionally, NAFLD group showed higher median triceps skin fold thickness z-score of 0.09 vs -0.51 in non-NAFLD group, p = 0.002. However, there was no difference between patients with and without NAFLD in all studied patients regarding body composition parameters. Higher percentage (42.9%) of patients who had high LDL level (mg/dl) had been found in NAFLD group versus (10.9%) in non NAFLD, p = 0.022, while there was no difference found between patients with and without NAFLD in all studied patients regarding LDL serum levels. Body fat percentage positively correlated with serum LDL- cholesterol during ALL treatment with (r = 0.508, and p = 0.044). There was no difference found between patients with and without NAFLD in all treatment phases regarding median ALT (21, 18 IU/L in non-NAFLD and NAFLD group respectively), p = 0.588, median AST serum level (28, 30 IU/L in non-NAFLD and NAFLD group respectively), p = 0.612. Conclusion NAFLD is a relatively common finding in childhood ALL especially in the post-induction phase. ALL patients treated with total XV-HR protocol of therapy more frequently developed NAFLD than patients on total XV-LR and total XV-SR protocols. NAFLD patients had significantly higher dietary intake compared to non NAFLD patients. There was a positive correlation between body fat percentage and serum levels of LDL in children during ALL treatment.

Clinical Profile, Toxicities, and Survival Outcome of MCP841 in Pediatric Acute Lymphoblastic Leukemia in Current Era: A Retrospective Study from Eastern India

Abstract Introduction: The overall survival in pediatric acute lymphoblastic leukemia (ALL) ranges from 45 to 81% in India. Aggressive chemotherapy protocols like MCP841 have improved the outcome and it can be delivered with minimal supportive care. This study retrospectively analyses the clinical profile and overall survival of patients treated by this protocol. Objective: This single-center study aims to estimate the event-free survival of patients treated accordingly to the MCP841 protocol with high-dose cytarabine (HDAC) at 2 g/m2 as the backbone, along with the risk-stratified incidence and cause of mortality in childhood ALL. Material and Methods: Records of 156 patients aged 1 to 19 years, newly diagnosed with ALL from June 2009 to August 2013 who were treated according to the forementioned protocol were analyzed. Risk stratification for both precursor B-cell ALL (B-ALL) and T-cell ALL (T-ALL) was done, followed by an analysis of the correlation of risk-stratified groups with mortality and survival outcomes. Result: Precursor B-ALL was found in 70% patients (including 69.7% [n = 76] standard risk, 20.1% [n = 22] intermediate risk, and 10% [n = 11] high risk), while 30% had T-ALL (including 74.4% [n = 35] standard risk and 25.5% [n = 12] high risk). Death during induction occurred in 0.04% (n = 5) precursor B-ALL and 23% (n = 11) T-ALL patients. The causes were infection in 62.5%, hemorrhage in 25%, and cortical venous thrombosis in 12.5%. Among those who attained remission (89.7%, n =140), relapse occurred in 26% (n = 27) precursor B-ALL and 28% (n = 10) T-ALL patients. Approximately 31% patients died in the postinduction phase, with progressive disease due to relapse being the most common cause and bone marrow the most common site. Event-free survival at 168 months for overall population, precursor B-ALL, and T-ALL was 59, 62.4, and 51.1%, respectively. Conclusion: A comparable survival outcome in par with similar centers in developing countries with the MCP841 protocol was found. Infections are a major cause of mortality during treatment, especially when associated with malnourishment. Relapsed disease and poor salvage rates remain a major hurdle to achieving better survival in developing countries; however, better supportive care and infection control measures along with implementing risk-stratified high-dose chemotherapy protocols might improve outcome in the future.

Predictive factors for L-asparaginase hypersensitivity in pediatric acute lymphoblastic leukemia.

L-Asparaginase is a crucial component of acute lymphoblastic leukemia (ALL) treatment. However, hypersensitivity is a common adverse event. This study aimed to identify risk factors for L-asparaginase hypersensitivity in childhood ALL. Children treated for ALL at Chiang Mai University Hospital, Thailand, between 2005 and 2020 were included. Demographic data, clinical characteristics, and factors related to L-asparaginase were retrospectively reviewed. L-Asparaginase hypersensitivity was observed in 24 of 216 children with ALL (11.1%). All patients received native L-asparaginase intramuscularly, and events occurred exclusively during the post-induction phase without concurrent corticosteroid use. Univariable analysis showed that relapsed ALL, higher accumulated doses, increased exposure days, and longer interval between drug administrations were potential risk factors. In multivariable logistic regression analysis, interruption of L-asparaginase administration for ≥ 52weeks and exposure duration of ≥ 15days were independent risk factors, with adjusted odds ratio of 16.481 (95% CI 3.248-83.617, p = 0.001) and 4.919 (95% CI 1.138-21.263, p = 0.033), respectively. Children with ALL who require re-exposure to L-asparaginase after 52-week interruption or who have received L-asparaginase for ≥ 15 exposure days are at risk of developing L-asparaginase hypersensitivity. Further management strategies in this setting should be evaluated.

A Propensity Score Weighting Analysis Emphasizes the Progress of the Gimema Approach in Adult Ph-Positive Acute Lymphoblastic Leukemia in the TKI Era

Introduction. In 2000, the GIMEMA cooperative study group launched the first frontline protocol with a tyrosine kinase inhibitor (TKI) alone plus steroids and without systemic chemotherapy for elderly (>60 years) Ph+ acute lymphoblastic leukemia (ALL) patients (LAL0201-B; Vignetti et al, Blood 2007). Thereafter, 4 academic clinical trials were conducted for adult patients (>18 years). In all studies, the induction was always based on a TKI alone plus steroids and CNS prophylaxis without systemic chemotherapy. In the GIMEMA LAL0904 trial, patients (18-60 years) received imatinib followed by chemotherapy in the post-induction phase (Chiaretti et al, Haematologica 2016). In the GIMEMA LAL1205 trial (no upper age limit), patients received dasatinib plus steroids, while the post-induction treatment was left to the investigator's choice (Foà et al, Blood 2011). In the GIMEMA LAL1509 total therapy protocol, patients (18-60 years) received dasatinib plus steroids followed by dasatinib alone in patients in complete molecular response (CMR) or chemotherapy and/or allogeneic transplant for those who did not reach a CMR (Chiaretti et al, Haematologica 2021). In the last LAL2116 trial, dasatinib plus glucocorticoids were administered in induction followed by at least two blinatumomab cycles as consolidation (Foà et al, N Engl J Med 2020). The rates of hematologic CR were comparable in the four trials, ranging from 96 to 100%. Methods. In order to perform a reliable comparison, patient-level data from the Ph+ ALL patients enrolled in the LAL0904 (n=51), LAL1205 (n=63), LAL1509 (n=60) and LAL2116 (n=63) protocols were used to conduct a multilevel propensity score weighting analysis. The median follow-up was similar in LAL0904, LAL1509 and LAL2116 - namely, 51.8, 57.4, 52.9 months - while LAL1205 had a shorter follow-up of 24.8 months, due to the trial design. Survival estimates were thus calculated at 24 months, representing the minimum median follow-up within the 4 trials. The weights were calculated with a multinomial logistic regression model. The variables age at diagnosis, gender, WBC, BCR::ABL1 isoform and allogenic transplant rate were included in this propensity score model. Differences in MRD rates were computed after the TKI alone induction using the chisq test. Given that the post-remission strategy was not defined in all protocols, the comparison of post-induction MRD was not appropriate. Survival curves were compared by standard and pairwise log-rank test. Results. Among the balancing weights methods, the matching weights produced the best balance, with standardized mean differences <0.2 for all variables. As shown in Table 1, before weighting the baseline features were uneven; upon weighting, the 4 cohorts were balanced in terms of age, gender, WBC, BCR::ABL1 isoform and transplant rate. After weighting, the MRD negativity rates at the end of induction were as follows: LAL0904 0%, LAL1205 23.9%, LAL1509 18.4%, LAL2116 29% (p=0.0007), mostly sustained by the different effect of dasatinib vs imatinib on the early molecular clearance. Survival outcomes after weighting underlined the superiority of the LAL2116 approach in comparison with the other protocols and the worse outcome for patients treated according to the LAL1205 scheme, presumably due to the lack of a uniform post-induction strategy. Indeed, the OS at 24 months was 89.8% in LAL2116, 71.2% in LAL1509, 52.9% in LAL1205, 66.2% in LAL0904 (p=0.001). Likewise, DFS at 24 months was 84.3% in LAL2116, 53.7% in LAL1509, 32.4in LAL1205, 61.1% in LAL0904 (p=0.001). Conclusions. By using a multilevel propensity score weighting approach, we were able to compare with statistical accuracy the results of 4 GIMEMA protocols for the frontline treatment of adult Ph+ ALL patients. After weighting, two results clearly emerged: on the one hand the markedly superior survival of patients enrolled in the LAL2116 protocol and on the other hand the unfavorable outcome of LAL1205. The marked improvement observed with the LAL2116 trial is ascribable to the consolidation strategy based on blinatumomab, since LAL2116 shared with the earlier LAL1509 and LAL1205 protocols the same induction strategy (dasatinib). It also appears evident that a center-specific post-induction strategy - as in LAL1205 - is not beneficial.

Adrenal Suppression in Children During the Treatment for Acute Lymphoblastic Leukemia Beyond Induction.

Adrenal suppression (AS) is an iatrogenic, life-threatening condition that can occur after glucocorticoid exposure. Despite recognition that AS occurs after induction phase treatment in children with acute lymphoblastic leukemia (ALL), the risk of AS in phases beyond induction is unknown. We conducted a pilot study in pediatric patients with ALL to ascertain whether the risk of AS persists in post-induction phases of treatment. Patients diagnosed between 12 months to younger than 18 years with B or T-ALL and starting any new phase of treatment were eligible for the study. Relapsed or infant ALL were excluded. Low dose ACTH stimulation testing (LDST), measurement of albumin and cortisol binding globulin were performed in all patients. Screening for symptoms of AS was done. Twenty-four patients enrolled in the study. One was diagnosed with clear AS. Five others had a borderline cortisol peak, representing possible mild AS. Symptoms were nonspecific and did not help distinguish patients with normal LDST from those with borderline or abnormal results. Patients on treatment for ALL continue to be at risk of AS beyond induction treatment. Although this risk appears small, physicians must be vigilant as patients may be asymptomatic but could develop adrenal crisis during treatment.

Forced-air prewarming prevents hypothermia during living donor liver transplantation: a randomized controlled trial

Despite various intraoperative thermal strategies, core heat loss is considerable during liver transplantation and hypothermia is common. We tested whether forced-air prewarming prevents hypothermia during liver transplantation. Adult patients undergoing living donor liver transplantation were randomly assigned to non-prewarming group (n = 20) or prewarming group (n = 20). Patients in prewarming group underwent 30-min forced-air warming before anesthetic induction. During surgery, core temperature was measured in the pulmonary artery. The primary outcome was intraoperative hypothermia (< 36.0 °C). The secondary outcomes included plasma lactate concentration. Intraoperative hypothermia risk was significantly lower in prewarming group than in non-prewarming group (60.0% vs. 95.0%, P = 0.020). The difference in hypothermia incidence between groups was greater in the post-induction phase (20.0% vs. 85.0%, P < 0.001) than in the anhepatic or post-reperfusion phase, suggesting that prewarming mainly acts on preventing post-induction core-to-peripheral heat redistribution. Hypothermia duration was significantly shorter in prewarming group (60 [0–221] min vs. 383 [108–426] min, P = 0.001). Lactate concentration decreased during 3 h after graft reperfusion in prewarming group, whereas it continuously increased in non-prewarming group (− 0.19 [− 0.48 to 0.13] mmol/L vs. 1.17 [3.31–0.77] mmol/L, P = 0.034). In conclusion, forced-air prewarming decreases the incidence and duration of intraoperative hypothermia with potential clinical benefit while mainly acting by preventing the core-to-peripheral heat redistribution.Clinical trial registration: Registered at the Clinical Research Information Service (https://cris.nih.go.kr, [KCT0003230]) on 01/10/2018.

Therapeutic Drug Monitoring of Vedolizumab in Inflammatory Bowel Disease Patients during Maintenance Treatment—TUMMY Study

There are limited data on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients treated with vedolizumab (VDZ). Although an exposure-response relation has been demonstrated in the post-induction phase, this relationship is more uncertain in the maintenance phase of treatment. The aim of our study was to determine whether there is an association between VDZ trough concentration and clinical and biochemical remission in the maintenance phase. A prospective, observational multicenter study has been performed on patients with IBD on VDZ in the maintenance treatment (≥14 weeks). Patient demographics, biomarkers, and VDZ serum trough concentrations were collected. Clinical disease activity was scored by the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and the Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Clinical remission was determined as HBI < 5 and SCCAI < 3. Biochemical remission was defined as fecal calprotectin <250 mg/kg and serum CRP <5 mg/L. A total of 159 patients (59 CD, 100 UC) were included. In none of the patient groups, a statistically significant correlation between trough VDZ concentration and clinical remission was observed. Patients in biochemical remission had higher VDZ trough concentrations (p = 0.019). In this population, higher trough VDZ concentrations were associated with biochemical remission but not with clinical remission.

Effects of Mood and School Related Stress on Academic Performance: A Mood Induction Investigation

This experimental research has been designed to explore the impact of visual cues (visual clips) of school stress on student’s mood and academic performance. It was aimed at investigating the relation between positive guided imagery and negative mood. Participants in the study included 90 boys and 95 girls (N = 185) with the age range of 10-14 years. The sample was randomly selected from different public and private schools of Multan and Bahawalpur. They were randomly assigned to two groups: Group 1 had negative Mood Induction Procedure (MIP) only; group 2 was treated with negative mood induction procedure which was followed by a Positive Guided Imagery (PGI). Students completed demographic sheet and School Situation Survey (Helms &amp; Gablem, 1989) prior to experimentation. The results revealed that academic performance decreases after negative mood induction but not after positive guided imagery. Both groups showed insignificant difference at pre and post-induction 1 level, while a significant difference was found between both groups at post induction phase 2.

Persisting high rates of omissions during anesthesia induction are decreased by utilization of a pre- & post-induction checklist

IntroductionAlthough Checklists (CL) for routine anesthesia cases have demonstrated their values in various studies, they have found little traction so far. While several reports have shown the benefit of CL preventing omissions prior to anesthesia induction, no investigation yet has scrutinized omissions during the post-induction phase immediately after intubation. This study evaluated the rate of omissions prior to and following the induction of non-emergent general anesthesia, as well as the impact of checklists on omission prevention. MethodsWe performed a monocentric, prospective, observational study during induction of general anesthesia cases. We evaluated the omission rate made for the pre- as well as the immediate post-induction phase and determined the impact of pre-and post-induction CL on the rate of omission corrections. The CL used were introduced two years prior to the study. The observed providers were limited to those familiar with the institutional CL. Usage of CL was not mandated. Results237 general anesthesia inductions were included in the observation. At least one omission in 32% of all cases in the pre-induction setup was found and in 40% within the immediate post-induction phases. CL significantly reduced omission rates (relative risk = 0.64, 95% CI = 0.45−0.92, p = 0.01). ConclusionOmission rates during the pre- and post-induction phases of routine general anesthesia procedures remain high. Pre- and post-induction CL have the potential to increase patient safety and should be considered for routine anesthesia with appropriate training provided.

ALL-228 Unfavorable Influence of Minimal Residual Disease on the Outcome of Allogeneic Hematopoietic Cell Transplantation in Acute Lymphoblastic Leukemia in the First Remission

Persistence of minimal residual disease (MRD) is the most important adverse prognostic factor for patients with acute lymphoblastic leukemia (ALL), irrespective of classical risk factors identified at onset. Detection of MRD in the post-induction phase of ALL treatment is the only generally accepted risk factor that is considered a direct indication for inclusion in the treatment of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several studies in recent years have shown that MRD determined before transplantation may increase the risk of disease relapse in ALL patients. To assess the impact of pre-transplant MRD status determined by multiparameter flow cytometry (MFC) on the long-term results of allo-HSCT in ALL patients. The study involved 98 patients with ALL in the 1st CR (n=58) and 2nd or 3rd CR (n=40) who underwent allo-HSCT in our center from November 2015 to July 2021. The median follow-up was 11.7 (1-65.5) months. To determine MRD, 12-color MFC was performed on bone marrow samples obtained before allo-HSCT. The probabilities of OS and DFS and the probability of relapse (PR) were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to assess the influence of various independent factors (donor type, conditioning regimen, graft source, GVHD prophylaxis, pre-transplant MRD status, age) on PR. Ten patients in 1st CR and 14 patients in 2nd or 3rd CR were identified as MRD+ before allo-HSCT. OS of MRD+ patients in 1st CR did not significantly differ from MRD- patients, although it was worse (28% vs. 78%, P=0.09). Significant differences were found in the DFS of MRD+ and MRD- patients (20% vs. 56%, P=0.0317); PR was also significantly higher in MRD+ patients (73% vs. 22%, P=0.0079). OS, DFS, and PR in MRD+ and MRD-patients were comparable. In our study, the presence of MRD before allo-HSCT (HR=3.858) was an independent factor influencing the probability of relapse. MRD determined by MFC is an independent predictor of the risk of relapse after allo-HSCT in ALL patients. Detection of MRD in patients with ALL in 1st CR before allo-HSCT is necessary to stratify the risk and identify patients who need post-transplant therapy.

Chemopreventive Efficacy of Thymoquinone in Chemically Induced Urinary Bladder Carcinogenesis in Rat.

The effects of thymoquinone (TQ) in a carcinogen-based models of urinary bladder cancer were evaluated, using 45 male rats in five groups. In negative control (n = 10), only tap water was given. In positive control (n = 10), the rats received 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) in drinking water for 9 weeks. In preventive groups with 25 mg/kg (n = 10) and 50 mg/kg (n = 10), oral TQ was concurrently given with 0.05% BBN for 9 weeks and continued for one more week after cessation of BBN. Preventive-treatment group (n = 5) received 50 mg/kg TQ orally for 20 weeks. Five rats from each group were sequentially sacrificed in two phases: the induction phase at 12th week (except the last group) and the rest in postinduction phase at 20th week. The bladders were examined macroscopically for lesion formation, and the masses were submitted for histopathological evaluation. Markers for total oxidant status (TOS), inflammation (nuclear factor kappa B (NF-κB)), and angiogenesis (vascular endothelial growth factor (VEGF)) were also assessed. There was a reduced number of bladder lesions in the TQ groups versus the carcinogen group at both phases. Histopathological findings demonstrated a significant improvement in the abnormal morphological changes in the urothelium of the TQ-treated groups. Thymoquinone exerted a significant antioxidant and anti-inflammatory effect by a decrease in serum level of TOS and NF-κB at week 12 which was maintained low in phase two at week 20. The serum level of VEGF was also alleviated in the induction phase at week 12 and maintained low in postinduction period. In TQ preventive-treatment approach, a nonsignificant elevation of serum level of TOS and NF-κB and slight reduction in VEGF were observed at the end of the experiment. These data suggest that TQ may be effective in preventing bladder carcinogenesis, and the suggested mechanisms might be related to antioxidant, prooxidant, and anti-inflammatory properties of TQ.

Hemostatic and thrombotic parameters in acure leukemia- A comparison of pre and post remission induction phase

This study was aimed to compare hemostatic, fibrinolytic and thrombotic parameters in pre and post induction chemotherapy in acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). A total of 110 diagnosed acute leukemia patients and 40 normal individuals were enrolled in the study. Questionnaire were filled and patients’ blood specimens were collected before the commencement and post induction chemotherapy. Prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor antigen (vWF Ag), fibrinogen level, factor VIIIc (FVIIIc), D-Dimers, fibrinogen degradation products (FDPs), anti-thrombin III (AT), lupus anticoagulant (LA), protein C (PC), protein S and diluted russel viper venom test (DRVVT) were conducted in all the participants. A significant rise was identified in post-induction levels of PT, aPTT, vWF Ag, fibrinogen and factor VIII in acute leukemia patients. Analysis of fibrinolytic markers indicated increased D-Dimers and plasminogen levels while the levels of alpha 2 anti-plasmin were reduced in pretreated patients. Thrombotic markers’ assessment showed increased levels of AT and LA while decreased level of PC in pretreated acute leukemia patients. It was concluded that remission induction chemotherapy, in acute leukemia patients, significantly affects the coagulation, fibrinolytic and thrombotic parameters.

Abstract 3636: Ethnic disparities in methotrexate neurotoxicity during pediatric acute lymphoblastic leukemia therapy: A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium

Abstract Introduction: Methotrexate (MTX) is a key component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL). However, delivery of MTX is often interrupted by dose-limiting acute neurotoxicity, which manifests as seizures, stroke-like symptoms, or altered mental status. Because incidence and risk factors for MTX neurotoxicity are poorly defined, we evaluated clinical and demographic predictors of MTX neurotoxicity using the multi-ethnic REDIAL Consortium. Methods: The REDIAL cohort includes pediatric patients diagnosed with ALL at six treatment centers in the southwestern U.S. This interim analysis evaluated 756 patients age 1-21 years diagnosed with B-ALL (2005-2018). Electronic health records were reviewed to determine race/ethnicity (Latino, non-Latino White, non-Latino Black, or Other), body mass index, sex, age, and intravenous (IV) MTX dose. Applying Ponte di Legno criteria, acute MTX neurotoxicity was defined as neurologic episodes occurring &amp;lt;21 days from intrathecal or IV MTX, which resulted in MTX treatment modifications. The proportion of patients who experienced MTX neurotoxicity and corresponding 95% confidence interval (CI) was calculated overall and within the induction, post-induction, and maintenance treatment phases. Multivariable logistic regression was used to estimate adjusted odds ratios (aOR) for the association between clinical factors and MTX neurotoxicity. Results: The study population was 56.6% Latino, 52.8% male, 41.4% treated with &amp;gt;5g/m2 IV MTX, and diagnosed at a median age of 5 years. Overall, 15.5% (95% CI: 12.9-18.3%) of patients experienced neurotoxic events (n=117), including 1.9% (n=14, 95% CI: 1.0-3.1%) during induction, 13.0% (n=98, 95% CI: 10.7-15.6%) during post-induction, and 0.7% (n=5, 95% CI: 0.2-1.5%) during maintenance therapy. Ethnic differences were not statistically significant during induction or maintenance phases. Compared to non-Latinos, post-induction neurotoxicity was significantly more frequent among Latinos (aOR = 2.87, 95% CI: 1.68-5.10), with disparities observed during consolidation, interim maintenance and delayed intensification phases. Exposure to &amp;gt;5g/m2 IV MTX (aOR = 2.16, 95% CI: 1.08-3.24) and older age at diagnosis (aOR = 1.16, 95% CI: 1.08-1.24) were also associated with a significantly more post-induction neurotoxicity. No factors evaluated were significantly associated with neurotoxicity during induction and maintenance therapy. Conclusions: MTX neurotoxicity disproportionally affects Latino children during ALL post-induction therapy. Additional work is warranted to identify risk factors for neurotoxicity during induction and maintenance therapy as well as the specific clinical and host biological factors responsible for post-induction ethnic differences in MTX neurotoxicity. Citation Format: Austin L. Brown, Rachel D. Harris, Olga A. Taylor, Melanie B. Bernhardt, Juan C. Bernini, Rodrigo A. Erana, Timothy Griffin, Kenneth Heym, Van T. Huynh, Kathleen Ludwig, Avner Meoded, Sandi L. Pruitt, Philip J. Lupo, Karen R. Rabin, Michael E. Scheurer. Ethnic disparities in methotrexate neurotoxicity during pediatric acute lymphoblastic leukemia therapy: A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3636.

Effects of buprenorphine on model development in an adjuvant-induced monoarthritis rat model.

Complete Freund’s adjuvant (CFA)-induced arthritis in rats is a common animal model for studying chronic inflammatory pain. However, modelling of the disease is associated with unnecessary pain and impaired animal wellbeing, particularly in the immediate post-induction phase. Few attempts have been made to counteract these adverse effects with analgesics. The present study investigated the effect of buprenorphine on animal welfare, pain-related behaviour and model-specific parameters during the disease progression in a rat model of CFA-induced monoarthritis. The aim was to reduce or eliminate unnecessary pain in this model, in order to improve animal welfare and to avoid suffering, without compromising the quality of the model. Twenty-four male Sprague Dawley rats were injected with 20 μl of CFA into the left tibio-tarsal joint to induce monoarthritis. Rats were treated with either buprenorphine or carprofen for 15 days during the disease development, and were compared to a saline-treated CFA-injected group or a negative control group. Measurements of welfare, pain-related behaviour and clinical model-specific parameters were collected. The study was terminated after 3 weeks, ending with a histopathologic analysis. Regardless of treatment, CFA-injected rats displayed mechanical hyperalgesia and developed severe histopathological changes associated with arthritis. However, no severe effects on general welfare were found at any time. Buprenorphine treatment reduced facial pain expression scores, improved mobility, stance and lameness scores and it did not supress the CFA-induced ankle swelling, contrary to carprofen. Although buprenorphine failed to demonstrate a robust analgesic effect on the mechanical hyperalgesia in this study, it did not interfere with the development of the intended pathology.

Hypersensitivity to Pegylated E.coli asparaginase as first-line treatment in contemporary paediatric acute lymphoblastic leukaemia protocols: a meta-analysis of the Ponte di Legno Toxicity working group

BackgroundHypersensitivity reactions to asparaginase challenge its use and occur frequently (30–75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of incidence of allergic reactions to pegylated E.coli asparaginase (PEGasparaginase) across contemporary paediatric acute lymphoblastic leukaemia (ALL) protocols is lacking. Method and patientsQuestionnaires were sent to all members of the international ALL Ponte di Legno Toxicity Working Group. Meta-analyses were conducted to estimate the incidence of three types of hypersensitivity (allergy, allergic-like reaction and silent inactivation). Information on protocol level regarding PEGasparaginase dosing regimen, administration route and use of therapeutic drug monitoring was collected for risk analysis. ResultsNewly diagnosed patients with ALL (n = 5880), aged 1–24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The incidence of allergic reactions (sum of allergies and allergic-like reactions) [95% confidence interval] was 2% [1%; 3%] during induction and 8% [5%; 11%] during postinduction. Route of administration, number of doses, dosage and number of PEGasparaginase-free weeks did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis suggests that initiation of PEGasparaginase in postinduction and higher number of PEGasparaginase-free intervals increased the risk for allergic reactions. 9–16% and 23–29% of all hypersensitivities were allergic-like reactions and silent inactivation, respectively. ConclusionThe incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared with that reported for E.coli asparaginase or PEGasparaginase after E.coli asparaginase.Postinduction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in postinduction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy.

A Meta-Analysis of Hypersensitivity to Pegylated Escherichia coli Asparaginase Used As First-Line Treatment in Contemporary Pediatric Acute Lymphoblastic Leukemia Protocols

PURPOSEAsparaginase is a key component of acute lymphoblastic leukemia (ALL) therapy. Hypersensitivity reactions challenge its use and occur frequently (30-75%) after native Escherichia. Coli (E.coli) asparaginase (Appel et al., 2008; Muller et al., 2001; Panosyan et al., 2004; Silverman et al., 2001). The international ALL Ponte di Legno Toxicity Work Group (PTWG) classifies hypersensitivity to asparaginase as (i) allergy in case of symptoms of allergy (always associated with undetectable asparaginase activity levels), (ii) allergic-like reactions in case of symptoms without inactivation, and (iii) silent inactivation (SI) with inactivation of asparaginase activity, but without hypersensitivity symptoms (Schmiegelow et al., 2016). Allergic-like reactions and SI can only be diagnosed with monitoring of asparaginase activity levels. A meta-analysis was performed based on data from the PTWG to estimate the incidence of hypersensitivity and risk factors for hypersensitivity to asparaginase in ALL protocols using pegylated E.coli asparaginase (PEGasparaginase) as first line of treatment.PATIENTS AND METHODSQuestionnaires were sent to all members of the PTWG. Information on protocol level regarding PEGasparaginase dose, dosing regimen (e.g. dosing frequency, total number of doses, PEGasparaginase-free intervals(s)), administration route, total induction and post-induction hypersensitivity rates per protocol and per risk group and use of therapeutic drug monitoring (TDM). To facilitate comparison between protocols with and without TDM, we defined allergic reactions as the sum of allergies and allergic-like reactions. Silent inactivation was analyzed separately.RESULTSA total of 5880 patients with newly diagnosed ALL, aged 1 to 24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The overall incidence of allergic reactions along with 95% confidence interval (CI) were 9% [6%; 13%], 2% [1%; 3%] and 8% [5%; 11%] in the overall protocol, induction and post-induction, respectively (Figure 1). Severity of allergic reactions were described, according to the CTCAE version 3.0 or 4.03, per protocol. 47% of the reactions were classified as grade 3/4.Univariate meta-regression analysis showed a positive association between the incidence of allergic reactions and number of PEGasparaginase-free intervals (P=0.005). High risk group stratification (P<0.001), post-induction treatment phase (P<0.001) and start of PEGasparaginase treatment in post-induction (P=0.006) were also associated with a higher incidence of allergic reactions. Route of administration (IV (8.9%, range 8.6-10.5%) versus IM (6.5%, range 5.5-14.8%)) did not significantly influence risk of hypersensitivity. Number of doses, duration of first PEGasparaginase-free interval and dosage did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis showed a positive association between the incidence of allergic reactions and the number of PEGasparaginase-free intervals (P=0.006) and start of PEGasparaginase in the post-induction treatment phase (P=0.02).Two out of seven study groups reported an incidence of allergic reactions of 1.6-2.0%, which was 9-16% of all hypersensitivity. Three out of seven study groups reported an incidence of SI of 3.7-4.1%, which was 23-29% of all hypersensitivity reactions.All protocols prescribed a switch to Erwinia asparaginase in case of clinical hypersensitivity and/or SI. 308 out of 348 (89%) of the patients with hypersensitivity to PEGasparaginase received Erwinia asparaginase. 19 out of these 308 (6%) exposed patients had an allergic reaction to Erwinia asparaginase, of which 7 out of 19 (37%) were grade 3/4.CONCLUSIONThe incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared to that reported for native E.coli asparaginase or PEGasparaginase after native E.coli asparaginase. Post-induction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in post-induction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy. [Display omitted] DisclosuresAlbertsen: Erytech: Honoraria, Speakers Bureau; Servier: Speakers Bureau; BKA: Other: Sponsor of the investigator-initiated trial NOR-GRASPALL2016.

Therapy-Related Mixed Phenotype Acute Leukemia: Report of two cases with clinicopathological and molecular data

Abstract Introduction/Objective Therapy-related mixed phenotype acute leukemia (Tr-MPAL) is a rare and aggressive disease comprising blast cells of more than one hematopoietic cell lineage. There is limited patient outcome data with this diagnosis. Hence, we present two such cases with clinicopathologic correlation. Methods/Case Report Clinical and pathology data were obtained from institutional electronic health records for two cases of Tr-MPAL identified in the past three years (2018-2020). Results (if a Case Study enter NA) Case 1: 60-years old female, history of chemo-radiotherapy for breast carcinoma, had 49% circulating dimorphic blasts. By immunophenotype, blasts were positive for CD34, CD117, HLA-DR, cCD3, TdT, CD13, CD15, CD38, CD2, CD7, and MPO by cytochemistry, negative for B-cell lineage markers, consistent with Tr-MPAL, T/Myeloid. Ancillary studies revealed normal female karyotype, FLT3-ITD positivity, and DNMT3A frameshift mutation. The patient achieved remission with ALL regimen Hyper-CVAD/methotrexate-cytarabine and underwent an allogeneic stem cell transplant (SCT). The patient was disease-free and on maintenance therapy post 2 years of initial diagnosis. Case 2: 49-years old female, history of chemotherapy for breast carcinoma, had 77% circulating dimorphic blasts (MPO+/PAX5- and MPO-/PAX5+/CD79a+). By immunophenotype, blasts were positive for CD34, CD117, HLA-DR, CD13, CD33, CD15, CD11b, CD19+(dim), cytoCD79a(subset), MPO(subset) and negative for CD14, CD10, CD7, CD8, cCD3, cCD22, and TdT, consistent with Tr-MPAL, B/Myeloid. Ancillary studies revealed normal female karyotype, FLT3-ITD positivity, mutations in RUNX1(frameshift insertion S318fs), SETD2(frameshift insertion P1403fs), WT1(frameshift deletion T377fs), ATM (LI555H), CREBBP (P84S), and DNMT3A (W305). The patient was treated with ALL regimen Hyper-CVAD/methotrexate-cytarabine but relapsed in the post-induction phase with a similar genetics profile. Once remission was achieved, the patient underwent allogeneic SCT and is disease-free while on maintenance therapy post 18 months of initial diagnosis. Conclusion Phenotypically different Tr-MPAL also differ by their underlying genetic abnormalities and may vary in response to therapy. A large cohort of cases may provide us further insights into the genetics and survival outcome of this therapy-related leukemia subtype.

Regulation of Mindfulness-Based Music Listening on Negative Emotions Related to COVID-19: An ERP Study.

The current study aimed to explore the behavioral and neural correlates of mindfulness-based music listening regulation of induced negative emotions related to COVID-19 using the face–word Stroop task. Eighty-five young adults visited the laboratory and were randomly assigned to three groups: a calm music group (CMG: n = 28), a happy music group (HMG: n = 30), and a sad music group (SMG: n = 27). Negative emotions were induced in all participants using a COVID-19 video, followed by the music intervention condition. Participants underwent the face–word Stroop tasks during which event-related potentials (ERPs) were recorded. The N2, N3, P3, and late positive component (LPC) were investigated. The results showed that calm music and happy music effectively regulate young adults’ induced negative emotions, while young adults experienced more negative emotions when listening to sad music; the negative mood states at the post-induction phase inhibited the reaction of conflict control in face–word Stroop tasks, which manifested as lower accuracy (ACC) and slower reaction times (RTs). ERP results showed negative mood states elicited greater N2, N3, and LPC amplitudes and smaller P3 amplitudes. Further studies are needed to develop intervention strategies to enhance emotion regulation related to COVID-19 for other groups.

A Prospective Phase 2 Study to Assess Minimal Residual Disease after Ixazomib, Lenalidomide and Dexamethasone Treatment for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients

A Prospective Phase 2 Study to Assess Minimal Residual Disease after Ixazomib, Lenalidomide and Dexamethasone Treatment for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients

Pegaspargase Re-Challenge after Grade 2 Hypersensitivity Reaction in Childhood Acute Lymphoblastic Leukemia: Results from DFCI 16-001

Introduction: Hypersensitivity reactions with asparaginase occur frequently in pediatric patients (pts) with acute lymphoblastic leukemia (ALL). The standard approach for pts with reaction to E.coli-derived asparaginase is to switch to Erwinia asparaginase, given concern that clinical reactions reflect presence of neutralizing antibodies; however, Erwinia requires more frequent dosing and is often unavailable. Therapeutic drug monitoring allows for discrimination between pts with pegaspargase hypersensitivity who have sub-therapeutic asparaginase activity and those still able to derive therapeutic benefit from pegaspargase. We prospectively piloted re-challenging pts with pegaspargase after initial Grade 2 hypersensitivity to this agent, with premedication at re-challenge and assessment of serum asparaginase activity (SAA). Methods: Pts aged 1 to &amp;lt; 22 years with newly diagnosed ALL were eligible for DFCI 16-001. Pts received 1 dose of intravenous pegaspargase during Induction, and every 2 weeks for 15 total doses in Post-Induction phases, without routine premedication. Pts were monitored during/after pegaspargase for allergy, with CTCAE version 4.0 event grading. Those with ≥Grade 3 allergy discontinued pegaspargase and were switched to Erwinia. Those with Grade 2 allergic reaction were eligible for pegaspargase re-challenge with pre-medication (acetaminophen, diphenhydramine, and hydrocortisone, or per institutional standard) and slower infusion rate. If &amp;lt; 50% of the intended dose had been administered when reaction occurred, re-challenge was within 1-7 days of initial reaction. If ≥ 50% of the intended dose had been given, re-challenge was at next planned pegaspargase dose. SAA was measured 1-hour, 7-days, and 14-days after the re-challenge infusion (if dose completed). If 1-hour or 7-day level ≥ 0.1 IU/mL, and 14-day level ≥ 0.025 IU/mL, SAA was considered adequate, and the pt continued to receive pegaspargase with premedication. Pts with an inadequate SAA level, or with new ≥ Grade 2 allergic reaction with the re-challenge dose were considered to have failed re-challenge and were changed to Erwinia (or enrolled on a clinical trial of recombinant crisantaspase, an alternative Erwinia preparation). Results: Between 3/2017- 7/2020, 317 eligible pts enrolled. Overall, 81 of 299 (27%) total evaluable pts experienced a first allergic reaction to pegaspargase, 68 pts with Grade 2 reaction, 13 with Grade ≥3. During Induction, 17 of 299 (6%) evaluable pts had allergic reaction to pegaspargase; all Grade 2. Of the 17 Grade 2 reactions, 13 pts (76%) underwent re-challenge in Induction, 9 (69%) re-challenges successful and 4 failed. Post-Induction, 64 of 241 evaluable pts (27%) had a first allergic reaction; 51 Grade 2 and 13 Grade ≥3. Thirty-six of 51 (71%) pts with Grade 2 allergy during Post-Induction underwent re-challenge, as did 1 additional pt with allergy during Induction who was re-challenged with first Post-Induction pegaspargase dose (per protocol guideline, due to receiving ≥50% of Induction dose). Among these re-challenges, 16 were successful, 21 failed. Overall, 25 of 50 (50%) pts who were re-challenged after Grade 2 reaction had a successful challenge and were able to continue pegaspargase. Among the 25 pts with failed re-challenge, 6 pts (24%) had inadequate SAA alone as cause of failure, 17 pts (68%) had an allergic reaction with the re-challenge dose, and 2 (8%) additional patients had both allergic reaction and documented inadequate SAA. Three pts who were successfully re-challenged had a subsequent allergic reaction to pegaspargase. Among the 22 pts who experienced another allergic reaction with pegaspargase (at re-challenge or subsequent dose), 19 pts (86%) experienced Grade 2, and 3 pts experienced Grade 3 reaction. Conclusion: Fifty percent of pts with a Grade 2 reaction to pegaspargase were able to tolerate and achieve adequate SAA when re-challenged with premedication. For those who did react with or after re-challenge, reactions were not more severe. The re-challenge approach limits premedication exposure only to a minority of pts with a history of prior reaction and substantially decreases the number of pts needing to switch to Erwinia asparaginase, which can be challenging to deliver due to administration schedule and drug shortage. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board.