Asparaginase-associated Pancreatitis Research Articles

Octreotide as prophylaxis against asparaginase-associated pancreatitis: a case series study

Octreotide as prophylaxis against asparaginase-associated pancreatitis: a case series study

Pancreas-related persisting sequelae in ALL survivors with a history of asparaginase-associated pancreatitis: A part of the ALL-STAR study.

Asparaginase-associated pancreatitis (AAP) occurs in up to 18% of patients treated for acute lymphoblastic leukemia (ALL); however, long-term sequelae are largely unexplored. We aimed to explore pancreatic sequelae among ALL survivors with and without AAP. We investigated pancreatic sequelae in a national cohort of ALL survivors, aged 1-45 years at ALL diagnosis treated according to the NOPHO-ALL2008 protocol and included sex- and age-matched community controls. We included 368 survivors (median follow-up 6.9 years), including 47 survivors with AAP and 369 controls. The p-lipase and p-pancreas-type amylase levels were lower in AAP survivors compared with both non-AAP survivors (Medians: 23 U/L [IQR 14-32] and 18 U/L [IQR 10-25] versus 29 [IQR 24-35] and 22 [17-28], p < .001 and p = .002) and community controls (28 U/L [IQR 22-33] and 21 U/L [IQR 17-26], both p < .006). Fecal-elastase was more frequently reduced in AAP survivors compared with non-AAP survivors (7/31 vs. 4/144, p = .001). Persisting pancreatic sequelae were found in 15/47 of AAP survivors and 20/323 of non-AAP survivors (p < .001), including diabetes mellitus in 2/39 of AAP survivors and 2/273 of non-AAP survivors. ALL survivors with AAP are at increased risk of persisting pancreatic dysfunction and require special attention during follow-up.

A Machine Learning Approach for Predicting the Occurrence of Asparaginase-Associated Pancreatitis in Pediatric Patients with Acute Lymphoblastic Leukemia

Introduction Children being treated for acute lymphoblastic leukemia (ALL) are frequently affected by asparaginase-associated pancreatitis. Additionally, pancreatitis is among the most troublesome and frequent side effects of asparaginase therapy and is a significant contributor to early drug discontinuation and poor outcomes. There are inadequate odds ratios for known risk factors, such as asparaginase dosage, advanced age, and single nucleotide polymorphisms, to predict pancreatitis occurrence. The goal of this study was to use machine learning to develop a predictive model for asparaginase-induced pancreatitis in pediatric ALL patients. Methods Data were collected from 711 patients who had childhood ALL and received asparaginase. Pancreatitis was defined as serum amylase and/or lipase levels greater than three times the upper limit of normal or acute pancreatitis on abdominal images. One month from the time of asparaginase administration for each patient was defined as one “timestep”, and when asparaginase was administered thereafter, it was defined as a new individual timestep. Each timestep was defined as one training case, and a case in which pancreatitis occurred at that timestep was defined as an event. Finally, 3193 training cases were defined in a total of 711 patients. The physical measurement results, prescription codes, blood test results, and blood transfusion history data were collected from electronic health records (HER) during the entire treatment period of the patients. Among these are age, body mass index, body surface area, gender, type of asparaginase (Native, Erwinia, or Pegylated), previous history of pancreatitis, cumulative number of asparaginase administrations, and asparaginase change history before the current time point. The results of 47 blood tests on the start date of asparaginase in each timestep were also used as predictive variables (Figure 1). Using logistic regression, Random forest, and XCBoost as machine learning methods, we assessed a model predicting asparaginase-associated pancreatitis through 5-fold cross-validation. Performance indicators such as area under the receiver operating characteristic curve (AUC) score, Precision Recall (PR) score, F0.5 score, and F2 score were employed to evaluate the binary classification of imbalanced data. The selection of the model was determined based on these two criteria. Results When considering the F(0.5+F2.0)/2 score as the basis for model selection, the logistic regression model demonstrated an AUC of 81% (PR 32.86%, F(0.5+F2.0)/2 score 23.23%). On the other hand, the XGboost model exhibited an AUC of 79% (PR 33.7%, F(0.5+F2.0)/2 score 32.07%), while the Random Forest model achieved an AUC of 84% (PR 33.34%, F(0.5+F2.0)/2 score 39.48%). Among these models, the Random Forest model demonstrated the highest predictive power. When the model was chosen using the PR score, the logistic regression model achieved an AUC of 80% (PR 34.97%, F(0.5+F2.0)/2 score 22.08%), whereas the XGboost model achieved an AUC of 79% (PR 31.58%, F(0.5+F2.0)/2 score 31.6%). Also, it was seen that the Random Forest model had the best performance across all metrics, with an AUC of 85%, a precision-recall (PR) score of 32.26%, and a F(0.5+F2.0)/2 score of 36.4% (Figure 2, left). According to Shapley values, it is evident that some parameters, namely greater lipase levels, higher cumulative asparaginase dosages, higher amylase levels, higher glucose levels, and older age, have significantly contributed to the occurrence of asparaginase-associated pancreatitis (Figure 2, right). Conclusions A machine learning model was employed to successfully forecast the occurrence of acute pancreatitis following the administration of asparaginase in pediatric patients with AAL. This study specifically focused on making predictions regarding pancreatitis within a month based on the test results obtained at the commencement of asparaginase treatment. This approach offers the potential for promptly predicting the development of pancreatitis. In further stages, following external validation and prospective observational clinical trials, the prediction model has the potential to be included in the EHR and serve as a Clinical Decision Support System (CDSS).

Efficacy and safety of endoscopic retrograde cholangiopancreatography in recurrent pancreatitis of pediatric asparaginase-associated pancreatitis.

Asparaginase (ASP) is an important drug in combined chemotherapy regimens for pediatric acute lymphoblastic leukemia (ALL); ASP-associated pancreatitis (AAP) is the main adverse reaction of ASP. Recurrent pancreatitis is a complication of AAP, for which medication is ineffective. To evaluate the efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) in treating recurrent pancreatitis due to AAP. From May 2018 to August 2021, ten children (five males and five females; age range: 4-13 years) with AAP were treated using ERCP due to recurrent pancreatitis. Clinical data of the ten children were collected, including their sex, age, weight, ALL risk grading, clinical symptoms at the onset of pancreatitis, time from the first pancreatitis onset to ERCP, ERCP operation status, and postoperative complications. The symptomatic relief, weight change, and number of pancreatitis onsets before and after ERCP were compared. The preoperative symptoms were abdominal pain, vomiting, inability to eat, weight loss of 2-7 kg, and 2-9 pancreatitis onsets. After the operation, nine of ten patients did not develop pancreatitis, had no abdominal pain, could eat normally; the remaining patient developed three pancreatitis onsets due to the continuous administration of ASP, but eating was not affected. The postoperative weight gain was 1.5-8 kg. There was one case of post ERCP pancreatitis and two cases of postoperative infections; all recovered after medication. ERCP improved clinical symptoms and reduced the incidence of pancreatitis, and was shown to be a safe and effective method for improving the management of recurrent pancreatitis due to AAP.

Long-term effects of asparaginase-associated pancreatitis.

Pancreatitis is a common and severe toxicity that occurs during asparaginase treatment for acute lymphoblastic leukemia, and has received increasing attention during the last decades. However, no consensus regarding follow-up exists. In this commentary, we highlight potential long-term health-related effects following asparaginase-associated pancreatitis, thereby providing clinicians with a framework when following these patients during and after cessation of therapy.

A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis.

Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A.Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.

Clinical summary of pediatric acute lymphoblastic leukemia patients complicated with asparaginase-associated pancreatitis in SCCLG-ALL-2016 protocol

ABSTRACTAsparaginase-associated pancreatitis (AAP) is a common and fatal complication after ASNase treatment in acute lymphoblastic leukemia(ALL). Here, a total of 1063 pediatric ALL patients treated with SCCLG-ALL-2016 regimen were collected since October 2016 to June 2020, including 35 patients with AAP. The clinical characteristics of AAP and non-AAP patients were compared. In AAP patients, the possible factors that affected the recurrence of AAP were analyzed, and the possible risk factors related to ALL-relapse were discussed. The results showed that age was a risk factor (P = .017) that affect the occurrence of AAP. In AAP patients, AAP tended to develop after the second use of PEG-ASNase (25.71%). In the follow-up chemotherapy, 17 patients re-exposed to ASNase and 7 cases developed AAP again with a percentage was 41.2%. There were no special factors that related with the recurrence of AAP. This study also found no association between the occurrence of AAP and prognosis of ALL, with the 4-year incidence of ALL relapse in AAP and non-AAP patients were 15.9% v.s.11.7% (HR: 1.009, 95% CI:0.370–2.752, P = .986), and there were no special factors that related with the ALL relapse among AAP patients. Based on the above results, the occurrence of AAP is related to age and should be vigilant after the second use of PEG-ASNase after use in pediatric ALL patients. Moreover, AAP is not associated with ALL relapse, but there is a high AAP recurrence rate when re-exposure to ASNase.

Clinical analysis of asparaginase-associated pancreatitis in children

ObjectiveTo investigate the clinical characteristics, diagnosis, and treatment of asparaginase-associated pancreatitis (AAP) in children to assess the risk factors of AAP and improve its clinical prognosis. MethodsWe performed a retrospective analysis of 24 patients with AAP who suffered from acute lymphoblastic leukemia (ALL) and received asparaginase chemotherapy, and who were admitted to the Children's Hospital of Zhejiang University School of Medicine from January 2009 to January 2019. We analyzed the general situation, drug application, clinical manifestations, laboratory tests, imaging findings, treatment, and prognosis. ResultsIn 796 patients with ALL who received asparaginase chemotherapy, the incidence of AAP was 3% (24/796). Among these patients, 11 (45.8%) developed AAP during the first application of asparaginase during the induction of remission, six cases developed AAP during the second application of asparaginase, and seven cases developed AAP during the third and above application. The median time from the diagnosis of AAP in 24 patients to the last asparaginase treatment was 8 days (1–18 days), among whom, the main clinical symptoms were abdominal pain, vomiting, nausea, bloating, and fever, which accounted for 95.8%, 37.5%, 33.3%, 20.8%, 4.0%, and 42.7%, respectively. Additionally, seven patients had peritoneal effusion. At initial diagnosis, 62.5% of the patients (15/24) had an increase in blood amylase levels to more than three times the upper limit of normal. The abdominal ultrasound results of 91.7% (22/24) of the patients were consistent with the imaging changes observed in pancreatitis. All 24 patients immediately stopped asparaginase treatment and received symptomatic supportive treatment, including fluid resuscitation, fasting, nutritional support, antibiotics, pancreatin inhibitors, and treatment of complications, as needed. Twenty-three patients were relieved after treatment, and one died. Following the resolution of symptoms in 14 patients with AAP, asparaginase chemotherapy was reintroduced, and 3 patients relapsed with AAP, all of which were mild. Symptoms were relieved 72 h after stopping asparagine chemotherapy. ConclusionAccording to the data from this single-center study, the incidence of AAP in patients with ALL was 3%, most of which occurred during the first or second exposure to asparaginase. Abdominal pain was the most common clinical manifestation. The diagnosis of AAP should be based on clinical manifestations, laboratory tests, and imaging findings. The prognosis of AAP is good, and whether asparaginase treatment can be reintroduced requires an evaluation of the benefits of asparaginase treatment and the risk of recurrence of pancreatitis.

Vitamin A and association with asparaginase-associated pancreatitis in children with acute lymphocytic leukemia.

10021 Background: Asparaginase is a key component of treatment of acute lymphoblastic leukemia (ALL), which is the most common cancer in the pediatric population. However, asparaginase is associated with many toxicities, including pancreatitis, which is observed in up to 10% of patients and can lead to severe sequelae. Methods: We performed analysis of (1) transcriptomic data from (a) asparaginase-treated leukemic cells, and (b) the pancreas of mice that were induced with a chemical form of pancreatitis; (2) the US FDA Adverse Reporting System (FAERS) and electronic health records (TriNetX); (3) global plasma metabolomic screen and dietary intake evaluation from ALL patients; and (4) experimental animal studies to identify factors that impact asparaginase-associated pancreatitis (AAP). Results: Connectivity map analysis showed that asparaginase-induced gene signatures are potentially reversed by the retinoids (vitamin A and its natural and synthetic analogs). Analysis of TriNetX and FAERES demonstrated a 2-fold reduction in AAP risk with concomitant exposure to vitamin A. Further, we performed a case-control metabolomic study of 50 subjects with ALL enrolled in the Dana-Farber Cancer Institute DFCI ALL clinical trial protocols 05-001 (NCT00400946) and 11-001 (NCT01574274). All subjects were given a single dose of pegylated E. Coli asparaginase during induction therapy. Twenty-four subjects developed pancreatitis within 9 months from the start of induction therapy and were considered cases. The median time to develop pancreatitis among cases was 3.68 months (interquartile range: 3.58 months). Twenty-six control subjects were identified among patients who did not develop pancreatitis within the same evaluation period. The controls were matched for age, sex, and initial ALL risk. The screening revealed that the plasma levels of carotene diol isomers, from the start of induction to its end, were reduced by about 60% in the cases compared to the controls. A detailed 30-day dietary recall showed that the cases had received less dietary vitamin A than the controls during induction therapy. Notably, the median value for the composite intake of vitamin A constituents, termed the RAE (retinol activity equivalents) was 656.92 mcg per day among the controls, but was 34.6% lower among in the cases (median of 429.40 mcg per day, which is just above the recommended dietary allowance level of 400 mcg per day for the 4–8 year-old age group). In mice, asparaginase administration as a single agent was sufficient to reduce circulating and hepatic retinol levels. Conclusions: Based on these data, we propose that circulating retinoids maintain pancreatic health, that asparaginase reduces circulating retinoids, and AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach provides the impetus to examine the role of dietary vitamin A supplementation for preventing or treating AAP.

The Characteristics and Risk Factors of Asparaginase-Associated Pancreatitis in Pediatric Acute Lymphoblastic Leukemia.

This study aimed to elucidate the characteristics and the risk factors for asparaginase-associated pancreatitis (AAP) in pediatric acute lymphoblastic leukemia (ALL) under the Taiwan Pediatric Oncology Group (TPOG)-ALL regimen. The study was conducted by reviewing the chart records of 191 patients aged 1 to 18 years treated with TPOG-ALL (2002 and 2013) protocols at the National Cheng Kung University Hospital, Tainan, Taiwan, from 2002 to 2019. The disease incidence, clinical presentations, laboratory data, complications, and outcomes of AAP were investigated. The incidence of AAP was 4.7%. The incidence was significantly higher in children treated with the TPOG-ALL-2013 (n = 62) than TPOG-ALL-2002 (n = 129) protocol (11.3% vs 1.6%, P = 0.006). Multivariate analysis identified using TPOG-ALL-2013 protocol was an independent risk factor for AAP. Pancreatic necrosis or pseudocysts developed in 7 patients (78%). Notably, 1 AAP case (11%) developed diabetes mellitus and 4 (44%) had chronic pancreatitis during a 1-year observational period. None were mortality. The incidence of AAP was 4.7% in ALL patients treated with TPOG-ALL protocol. Although a higher cumulative dose of asparaginase in TPOG-ALL-2013 may attribute to the pancreatic toxicity, unidentified factors such as genetic predisposition or other drugs still need further study.

Asparaginase-associated pancreatitis in chemotherapy-treated pediatric patients: a five-year retrospective study.

Asparaginase-associated pancreatitis in chemotherapy-treated pediatric patients: a five-year retrospective study.

Children With Asparaginase-associated Pancreatitis Present Elevated Levels of Insulin, Total Cholesterol, and HOMA-IR Before Starting Acute Lymphoblastic Leukemia Treatment.

Asparaginase-associated pancreatitis frequently occurs in children with cancer. It is unknown if other factors can influence the development of pancreatitis. A total of 33 pediatric patients with a confirmed diagnosis of acute lymphoblastic leukemia were included in this study. Before acute lymphoblastic leukemia drug treatment, the metabolic parameters (glucose, insulin, homeostasis model assessment insulin resistance, total cholesterol, triglycerides) and body mass index percentile were compared. Children who had acute pancreatitis had higher levels of insulin, homeostasis model assessment insulin resistance, and total cholesterol, compared with children who did not develop acute pancreatitis. These metabolic alterations could play a role in the development of pancreatitis.

Posterior Reversible Encephalopathy Syndrome in the Setting of Asparaginase-associated Pancreatitis in 2 Pediatric Patients With Acute Leukemia.

Asparaginase, a critical component of current pediatric acute leukemia treatment protocols, is associated with a number of serious side effects, one of which is pancreatitis. Pancreatitis can result in significant morbidity and mortality from necrosis, pseudocyst formation, hemorrhage, systemic inflammation, intestinal perforation, and sepsis. Another rare complication of pancreatitis is posterior reversible encephalopathy syndrome, likely mediated by systemic inflammation secondary to pancreatic autodigestion and proinflammatory cytokine-mediated vascular endothelial damage. Here, we review this association in the literature and report 2 pediatric patients with leukemia who developed posterior reversible encephalopathy syndrome in the setting of asparaginase-associated pancreatitis.

Acute pancreatitis in children with acute lymphoblastic leukemia correlates with L-asparaginase dose intensity.

L-Asparaginase (L-Asp) is an important therapeutic for childhood acute lymphoblastic leukemia (ALL). Asparaginase-associated pancreatitis (AAP) is a severe complication of L-Asp related to the dosage. We investigated the incidence of, and risk factors for, AAP in pediatric patients with ALL. From January 2002 to December 2018, pediatric patients with ALL treated at National Taiwan University Hospital were enrolled in this study. The diagnosis of AAP was based on the criteria of the Ponte di Legno Toxicity Working Group. Of the 353 patients enrolled in this study, 14 (4.0%) developed AAP. The incidence of AAP in ALL patients was significantly higher after treatment with the 2013 protocol compared with the 2002 protocol of the Taiwan Pediatric Oncology Group (9.5% vs. 1.3%). Multivariate analysis showed that a high peak L-Asp dose intensity (>45,000 U/m2/month) and older age at diagnosis (>6.8 years) were independently predictive of AAP development. The incidence of acute pancreatitis in childhood ALL was correlated more strongly with the peak dose intensity than with the cumulative dose of L-Asp. These results could be used to reduce the treatment-related complications of ALL. L-Asparaginase is an important therapeutic for childhood acute lymphoblastic leukemia, and the accumulated dosage of L-asparaginase is considered as a major risk factor of asparaginase-associated pancreatitis. This article demonstrated that the incidence of pancreatitis correlates with the dose-intensity of L-asparaginase, but not the accumulated dosage. Identification of patient group with high risk of pancreatitis could lead to early diagnosis and reduce the complication. This finding could aid in developing further new protocol or therapeutic strategy design to reduce treatment-related complications and improve clinical outcomes of childhood acute lymphoblastic leukemia.

Clinical Characteristics and Short-Term Outcomes of Children With Asparaginase-Associated Pancreatitis.

Acute pancreatitis is a significant toxicity of l-asparaginase, a chemotherapeutic agent used to treat acute lymphoblastic leukemia. This case series describes the short-term clinical course and disposition of patients who developed asparaginase-associated pancreatitis (AAP) at one quaternary pediatric center. Clinical data, including laboratory data, inpatient and intensive care unit (ICU) days, imaging findings, presence of complications such as need for ventilation, dialysis, and the development of pleural effusions, and mode of nutrition were abstracted from the medical record of patients with AAP. Pediatric criteria were used to classify episode severity based on the development of organ failure and local complications, such as pancreatic necrosis. Between 2005 and 2015, 34 patients had AAP with 43 distinct episodes of pancreatitis. The median inpatient length of stay was 10 days (range 2-65). Seven episodes (16.3%) required intensive care unit (ICU)-level care. Seventeen episodes (39.5%) were severe based on the development of organ failure or presence of pancreatic necrosis. Total parenteral nutrition (TPN) was used in 17 episodes (39.5%); for 34 episodes (79.1%), patients were discharged on entirely oral feeds. Antibiotics were administered in 20 episodes (46.5%). Pancreatic necrosis was identified within the first week in 12 episodes (27.9%). There were no deaths due to AAP. The clinical course varies widely among patients with AAP. Over one-third of the patients in this series developed severe pancreatitis. Although the prognosis of AAP is generally good, many patients develop systemic complications of AAP, requiring TPN or ICU-level care.

Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia.

Asparaginase-associated pancreatitis (AAP) frequently affects children treated for acute lymphoblastic leukemia (ALL) causing severe acute and persisting complications. Known risk factors such as asparaginase dosing, older age and single nucleotide polymorphisms (SNPs) have insufficient odds ratios to allow personalized asparaginase therapy. In this study, we explored machine learning strategies for prediction of individual AAP risk. We integrated information on age, sex, and SNPs based on Illumina Omni2.5exome-8 arrays of patients with childhood ALL (N=1564, 244 with AAP 1.0 to 17.9 yo) from 10 international ALL consortia into machine learning models including regression, random forest, AdaBoost and artificial neural networks. A model with only age and sex had area under the receiver operating characteristic curve (ROC-AUC) of 0.62. Inclusion of 6 pancreatitis candidate gene SNPs or 4 validated pancreatitis SNPs boosted ROC-AUC somewhat (0.67) while 30 SNPs, identified through our AAP genome-wide association study cohort, boosted performance (0.80). Most predictive features included rs10273639 (PRSS1-PRSS2), rs10436957 (CTRC), rs13228878 (PRSS1/PRSS2), rs1505495 (GALNTL6), rs4655107 (EPHB2) and age (1 to 7 y). Second AAP following asparaginase re-exposure was predicted with ROC-AUC: 0.65. The machine learning models assist individual-level risk assessment of AAP for future prevention trials, and may legitimize asparaginase re-exposure when AAP risk is predicted to be low.

Asparaginase-Associated Pancreatitis in Pediatric Patients with Acute Lymphoblastic Leukemia: Current Perspectives.

Asparaginase therapy is a vital agent in the treatment of acute lymphoblastic leukemia (ALL), with increasing evidence of its high importance in high-risk ALL populations. However, despite the clear clinical and biological benefits of asparaginase therapy, many patients experience toxicities. A well-known treatment-limiting toxicity is asparaginase-associated pancreatitis (AAP). If severe, it necessitates discontinuation of asparaginase therapy, which can lead to a higher risk of relapse in patients with ALL. New protocols for ALL therapy have increased overall total doses of asparaginase therapy in select high-risk populations and have incorporated longer half-life formulations of pegylated asparaginase. Treatment drug monitoring has also allowed assurance of adequate levels of asparagine depletion throughout treatment. It is currently unknown if these changes will increase rates of AAP. Interestingly, important pharmacogenomics data, such as single nucleotide polymorphisms, can identify patients at the highest risk for severe AAP. The incidence of AAP in recent trials, current pharmacogenomic data that could further our understanding of the disease, and the importance of cautiously re-exposing patients to further asparaginase treatment after an initial episode of AAP are discussed.

713b A Multi-Systems Approach with Big Data from Adverse Event Reporting and Health Records, Clinical Biospecimens, and Experimental Animal Data Reveal That Retinoids Impact Asparaginase-Associated Pancreatitis Outcomes in Leukemic Patients

Asparaginase is a crucial cornerstone chemotherapy for the most common cancer in children, acute lymphoblastic leukemia (ALL). However, a major concern is that 5-10% of all asparaginase users develop the painful, life-threatening complication of pancreatitis. Asparaginase-associated pancreatitis (AAP) is a more severe form of pancreatitis, and discontinuation of asparaginase is associated with inferior disease-free survival in high-risk cancer patients. Thus, there is a major unmet need to mitigate AAP. In this study, we took a multi-systems approach that combined adverse event reporting data and electronic health records (EHR), clinical biospecimens, and experimental data to identify factors that impact AAP. An analysis of 14 million records from the FDA Adverse Events Reporting System (FAERS) demonstrated the novel finding that vitamin A supplementation to asparaginase was correlated with reduction in the risk of AAP. To home in the role of systemic vitamin A exposure, versus topical agents, an analysis of over 64 million records from an EHR database (TriNetX Research) identified a protective effect of non-topical vitamin A supplementation on AAP. To pursue this further, we performed a case control study of 26 ALL patients who developed pancreatitis at a median of 3 months after the start of chemotherapy and compared them with 24 well-matched control ALL patients who did not develop pancreatitis over the course of leukemia therapy. We performed non-targeted metabolomics of plasma before and after induction chemotherapy. The striking difference between the two groups was that the precursors of vitamin A were reduced in the pancreatitis cases post-induction compared to the controls. In mice, we found that single agent asparaginase administration by itself led to reduce retinol levels in serum. Analysis of transcriptomic data from leukemic cells demonstrated that the transcriptional signature from asparaginase exposure was potentially reversed by retinoid interventions. The finding was similar in transcriptomic data from a cerulein model of pancreatitis. Taken together, these data suggest that reductions in retinol levels may be correlated with AAP, that asparaginase causes those reductions, and that retinoid supplementation may prevent AAP. The major novelty of the current work is that it provides crucial insight into mitigating the adverse event of AAP and elucidates a broader role for retinoids in preventing the sterile inflammation of the pancreas. Fig 2Vitamin A metabolite levels between pancreatitis patients and controls. The y-axis represents log2 post/pre. * q<0.1. View Large Image Figure Viewer Download Hi-res image

Clinical Utility of Pegaspargase in Children, Adolescents and Young Adult Patients with Acute Lymphoblastic Leukemia: A Review.

Acute lymphoblastic leukemia (ALL) is a heterogenous hematological malignancy representing 25% of all cancers in children less than 15 years of age. Significant improvements in survival and cure rates have been made over the past four decades in pediatric ALL treatment. Asparaginases, derived from Escherichia coli and Erwinia chrysanthemi, have become a critical component of ALL therapy since the 1960s. Asparaginases cause depletion of serum asparagine, leading to deprivation of this critical amino acid for protein synthesis, and hence limit survival of lymphoblasts. Pegaspargase, a conjugate of monomethoxypolyethylene glycol (mPEG) and L-asparaginase, has become an integral component of pediatric upfront and relapsed ALL protocols due to its longer half-life and improved immunogenicity profile compared to native asparaginase preparations. Over the past two decades great strides have been made in outcomes for pediatric ALL due to risk stratification, incorporation of multiagent chemotherapy protocols, and central nervous system prophylaxis with pegaspargase having played an important role in this success. However, adolescents and young adults (AYA) with ALL when treated on contemporaneous trials using adult ALL regimens, continue to have poor outcomes. There is increasing realization of adapting pediatric trial regimens for treating AYAs, especially those incorporating higher intensity of chemotherapeutic agents with pegaspargase being one such agent. Dose or treatment-limiting toxicity is observed in 25–30% of patients, most notable being hypersensitivity reactions. Other toxicities include asparaginase-associated pancreatitis, thrombosis, liver dysfunction, osteonecrosis, and dyslipidemia. Discontinuation or subtherapeutic levels of asparaginase are associated with inferior disease-free survival leading to higher risk of relapse, and in cases of relapse, a higher risk for remission failure. This article provides an overview of available evidence for use of pegaspargase in pediatric acute lymphoblastic leukemia.

Progress on asparaginase-associated pancreatitis

Acute lymphoblastic leukemia(ALL)is the most common childhood malignancy.As an essential component of multiagent chemotherapy, asparaginase(ASP)has significantly improved the remission rate and event-free survival rate of children with ALL since its application in clinical practice.However, there are many adverse events due to ASP, including asparaginase-associated pancreatitis(AAP). The mechanisms behind and the risk factors predisposing AAP are unknown.This review summarizes the latest research progresses on AAP. Key words: Asparaginase; Child; Acute lymphoblastic leukemia; Pancreatitis