High-Grade Pegylated Asparaginase-Related Hepatotoxicity Occurrence In a Pediatric-Inspired Adult Acute Lymphoblastic Leukemia Regimen Does Not Necessarily Predict Recurrent Hepatotoxicity In Subsequent Cycles

Abstract Introduction Cure rates of pediatric acute lymphoblastic leukemia (ALL) have markedly improved to approximately 80%, while in adult ALL the rates remain 40-50%. Pediatric ALL regimens contain higher doses of non-myelosuppressive chemotherapy, e.g., vincristine, corticosteroids, and, particularly, higher cumulative doses of asparaginase. Asparaginase use in adults was previously limited due to toxicity concerns. However, several recent studies, using pediatric regimens in adults, contain higher cumulative doses of asparaginase and are showing promising preliminary results. In these studies it was also noted that the long-acting pegaspargase (PEG-ASN) was much more commonly associated with hepatotoxicity in adults than in children. Although hepatotoxicity appears to be the commonest adverse effect of PEG-ASN in adults, it has not been well defined. We report the frequency and characteristics of PEG-ASN-related high-grade hepatotoxicity after multiple doses in adults treated by a pediatric regimen. Methods Between July 2004 and July 2009, 51 adults aged 18 to 57 years were enrolled on a phase II trial with a pediatric ALL regimen that included six planned PEG-ASN doses. PEG-ASN-related toxicities were carefully monitored on a weekly basis after each dose and reported using NCI CTCAE v3.0 for 185 doses delivered. The PEG-ASN dosing schedule was: two doses in induction phases I and II, and four during post-induction cycles (ASH Abstract 1495, 2012). Each PEG-ASN dose was 2000 IU/m2/dose IV, given at intervals of four weeks or greater. Pegaspargase was not discontinued and subsequent doses were not reduced after hepatotoxicity. Results A total of 192 pegaspargase doses were delivered (3.8 doses/patient), with 23 patients receiving all six doses. Of the 28 patients who received fewer than six doses, only 10 (20%) discontinued due non-hepatic toxicity (pancreatitis, allergy, and DVT). Eight (16%) patients discontinued due to allogeneic HSCT while in CR1, while nine (18%) discontinued for other reasons (death post-induction, induction failure, and relapse). Grade 3/4 hyperbilirubinemia occurred in 16 patients (31%) and in 23 doses (12%); grade 3/4 transaminitis occurred in 33 patients (65%) and in 62 doses (34%). Patients with grade 3/4 hyperbilirubinemia tended to be older than those without hepatotoxicity (median age 39 vs 31 years), but all other baseline characteristics were similar. Results of different parameters related to high-grade liver toxicity are detailed in Table 1. Patients with grade 3/4 hyperbilirubinemia and transaminitis received a mean of 4.0 and 4.3 PEG-ASN doses, while the mean number of PEG-ASN doses causing hyperbilirubinemia and transaminitis was only 1.4 and 1.9 doses per patient, respectively. Those without hepatotoxicity received 2.8 PEG-ASN doses per patient. Induction I had the highest incidence (20% of doses delivered) of grade 3/4 hyperbilirubinemia. High-grade transaminitis was spread more evenly among cycles. Grade 3/4 hepatotoxicity was long, with a median duration of 34 days to return to grade 1 for bilirubin and 38 days to return to grade 2 for transaminitis. Of the 16 patients with grade 3/4 hyperbilirubinemia, five did not receive a subsequent PEG-ASN dose for other reasons; of the 11 other patients who received subsequent doses, five (45%) did not re-experience the same toxicity. Of the 33 patients with grade 3/4 transaminitis, eight did not receive a subsequent PEG-ASN dose due to other reasons; of the 25 other patients who received subsequent doses, 10 (40%) did not have this toxicity recur. Summary Our study shows in adults with ALL treated with multiple doses of PEG-ASN that: (1) high-grade hepatoxicity (grade 3/4 hyperbilirubinemia and transaminitis) is a common adverse effect of PEG-ASN; (2) recovery from hepatotoxicity is often long and can delay subsequent chemotherapy; (3) high-grade hepatotoxicity did not necessarily recur after subsequent doses and did not lead to PEG-ASN discontinuation; (4) the dose and schedule of other hepatically cleared or hepatotoxic drugs should be adjusted during periods of PEG-ASN-related hepatotoxicity. In conclusion, although PEG-ASN at this dose and interval is associated in adults with a high rate of hepatotoxicity, it is tolerable and can be given again despite earlier PEG-ASN-related hepatotoxicity. Disclosures: Douer: Sigma Tau Pharmaceuticals : Research Funding.

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Toxicities in Adults with Acute Lymphoblastic Leukemia (ALL) Treated with Regimens Using Pegasparaginase.

Blood ◽

10.1182/blood.v112.11.1924.1924 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1924-1924 ◽

Cited By ~ 4

Author(s):

Michael Rytting ◽

Marc Earl ◽

Dan Douer ◽

Brenda Muriera ◽

Anjali Advani ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Cleveland Clinic ◽

Adult Patients ◽

Close Monitoring ◽

Multiple Doses ◽

Elevated Liver Enzymes ◽

Grade 3 ◽

Long Acting ◽

Age Range

Abstract Background: The current therapeutic strategy of applying pediatric-based regimens for acute lymphoblastic leukemia (ALL) to adults with ALL exposes these patients to multiple doses of asparaginase (ASP). Exposure to long-acting or pegylated ASP is particularly prominent due to dosing convenience, since pegylated ASP can be administered intravenously and requires fewer doses than shorter-acting forms. Previously, adult patients were much less likely to be treated with ASP-containing regimens due to reports from the 1970s of increased toxicity from ASP in adults compared with children. We report on the toxicities encountered in 3 protocols that include multiple doses of pegylated ASP as part of therapy for ALL in adult patients. Methods: Thus far, the 3 protocols have enrolled 92 patients between the ages of 14 and 71 years. The pegylated ASP dose ranges from 2000–2500 IU/m2. Approximately 330 doses of pegylated ASP have been given. Results: Grade 3–4 hepatic toxicity is the most prominent; grade 3–4 transaminase elevation occurred in 47 (51%) patients, and grade 3–4 hyperbilirubinemia was seen in 22 (24%) patients (Table). Hyperglycemia was grade 3–4 toxicity in 30 (33%) patients. Grade 3–4 allergic reactions to pegylated ASP occurred in 5 (5%) patients. Twelve (13%) patients developed thromboses. Of note, 3 (3%) patients have had leukoencephalopathy on magnetic resonance imaging scans with reversible stroke-like symptoms. The majority of hepatic toxicities resolve spontaneously, allowing patients to continue chemotherapy. All of the patients with stroke-like symptoms have fully recovered. Conclusions: Considerable hepatotoxicity and hyperglycemia occur in adult ALL patients treated with polychemotherapy that includes long-acting ASP. Other toxicities occur with a frequency similar to that seen in pediatric patients treated with a long-acting ASP. This toxicity profile warrants close monitoring and continued data collection from clinical trials that use pegylated ASP in adults with ALL. USC Cleveland Clinic M.D. Anderson Total *No. of patients with grade 3–4 toxicities. Median age (years) 33 46 20 33 Age range (years) 18–57 20–71 14–34 14–71 No. doses/patients 127/39 56/25 147/28 330/92 Toxicity* Elevated liver enzymes 23 7 17 47 Hyperbilirubinemia 7 6 9 22 Hyperglycemia 12 5 13 30 Clinical pancreatitis 5 N/A 3 8 Fatigue 3 1 7 11 Thrombosis 3 (SVC only) 2 7 12 Hypofibrinogenemia N/A 8 N/A 8 Elevated PT / INR N/A 1 N/A 1 Bleeding 0 N/A 0 0 Nausea / vomiting 1 4 2 7 Allergy / hypersensitivity 0 2 3 5 Neuropathy 1 1 N/A 2 CNS stroke-like syndrome 0 0 3 3

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CNOT1 Microrna Single Nucleotide Polymorphism (SNP) Determines the Occurrence of Methotrexate Related Mucositis in Pediatric Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v126.23.1237.1237 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1237-1237

Author(s):

Natanja Oosterom ◽

Ángela Guttiérez-Camino ◽

Marissa Den Hoed ◽

Elixabet López-López ◽

Saskia MF Pluijm ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Candidate Snps ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Pediatric All ◽

Grade 3 ◽

And Function

Abstract BACKGROUND Cure rates of pediatric acute lymphoblastic leukemia (ALL) have reached 90% in the developed countries. However, toxicity due to chemotherapeutic regimens occurs frequently but with great heterogeneity. This suggests that genetic variation is involved. In order to identify determinants of adverse effects, recent studies have investigated pharmacogenetic features in relation to toxicity. Most of these studies examined coding regions of the genome. Recently, it has been described that epi genetic regulators, such as micro-RNA's (miRNA), might also have an important regulatory function in genes involved in drug related toxicity. In a recent study 25 miRNA SNPs were found to be related to toxicity in pediatric ALL treatment (Lopez-Lopez, PLoS ONE, 2014). In pediatric ALL mucositis is one of the most frequent side effects during high dose methotrexate (MTX) treatment. AIM The aim of this study was to detect novel, epigenetic biomarkers that predict MTX related oral mucositis in pediatric acute lymphoblastic leukemia (B- and T cell) by studying single nucleotide polymorphisms (SNP) involved in miRNA levels and function. METHODS DNA was isolated from whole blood of 118 pediatric ALL patients that were treated with high dose MTX (5 gr/m2) according to the Dutch Childhood Oncology Group ALL-10 protocol. The recently published 25 SNPs, involved in miRNA function and located in the DROSHA, CNOT1, CNOT4, EIF2C1, GEMIN3, GEMIN4, MIR604, MIR453, MIR2110, MIR2053, MIR1294, MIR1206, DICER, XPO5 and TNRC6B genes, were selected for genotyping. Toxicity data during the consolidation phase were prospectively collected and documented according to the National Cancer Institute (NCI) v.3.0 score system. Mucositis NCI grade ≥ 3 (grade 3: confluent ulcerations, bleeding with minor trauma), was considered as clinical significant toxicity and was used as endpoint. RESULTS Mucositis was the only recurring toxicity in this prospectively well-documented cohort and therefore used as endpoint of this study. A selection of 20 of the previously identified 25 candidate SNPs was studied based on technical feasibility. In addition, 1 SNP in the XPO 5 gene was not considered for analysis because it was not in Hardy Weinberg equilibrium. Mucositis occurred in 19% of the patients in at least one of the MTX courses. Only the TT genotype of rs11866002 in the CNOT1 (CCR4-NOT complex, subunit 1) gene was associated with a higher risk of developing mucositis (NCI ≥ 3) compared to carries of CC/CT. The other 18 candidate SNPs analyzed did not show statistically significant associations. CONCLUSION The inter-patient variability of mucosal toxicity was not associated with most of our investigated SNPs which are involved in miRNA transcription and function. CNOT1 rs11866002 C>T was the only single nucleotide polymorphism associated with the occurrence of oral mucositis during pediatric acute lymphoblastic leukemia treatment. We acknowledge the Foundation Children Cancerfree (KiKa), Amstelveen, The Netherlands, for funding this research. Disclosures No relevant conflicts of interest to declare.

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Genetic and Metabolic Determinants of Methotrexate Induced Mucositis in Pediatric Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v124.21.939.939 ◽

2014 ◽

Vol 124 (21) ◽

pp. 939-939

Author(s):

Marissa den Hoed ◽

E. Lopez-Lopez ◽

Mariël L. Te Winkel ◽

Wim Tissing ◽

Jasmijn de Rooij ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Plasma Homocysteine ◽

Nucleotide Polymorphisms ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Plasma Folate ◽

Pediatric All ◽

Erythrocyte Folate ◽

Grade 3

Abstract Introduction: Methotrexate (MTX) is an important and effective chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). However MTX can induce toxicity, which can lead to amendments of treatment and subsequent impaired survival. The aim of this study was to identify metabolic and genetic determinants of MTX toxicity. Patients and Methods: In this prospective study, 134 Dutch pediatric ALL patients were treated with four high dosages MTX (HD-MTX: 5 g/m2) every other week according to the DCOG-ALL10 protocol. Toxicity was prospectively scored and a National Cancer Institute (NCI) grade ≥3 was considered clinically relevant toxicity. Plasma MTX levels were measured at 24 and 48 hours after each HD-MTX infusion. Erythrocyte folate, plasma folate and plasma homocysteine levels were determined at the start of protocol M. Seventeen single nucleotide polymorphisms (SNPs) in 7 candidate genes in the MTX pathway were analyzed. Results: Grade ≥3 mucositis occurred in 20% of the patients, skin toxicity in 7%, diarrhea in 3%, and neurotoxicity in 3%. Mucositis occurred especially after the first course compared to the other courses (p=0.006). Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher baseline levels of erythrocyte folate (median 1.2 μmol/L vs. 1.4 μmol/L, p<0.008). Wildtype rs7317112 in the ABCC4 gene was the only SNP associated with a higher frequency of mucositis (AA (39%) vs. AG/GG (15%), p=0.016). Conclusion: Mucositis is the most frequent occurring toxicity during the HD-MTX phase in pediatric ALL treatment, and occurs especially after the first MTX course. Only a higher baseline erythrocyte folate, which reflects the accumulation of MTX polyglutamates in mucosal cells, and the wild-type variant of rs7317112 SNP in ABCC4 were determinants of mucositis in pediatric ALL during MTX-HD treatment. Disclosures No relevant conflicts of interest to declare.

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Asymptomatic hypoglycemia among children with acute lymphoblastic leukemia on maintenance therapy

Innovative Journal of Medical and Health Science ◽

10.15520/ijmhs.v9i1.2430 ◽

2019 ◽

Vol 9 (1) ◽

pp. 242-246

Author(s):

Janan G. Hassan*, Ayad .A. Mohamed

Keyword(s):

Adverse Effect ◽

Acute Lymphoblastic Leukemia ◽

Maintenance Therapy ◽

Lymphoblastic Leukemia ◽

Common Adverse Effect ◽

Total Sample ◽

Healthy Children ◽

Maintenance Chemotherapy ◽

Overnight Fasting ◽

Age And Sex

Background: Knowledge of the adverse effects of maintenance chemotherapy , therapy in children with acute lymphoblastic leukemia being treated according to the MRC modified protocols. Objective: To figure out the asymptomatic hypoglycemia in a sample of children patients at a stage of maintenance therapy. Methods: Prospective study was carried out over 6 months from the 1st of January 2004 till the 30th of June 2004. A total sample of 30 patients aged between (1 and 15 years) with acute lymphoblastic leukemia were included in study who were treated at Basra Maternity and child teaching hospital, all of them were being treated according to MRC modified protocol and on maintenance therapy (6 mercaptopurina + methotroxate), 35 healthy children matched for age and sex randomly selected as control. Results: Hypoglycemia were seen is 18 (60%) of patients with leukemia, 10 (55.5%) females and 8 (44.4%) males. Blood glucose level <3.33 mmol/L during 12 hours of overnight fasting. Conclusion: Hypoglycemia is the most common adverse effect in children with acute lymphoblastic leukemia on maintenance therapy.

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Transient Elevations in Markers of Hepatic Function during Pediatric Acute Lymphoblastic Leukemia Treatment Are Common but Do Not Influence Outcomes: A Study of 805 Patients from the Learn Consortium

Blood ◽

10.1182/blood-2019-123992 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3814-3814

Author(s):

Joanna S. Yi ◽

Tiffany Chambers ◽

Kelly D Getz ◽

Tamara P. Miller ◽

Evanette Burrows ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Intensity ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Chemotherapeutic Agents ◽

Children's Hospital ◽

Children’S Hospital ◽

Pediatric All ◽

Grade 3 ◽

All Treatment

Introduction: Hepatotoxicity is a frequent and challenging adverse event in children with acute lymphoblastic leukemia (ALL), but patient factors that are predictive of hepatotoxicity are not well understood. We leveraged a data repository jointly developed by two pediatric oncology centers within the Leukemia Electronic Abstraction of Records [LEARN] Consortium to assess the landscape and determinants of liver dysfunction throughout ALL therapy in patients who were risk-stratified to receive either standard- or high-intensity treatment blocks. Methods: The subjects were children ages 1-21 years who were treated for ALL between 2006-2014 at either Children's Hospital of Philadelphia or Texas Children's Hospital. Demographics, disease-related data, and every laboratory value collected during treatment were obtained by targeted manual abstraction and extensive semi-automated extraction of patient electronic medical record (EMR) data. To reduce cohort heterogeneity, we excluded patients who received non-standard ALL therapies. Patients were categorized as receiving either standard-intensity or high-intensity treatment for their first three blocks of therapy (Induction, Consolidation, Interim Maintenance 1 [IM1]) based on chemotherapeutic agents delivered in those blocks. Differences in laboratory value-determined hepatoxicity were then analyzed based on this categorization for all remaining phases of therapy. Hepatic lab values (AST [SGOT], ALT [SGPT], total bilirubin [t. bili], and conjugated bilirubin [c. bili]) were first normalized to the age-based upper limit of normal (ULN), and the median value was then determined. A multivariate mixed-effects linear regression model with random effects was used to identify differences in the treatment group medians and the following covariates: age, race/ethnicity, sex, BMI, and ALL immunophenotype. Laboratory values were classified by the CTCAE v5.0 grading system, with grade ≥ 3 considered 'elevated.' Results: 805 pediatric ALL patients were included in the analysis, representing 114,095 hepatic lab values (Table 1). Less than 10% of patients had elevated lab values at diagnosis. Throughout treatment, the majority of lab values fell within 1-2x ULN for age for both standard- and high-intensity treatment groups (Fig. 1a-d). The median hepatic lab values for the high-intensity group were slightly higher than the standard risk group across all treatment phases, and this difference was most consistently significant in Consolidation and Delayed Intensification. Among the four hepatic labs that were assessed, ALT had the most significant deviation above normal (up to 30x ULN, Fig 1a). Patients were more likely to have elevated transaminases during maintenance than prior to maintenance (Fig. 1e). Similarly, but to a lesser degree, patients were more likely to have elevated t. or c. bili during maintenance than prior to maintenance. Age, race, and BMI were correlated with elevated hepatic labs, with Hispanic and/or overweight patients more likely to have elevations in 3 or more phases of therapy (Table 2). However, no hepatic lab abnormalities were correlated with either overall or relapse-free survival. Conclusions: This is the first comprehensive study of measures of hepatotoxicity in a large and uniformly-treated cohort of pediatric ALL. While significantly elevated hepatic labs are rare at diagnosis, they are common during ALL treatment and are seen more commonly in maintenance than in prior phases. Patients who are overweight and/or Hispanic are more likely to experience grade 3 or higher hepatoxicity. We observed no relationship between hepatotoxicity and relapse or survival. Further studies are ongoing to delineate the temporal correlation of liver function and chemotherapy dosing and administration. Disclosures No relevant conflicts of interest to declare.

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A Dose Intensified Pediatric-Like Regimen Using Multiple Doses of Intravenous Pegylated Asparaginase in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v110.11.2823.2823 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2823-2823 ◽

Cited By ~ 1

Author(s):

Dan Douer ◽

Kristy Watkins ◽

Lisa Mark ◽

Ann Mohrbacher ◽

Allen S. Yang ◽

...

Keyword(s):

Phase I ◽

Lymphoblastic Leukemia ◽

Induction Phase ◽

Newly Diagnosed ◽

Neutropenic Sepsis ◽

Multiple Doses ◽

Elevated Liver Enzymes ◽

Pediatric All ◽

Remission Phase ◽

Grade 3

Abstract Introduction: Recent studies have suggested that more intensive pediatric regimens may improve the outcome of adults with ALL. In particular, higher dose of asparaginase (ASP) are often used in pediatric ALL protocols than in adults. Large randomized pediatric ALL trials have shown that multiple doses of E.Coli ASP given throughout the post remission phase are associated with improved outcome. PEG-asparaginase (PEG-ASP) is a modified formulation of E.coli ASP, with lower risk of hypersensitivity reactions and prolonged half life. Data on PEG-ASP in adults is limited. In a previous study we showed in adult ALL patients that a single IV dose of PEG-ASP given during induction produces a long duration of asparagine depletion (up to 3-4 weeks) with similar toxicity to equivalent multiple doses of E.coli ASP (Douer et al Blood19:2744, 2007). We currently report in adults the use of multiple doses of PEG-ASP given throughout the treatment course of patients with newly diagnosed previously untreated ALL as part of an intensive pediatric regimen. Methods: The therapeutic backbone of this protocol is based on an augmented BFM pediatric ALL protocol consisting of 8 cycles of multi-agent chemotherapy, followed by maintenance. PEG-ASP (2000 U/m2/dose) is given IV once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Results: 34 patients aged 19–57 (median 33) years with newly diagnosed ALL (precursor B cell - 29, T cell-5, Ph+ 7) were studied. Median WBC at diagnosis was 21,000/cumm (range 1,900–512,000). Thirty three patients (97%) achieved a CR after induction phase I. Eight (26%) patients discontinued the protocol because of undergoing allogeneic stem-cell transplantation. Other reasons for not completing all PEG-ASP doses are: relapse -3 pts., death in CR from neutropenic sepsis-2 pts., pancreatitis -4 pts. To date six patients received all 6 doses of PEG-ASP havingcompleted all consolidation cycles. The other patients are still being treated. So far the number of PEG-ASP doses given is: 6-6pts, 5-1 pt., 4-3 pts., 3-5 pts., 2-7 pts., 1-12 pts. Total number of doses was 94. Grade 3/4 toxicities during cycles after PEG-ASP was given were: elevated liver enzymes - 18/34 (53%) pts (25 doses), hyperbilrubinema - 7/34 (21%) pts (7 doses), hyperglycemia - 11/34 (32%) pts (13 doses), pancreatitis 4/34 (12%) pts, fatigue 3/34 (9%) pts, hypertriglyceridemia-2/34 (6%) pts, neuropathy, catheter thrombosis-1/34 pt each; no allergic reactions. All toxicities were reversible. In 20 patients anti-asparaginase antibodies were assayed and none were found. With a median follow up of 15 months event free survival at 3 yrs is 61%. Conclusion: Administration of multiple doses of PEG-ASP IV to adults (ages19–57 years) in an intensified BFM-based pediatric-like strategy is feasible and provides long term asparagine depletion. Such approach may benefit adults with ALL.

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L-Carnitine for Treatment of Pegasparaginase-Induced Hepatotoxicity

Acta Haematologica ◽

10.1159/000442342 ◽

2016 ◽

Vol 135 (4) ◽

pp. 208-210 ◽

Cited By ~ 23

Author(s):

Ruham Alshiekh-Nasany ◽

Dan Douer

Keyword(s):

Clinical Trials ◽

Case Report ◽

Acute Lymphoblastic Leukemia ◽

Liver Toxicity ◽

Lymphoblastic Leukemia ◽

Therapeutic Benefit ◽

Amino Acid Derivative ◽

High Grade ◽

Newly Diagnosed ◽

Multiple Doses

Introduction: Similar to pediatric regimens, multiple doses of L-asparaginase (PEG-Asp) are being increasingly used in adults with newly diagnosed acute lymphoblastic leukemia (ALL) with promising results. One of the most common side effects of the drug in adults is high-grade hyperbilirubinemia and transaminitis. Despite being almost always reversible and may not recur, clinicians may still be reluctant to continue with PEG-Asp in patients with liver toxicity, losing the benefit from multiple doses of the drug. Case Report: We describe a case of adult ALL who developed PEG-Asp-related high grade liver toxicity. The rising hyperbilirubinemia and transaminitis rapidly and permanently reversed using the amino-acid derivative L-carnitine. This case goes in line with similar observations in animal models and humans. Conclusion:L-Carnitine may show therapeutic benefit in PEG-Asp-related hepatotoxicity and should be considered in clinical trials of the drug.

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

Blood ◽

10.1182/blood-2020-138840 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Lynda M. Vrooman ◽

Yael Flamand ◽

Victoria Koch ◽

Melissa A. Burns ◽

Sarah M. Cronholm ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Allergic Reaction ◽

Lymphoblastic Leukemia ◽

Advisory Board ◽

Challenge Dose ◽

Post Induction ◽

Asparaginase Activity ◽

Erwinia Asparaginase ◽

Grade 3 ◽

Experienced Grade

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 < 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 < 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.

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Targeting Kinase-activating Genetic Lesions to Improve Therapy of Pediatric Acute Lymphoblastic Leukemia

Current Medicinal Chemistry ◽

10.2174/0929867324666170727101932 ◽

2018 ◽

Vol 25 (24) ◽

pp. 2811-2825 ◽

Cited By ~ 2

Author(s):

Raffaella Franca ◽

Natasa K. Kuzelicki ◽

Claudio Sorio ◽

Eleonora Toffoletti ◽

Oksana Montecchini ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Fusion Gene ◽

Hematologic Malignancy ◽

Lymphoblastic Leukemia ◽

Point Of View ◽

Lymphoid Cells ◽

Gene Encoding ◽

Pediatric All ◽

Blast Cells ◽

Tk Inhibitors

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, characterized by an abnormal proliferation of immature lymphoid cells. Thanks to risk-adapted combination chemotherapy treatments currently used, survival at 5 years has reached 90%. ALL is a heterogeneous disease from a genetic point of view: patients’ lymphoblasts may harbor in fact several chromosomal alterations, some of which have prognostic and therapeutic value. Of particular importance is the translocation t(9;22)(q34;q11.2) that leads to the formation of the BCR-ABL1 fusion gene, encoding a constitutively active chimeric tyrosine kinase (TK): BCR-ABL1 that is present in ~3% of pediatric ALL patients with B-immunophenotype and is associated with a poor outcome. This type of ALL is potentially treatable with specific TK inhibitors, such as imatinib. Recent studies have demonstrated the existence of a subset of BCR-ABL1 like leukemias (~10-15% of Bimmunophenotype ALL), whose blast cells have a gene expression profile similar to that of BCR-ABL1 despite the absence of t(9;22)(q34;q11.2). The precise pathogenesis of BCR-ABL1 like ALL is still to be defined, but they are mainly characterized by the activation of constitutive signal transduction pathways due to chimeric TKs different from BCR-ABL1. BCR-ABL1 like ALL patients represent a group with unfavorable outcome and are not identified by current risk criteria. In this review, we will discuss the design of targeted therapy for patients with BCR-ABL1 like ALL, which could consider TK inhibitors, and discuss innovative approaches suitable to identify the presence of patient’s specific chimeric TK fusion genes, such as targeted locus amplification or proteomic biosensors.

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