scholarly journals Asparaginase Induced Liver Enzyme Elevation Is More Prevalent in Hispanics Children with ALL and in Patients with SOD2 rs4880 CC Genotype

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2279-2279
Author(s):  
Sharon Wu ◽  
Mengxi Wang ◽  
Amani Ali Alqahatni ◽  
Mimi Lou ◽  
Wendy Stock ◽  
...  
Keyword(s):  
Liver Enzyme ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Post Treatment ◽  
European Ancestry ◽  
Risk Genotype ◽  
Significant Difference ◽  
Elevated Bilirubin ◽  
Hispanic Patients ◽  
Grade 3

Abstract Background: Asparaginase is an integral component of treatment for pediatric patients with acute lymphoblastic leukemia (ALL). Hepatotoxicity secondary to asparaginase-based treatment is one of the most common treatment-related toxicities in ALL therapy. Hispanic children are at higher risk of ALL and ALL treatment related toxicities compared with other ethnicities. The rs4880 variant in the SOD2 gene, a critical mitochondrial enzyme that protects cells against oxidative stress, was previously found to be associated with increased incidence of hepatotoxicity following asparaginase treatment in an adult ALL cohort of largely European ancestry. Whether this association is also present in pediatric patients with ALL and in Hispanics remains unknown. Importantly, the risk genotype (CC) of rs4880 is more frequent among Hispanics. Here we aim to investigate the prevalence of hepatotoxicity and risk genotype among pediatric patients with ALL particularly of Hispanics ancestry. Method: Blood samples, demographic and clinical data were obtained from 143 pediatric patients treated for ALL between 29 January 2015 and 24 January 2020 at Children's Hospital Los Angeles. We genotyped DNA samples isolated from the patient's blood for the rs4880 variant of SOD2 using TaqMan Allelic Discrimination Assay. Liver enzyme data, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels for each subject following multiple visits before and post asparaginase-based treatment were obtained. Hepatotoxicity is defined as grade 3/4 of both AST and ALT, grade 4 of either AST or ALT, or grade 3/4 of bilirubin. We performed Cox Proportional Hazards models to evaluate the predictive factors of hepatotoxicity overtime. Results: Among the 143 patients, 13 (9.09%) patients had grade > 3 elevated bilirubin levels, and 3 (2.1%) and 55 (38.46%) patients had grade > 4 and > 3 elevated AST levels respectively, and 19 (13.29%) and 109 (76.22%) had grade > 4 and > 3 elevated ALT levels respectively. Hepatotoxicity was observed in 60 (41.96%) of patients. After dichotomizing patients based on ethnicity (Hispanic and non-Hispanic), we found that BMI was significantly higher in Hispanics than non-Hispanic patients (mean BMI: 21.57 vs 18.64, p=0.002). While mean baseline levels of liver enzymes were not significantly different between Hispanic and non-Hispanic patients (bilirubin:0.69 vs 0.64, ALT: 156.06 vs 124.75, and AST: 99.98 vs 82.38), post-treatment levels were significantly higher in hispanics (ALT: 138.105 vs. 101.45, p=0.0005; AST: 84.131 vs. 64.045, p=0.0023). After chemotherapy, grade 3 or 4 elevated bilirubin was found in 11 (12.36%) of 89 Hispanic patients and only in 2 (3.7%) of 54 non-Hispanic patients. Also, there was a statistically significant difference in the frequency of elevated ALT level grade > 4 and grade > 3 between Hispanic and non-Hispanic patients (grade > 4: 17 (19.10%) vs 2 (3.70), p= 0.01; grade > 3: 74 (83.15%) vs 35 (64.8%), p=0.01). Consequently, Hepatotoxicity was more frequent among Hispanic patients than non-Hispanic, 47.19% vs 33.33%; p=0.10, respectively. We also compared hepatotoxicity parameters according to the patient's rs4880 genotypes. Among patients with the SOD2 rs4880 CC genotype 3 (6.32%) had grade > 4 and 23 (50%) had grade > 3 elevated AST compared with 0 (0%) and 21 (30%) among the CT and 0 (0%) and 11 (40.74%) among the TT genotype patients (CC vs. CT and TT; AST grade > 4: p=0.13; grade > 3 : p=0.05). In addition, elevated bilirubin grade > 3 was found more frequently in patients with the SOD2 rs4880 CC genotype (15.22%) compared with those with the CT (5.71%) and TT (7.41%) genotypes. Furthermore, post-treatment bilirubin, ALT and AST median levels were significantly higher in patients with the CC genotype than in patients with CT or TT genotypes (bilirubin: 0.8275 vs. 0.6, p=0.0007; ALT: 142.555 vs. 106.038, p=0.0089; AST: 85.399 vs. 67.888, p= 0.0302). In a multivariate Cox analysis, that included ethnicity, age, gender, BMI and genotype, we identified Ethnicity (Hispanic) as the only significant predictor of hepatotoxicity (hazard ratio [HR] = 1.862, 95% confidence interval [95% CI] 1.-3.465, p=0.0499). Conclusion: Overall, these findings suggested that hepatotoxicity is highly prevalent among Hispanic pediatric patients with ALL, especially those with CC genotype of rs4880. Disclosures Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria.

Pharmacogenomic Association with Neurotoxicity in Hispanic Children with Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3962-3962 ◽  
Author(s):  
Claire A McClain ◽  
M Brooke Bernhardt ◽  
Amanda Berger ◽  
Ryan Winslow ◽  
Michael E Scheurer ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Poor Metabolizers ◽  
Extensive Metabolizers ◽  
Hispanic Children ◽  
Significant Difference ◽  
Hispanic Patients ◽  
Grade 3 ◽  
Intermediate Metabolizers

Abstract Introduction Vincristine is vital in the treatment of acute lymphoblastic leukemia (ALL), but is dose-limited by the development of disabling neuropathies. Vincristine is metabolized extensively by polymorphically expressed CYP3A4/5, which contributes to its 10-fold inter-patient pharmacokinetic variability. Further, there is more recent evidence that an inherited polymorphism in the CEP72 rs924607 gene contributes to vincristine sensitivity. Hispanic children have among the lowest rates of ALL survival when compared to other ethnicities, and pharmacogenomic variability among races is postulated to contribute. This is the first study to examine specifically both CYP3A5 polymorphisms and CEP72 gene expression in correlation with vincristine neurotoxicity in a large cohort of Hispanic ALL patients. Methods Banked germline blood samples from 300 self-identified Hispanic patients with ALL treated at Texas Children's Hospital between 1990 and 2015 were interrogated for allelic discrimination of CEP72 and at the CYP3A5*3, *6, and *7 polymorphic loci using TaqMan assays. Patient medical records were electronically searched for evidence of neuropathic events. Neuropathies were categorized as motor or sensory and graded using the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies. Missing administered vincristine data was imputed using the patient's known treatment protocol and date of event coupled with protocol specifics retrieved from the literature. Multivariate analysis was run modeling the influences of CYP3A5 and CEP72 genotypes on the development and time to development of greater than or equal to Grade 3 neuropathies. Descriptive statistics were used to identify the prevalence of CYP3A5 and CEP72 genotypes and the associated phenotypes in this patient population. Time to neuropathy analysis was performed using the Kaplan-Meier failure estimates and log-rank test in Stata V.12.1 (College Station, TX). Results Based on CYP3A5 polymorphisms, overall, we found that 5% of our patients were extensive metabolizers of vincristine, 33% were intermediate metabolizers, and 62% were poor metabolizers. Additionally, we found that the TT risk CEP72 genotype is a rare finding in our cohort (9.3%). Clinically, we found that 18.4% of our patients experienced greater than or equal to Grade 3 neurotoxicity. Assessing the influence of being both a CYP3A5 intermediate or poor metabolizer and having the TT risk CEP72 genotype was limited by the paucity of patients with both genotypes (n=25). However, CYP3A5 poor metabolizers experienced neurotoxicity more often than intermediate or extensive metabolizers, although we did not find a statistically significant correlation between phenotype and incidence of neurotoxicity. Additionally, we found that there was a statistically significant difference in time to development of neurotoxicity within the first 100 days of treatment between intermediate and poor CYP3A5 metabolizers (P=0.036), with poor metabolizers experiencing greater than or equal to Grade 3 neurotoxicity sooner (Figure 1). Conclusions For the first time, we show that CYP3A5 poor metabolizers experienced greater than or equal to Grade 3 neurotoxicity significantly sooner than intermediate metabolizers within the first 100 days of treatment. We found a low prevalence of the minor allele of CEP72 rs924607TT in our Hispanic cohort. However, classification of CYP3A5 metabolizers and genotypes within our Hispanic population as well as our incidence of neurotoxicity are consistent with current literature. Further testing in a larger cohort should be performed but this study reinforces the significance of CYP3A5 metabolism of vincristine in leading to significant neurotoxicity and suggests that, at least in Hispanic patients, vigilance to early development of neurotoxicity should be performed by practitioners. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Toxicities of Intravenous (IV) Pegasparaginase (ONCASPAR®) in Adults with Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2811-2811 ◽  
Author(s):  
Anjali Advani ◽  
Marc Earl ◽  
Dan Douer ◽  
Michael Rytting ◽  
Archie Bleyer
Keyword(s):  
Pediatric Patients ◽  
Liver Enzymes ◽  
Lymphoblastic Leukemia ◽  
Elevated Serum ◽  
Cleveland Clinic ◽  
Adult Patients ◽  
Cancer Center ◽  
Elevated Liver Enzymes ◽  
Grade 3 ◽  
Chemotherapy Agents

Abstract Background: With the multiple reports of asparaginase-containing regimens used in pediatric ALL therapy achieving a greater survival rate that non-asparaginase treatment regimens used in adult patients, asparaginase therapy is now being increasingly applied in chemotherapy regimens for adults with ALL. One reason for this resurgence is the availability of a long-acting form of the enzyme, pegylated asparaginase, and more recently, flexibility in administration of pegasparaginase via either intramuscular or intravenous routes (Oncaspar®). Given an initial impression in the 1970s that adults were more vulnerable to the toxicities of asparaginase than were children, we assessed the initial experience of intravenous asparaginase in adults with ALL. Methods: The intial experience with pegylated asparaginase at the University of Southern California (USC), Cleveland Clinic, and University of Texas M.D. Anderson Cancer Center were compiled and compared between institutions and with published results in pediatric patients. Results (Table): In 76 adult patients administered 192 doses of pegasparaginase in combination with other chemotherapy agents for ALL, hepatotoxicity was most common, with grade 3–4 elevation of serum liver enzymes and grade 3–4 hyperbilirubinemia in 36% and 14% of the patients, respectively. Hyperglycemia and chemical pancreatitis were next most common, having occurred at grade 3–4 levels in 25% and 5% of patients, respectively. Grade 3–4 toxicities in the 5–10% range were thrombosis, hypofibrinogenemia, nausea/vomiting, and fatigue. Grade 3–4 allergy/hypersensitivity, neuropathy, and CNS ischemia were reported in 1–5% of patients. Conclusions: Intravenous pegasparaginase is hepatotoxic in ∼1/3 of adult patients and has a variety of other, non-hepatic toxicities in <10% of patients, of which the most common are pancreatitis, thrombosis, nausea/vomiting and fatigue. Intravenous pegasparaginase has a toxicity profile, in combination with other chemotherapy agents used in ALL therapy, in adult patients that similar to that in pediatric patients, and warrants increased use in adult patients with ALL. Grade 3–4 Toxicities of IV Pegasparaginase in Adults USC Cleveland Clinic MD Anderson Total Median Age (Years) 28 37 20 33 Age Range (Years) 17–57 20–68 14–28 17–68 No. Doses / Patients 81 / 45 41 / 18 70 / 13 192 / 76 % Patients with Grade 3–4 Toxicity Elevated liver enzymes 31% 28% 62% 36% Hyperbilirubinemia 13% 22% 15% 14% Hyperglycemia 27% 17% 31% 25% Elevated serum amylase 0% 0%R 0% 5% Fatigue 7% 0% 0% 7% Thrombosis 4% 6% 6% 0% Hypofibrinogenemia 0% 28% 28% 0% Elevated PT/INR 0% 0% 0% 7% Bleeding 0% 0% 0% 8% Nausea/vomiting 2% 17% 17% 1% Allergy/hypersensitivity 0% 0% 0% 1% Neuropathy 2% 0% 0% 4% CNS ischemia 0% 0% 15% 3%

Fludarabine, Mitoxantrone and Rituximab (FMR) Regimen in Previously Untreated Patients with Indolent Non-Hodgkin Lymphoma: Efficacy, Safety and PET Data On 285 Patients.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2736-2736
Author(s):  
Pier Luigi Zinzani ◽  
Cinzia Pellegrini ◽  
Enrico Derenzini ◽  
Alessandro Broccoli ◽  
Letizia Gandolfi ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Bone Marrow Involvement ◽  
Stage Ii ◽  
Hematologic Toxicity ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Significant Difference ◽  
Grade 3

Abstract Abstract 2736 In this retrospective single-center study we aimed at evaluating the efficacy and safety of fludarabine, mitoxantrone and rituximab (FMR) regimen as first line therapy in untreated patients with follicular non-Hodgkin lymphoma (NHL) and indolent non-follicular NHL considering also the role of positron emission tomography (PET) after this chemo-immunotherapy induction as predictor of survival. Between January 2000 and May 2011, 285 patients with stage II-IV untreated indolent follicular (excluding grade IIIb) NHL (n=142) and indolent non-follicular (including marginal zone lymphoma, MZL [n=111] and small lymphocytic lymphoma, SLL [n=31]) NHL (n=143) were diagnosed and treated at our institution in the outpatient clinic. Median age was 63 years (range, 25–83 years) and the median time from diagnosis to study entry was 3 months (range, 1–5 months). 20 patients had stage II, 75 patients had stage III, and 190 had stage IV disease (155 patients had bone marrow involvement). Standard fludarabine (25 mg/m2 iv on days 2, 3 and 4), mitoxantrone (10 mg/m2 iv on day 2) and rituximab (375 mg/m2 iv on day 1) were given every 28 days for six cycles. Globally, after FMR regimen, the overall response rate (ORR) was 83.2%, including a 71.6% complete remission (CR) rate (204 patients) and a 11.6% partial remission (PR) rate (33 patients). According to the histology, in the follicular subset, the ORR was 81.1% with a CR rate of 69.2% while in the indolent non-follicular subset the ORR was 85.2% with a CR rate of 73.9%. In particular, in the indolent non-follicular NHL subgroup the CR rate was 80.2% in MZLs and 51.6% in SLLs, respectively. Toxicities were generally mild and mainly hematologic. Overall 88 (30.8%) patients had grade ≥3 hematologic toxicity, and 26 (9.1%) patients had non-hematologic toxicity with 3 cases of grade ≥3 (1 neurologic toxicity and 2 hepatic toxicity). In terms of secondary malignancies, only 3 (1.0%) hematologic neoplasms were reported (1 myelodisplastic syndrome after 9 months from the end of the treatment and 2 acute lymphoblastic leukemia after 8 and 11 months from the end of the treatment, respectively). Globally with a median follow up of 40 months (range, 12–144 months), at 11 years the overall survival (OS) was 78.8%, the disease-free survival (DFS) was 73.4% (with only 29 relapses), and the progression-free survival (PFS) was 71.9%. Regarding the comparison between the two subsets, follicular vs indolent non-follicular, no statistically significant differences were observed in OS, DFS and PFS curves. Furthermore, a sub-sample of 132 patients (75 follicular NHLs and 57 indolent non-follicular NHLs) had a PET evaluation before the treatment (staging) and 4 to 6 weeks after completion of the sixth cycle of chemo-immunotherapy (restaging, final PET [f-PET]). Post-induction PET-positive patients had a significantly inferior OS at 6 years: 71.4% compared with 98.4% for f-PET-negative patients (p<0.0001, Figure 1a). In terms of PFS at 6 years, there was not a statistically significant difference among f-PET-positive patients and f-PET-negative patients (Figure 1b). Figure 1a. Figure 1a. Figure 1b. Figure 1b. In conclusion, this study suggests and confirms that FMR is a very active, well tolerated (in terms of acute and long-term side effects) chemo-immunotherapy front-line treatment for follicular NHL and indolent non-follicular NHL. PET status at the end of this chemo-immunotherapy induction is quite controversial as a predictor of survival. Disclosures: No relevant conflicts of interest to declare.

Comparison of chemotherapy dose intensity for AYAs on COG AALL1131 versus CALGB 10403.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10520-10520
Author(s):  
Jennifer Lynn McNeer ◽  
Lingyun Ji ◽  
Xinxin Xu ◽  
Michael Burke ◽  
Wanda Salzer ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Prospective Trial ◽  
Dose Intensity ◽  
Sensory Neuropathy ◽  
Patient Characteristics ◽  
Normal Weight ◽  
Significant Difference ◽  
Grade 3 ◽  
The Impact ◽  
To Receive

10520 Background: Outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are superior with pediatric-inspired therapy. CALGB 10403, the first US adult cooperative group prospective trial using a pediatric-inspired augmented BFM (ABFM)-based regimen, demonstrated feasibility and improved survival. We examined differences in drug delivery and targeted toxicities in AYAs who received the same therapy on C10403 vs the Children’s Oncology Group (COG) study AALL1131. Methods: The proportion of AYAs receiving full dose (within 10% of protocol- specified) vincristine (VCR) and pegaspargase (PEG) during induction (IND), consolidation (CON), and delayed intensification (DI); the likelihood of selected grade ≥3 adverse events (AEs); and the impact of patient characteristics were compared in AYAs 16-30 years. Targeted AEs with analogous reporting requirements in both studies included hyperbilirubinemia, pancreatitis, sensory neuropathy, and GI/intracranial hemorrhage. Thrombosis, transaminitis and hyperglycemia were not comparably captured. Fisher’s Exact test and logistic regression models were used for analyses. Results: After excluding AYAs removed from study after induction, 87 AALL1131 AYAs (accrued 2012-2016) and 188 C10403 AYAs (accrued 2007-2012) were analyzed with median ages of 17 (16-26) vs 22 (17-30) years, p < 0.001. There was no difference in the intensity of VCR delivery during IND, but in CON and DI, AALL1131 AYAs were more likely to receive all specified VCR (93.1% vs 81.9%, p = 0.02; 92.7% vs 72.1%, p = 0.01). Women were less likely to receive all specified VCR (OR 0.57, 95% CI 0.34-0.94, p = 0.03), and overweight/obese AYAs were somewhat less likely to receive all VCR compared to those considered normal weight (OR 0.88 and 0.59, p = 0.09). More C10403 AYAs were obese/overweight compared to AALL1131 AYAs (p = 0.04). There were no significant differences in dosing of PEG during IND/CON, but in DI AALL1131 AYAs were more likely to receive both doses (75.6% vs 57.1%, p = 0.03). No patient variables impacted delivery of PEG. There was no significant difference in grade ≥3 toxicities captured similarly on both studies. Conclusions: AYAs enrolled on AALL1131 were more likely to receive all protocol-specified VCR and PEG compared to those on C10403. Selected AE rates were comparable, suggesting that older AYAs do not tolerate doses of VCR and PEG for reasons other than toxicity, with body habitus as one potential variable. Further analyses to compare dose density, toxicities, and outcomes experienced by younger AYAs versus older are ongoing.

A Phase 1/2 Study Of Blinatumomab In Pediatric Patients With Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 70-70 ◽  
Author(s):  
Arend von Stackelberg ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Franco Locatelli ◽  
Carmelo Rizzari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Level ◽  
Pediatric Patients ◽  
Treatment Cycle ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Cell Precursor ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction Novel approaches are needed to treat pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blinatumomab is a bispecific T-cell engager (BiTE®) antibody that has shown remission in an exploratory study of 36 adult patients with relapsed/refractory ALL. Primary toxicities in adults have been cytokine release syndrome (CRS) and central nervous system (CNS) related toxicity. We initiated a phase 1/2 multicenter study to identify, in the phase 1 part, the optimal dose of blinatumomab in pediatric patients with relapsed/refractory BCP-ALL. Methods In this ongoing study, eligible patients are <18 years old and must have BCP-ALL that is refractory, in second or later bone marrow relapse, or in any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Blinatumomab is administered by continuous intravenous infusion over 28 days, followed by a 14-day treatment-free interval (up to five cycles). Data from the five doses that have been explored to date are presented. Maximum tolerated dose (MTD), defined as the highest dose level with less than two of six patients experiencing dose-limiting toxicity (DLT) within the first treatment cycle, is the primary endpoint in the phase 1 part of the study (rolling 6 design). Serum samples were collected for pharmacokinetics evaluation and cytokine measurement. Results In the phase 1 part of the study, 34 patients received a total of 56 cycles. Six (18%) patients had refractory disease and 6 (18%) had experienced at least two bone marrow relapses. Twenty-two (65%) patients had relapsed following HSCT. DLTs for dose levels 1 through 4 are summarized in the Table. The MTD for this patient population was established at 15 µg/m²/day. In order to reduce the risk of CRS, a dose of 5 µg/m²/day for 7 days escalating to 15 µg/m²/day for the remainder of the first cycle and all following cycles (5→15 µg/m²/day; dose level 5) was evaluated as recommended dose. None of the 11 patients treated at this dose level developed CRS and no grade 3 CNS-related adverse events (AEs) occurred. Across dose levels, the most common AEs regardless of causality were pyrexia (62% of patients), headache (35%), anemia (29%), and hypertension (29%). One patient treated at 5 µg/m²/day had a grade 3 seizure at the beginning of the second treatment cycle, which resolved clinically and showed no changes on MRI. Across all dose levels, 11 (32%) patients had complete remission (CR), one (3%) had hypocellular blast-free bone marrow, and two (6%) had partial remission within the first two treatment cycles, for an overall response rate of 41%. Some efficacy assessments are still ongoing, and full response data for the phase 1 part of the study will be available at the time of presentation. Two patients experienced hematologic relapse (one each at dose levels 2 and 3, during the fifth and third cycles, respectively). Pharmacokinetic parameters, such as steady-state concentration (Css) and clearance, appeared to be similar to those from adult patients with relapsed/refractory BCP-ALL who received body surface area-based blinatumomab dosing. Transient elevations of serum cytokines were observed mainly in the first two days after infusion start, in particular IL-6, IFN-gamma, IL-10, and, to a lesser extent, IL-2 and TNF-α. Conclusions In the ongoing phase 1 part of this study in pediatric patients with relapsed/refractory BCP-ALL, a dose of 15 µg/m²/day was established as MTD. Cytokine-release syndrome has been dose-limiting. Pharmacokinetic analysis at the recommended dose of 5→15 µg/m²/day is ongoing. This dose de-escalation strategy has been successful in ameliorating severe CRS to date. Blinatumomab treatment has shown promising antitumor activity in this relapsed/refractory patient population. Disclosures: von Stackelberg: Amgen Inc.: Honoraria. Zugmaier:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Rheingold:Novartis: Research Funding. Holland:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Mergen:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Fischer:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Zhu:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Hijazi:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Gore:Amgen Inc.: Travel expenses paid for DSMC meeting (Feb 2013) Other.

scholarly journals Hepatotoxicity in Adolescent and Young Adult Hispanic Patients Treated with Pediatric Regimens for Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4396-4396
Author(s):  
Mahir Khan ◽  
Eshana Shah ◽  
Saad Arain ◽  
Kaily Kurzweil ◽  
Carlos A. Murga-Zamalloa ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
Young Adult ◽  
Adverse Events ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Lymphoblastic Leukemia ◽  
Drug Discontinuation ◽  
Hispanic Patients ◽  
Grade 3

Abstract Introduction: Pediatric or pediatric-inspired regimens are used in the treatment of adolescent or young adult (AYA) patients with acute lymphoblastic leukemia (ALL). While overall survival is improved with these regimens, hepatotoxicity and metabolic complications are common adverse events related to the increased dosages of asparaginase and steroids used vs adult ALL regimens. Among ethnicities, prevalence of metabolic syndrome and hepatic steatosis is highest in the Hispanic population, which comprises ~20% of the US population and carries an increased risk of ALL. Surprisingly, there is limited literature describing hepatotoxicity in this at-risk population. Herein we describe our experience with this adverse effect in AYA Hispanic patients (&lt;50 yrs) treated with pediatric ALL regimens at an urban academic medical center. Methods: Single-center retrospective chart review of patients with ALL treated from January 1, 2010 to May 30, 2021 at the University of Illinois at Chicago. Patients with an associated ALL diagnosis were identified through an internal pathology database. Demographic information, clinical characteristics, treatment history and complications [grade 3/4 transaminitis, development of non-alcoholic fatty liver (NAFLD) on imaging, non-alcoholic steato-hepatitis (NASH)/fibrosis/cirrhosis on biopsy, pancreatitis, treatment change or drug discontinuation secondary to hepatotoxicity] were abstracted from the EMR. Descriptive statistics were used to determine outcome frequencies. Results: We identified 33 Hispanic (n= 20) and Non-Hispanic White (NHW; n = 13) patients with either B-ALL or T-ALL, with each demographic stratified by pediatric or adult regimen therapy (Table 1). Pediatric regimens include Children's Oncology Group protocols and E1910; the adult regimen was HyperCVAD. Of 16 Hispanic patients who received pediatric regimens, 7 (44%) had pre-existing diabetes, 1 had fatty liver on baseline imaging and 1 biopsy-confirmed NASH. During treatment, 12/16 (75%) developed grade 3/4 hepatotoxicity, 11 (69%) developed mild-severe NAFLD on imaging, 2 additional patients developed cirrhosis, and 4 (25%) pancreatitis. Treatment-related adverse events prompted therapy change or drug discontinuation in 25%. Hispanic patients, (n = 4), on adult and NHW patients, (n = 7), on pediatric regimens had low rates of pre-existing comorbidities, but of the older NHW patients, (n = 6), on an adult regimen, 4/6 (67%) and 1/6 had underlying diabetes or NAFLD, respectively. We found similar high rates of grade 3/4 hepatotoxicity in Hispanics on an adult regimen (100%) and NHW patients on either a pediatric (71%) or adult regimen (50%). However, fewer patients developed NAFLD (4/17, 24%), only 1 (Hispanic) patient developed fibrosis, and none developed pancreatitis. There was no difference in mean BMI between Hispanic and NHW patients. Conclusions: While grade 3/4 transaminitis is described during ALL treatment, in this retrospective analysis we observed that Hispanic AYA patients treated on pediatric protocols frequently develop more serious complications including hepatic steatosis, cirrhosis or pancreatitis. Co-existing metabolic syndrome is associated with a higher incidence of simple steatosis (SS; 70% in obesity, 90% in diabetes), and Hispanic patients have a higher baseline SS incidence (45% in Hispanics vs 33% in NHW), which in the context of use of higher doses of steroids and asparaginase may explain their increased frequency of progression to NASH and fibrosis. As few underwent biopsy, the true incidence is likely underrepresented. Additionally, Hispanics treated on a pediatric regimen more frequently developed pancreatitis than NHW patients on the same regimen. SS is related to the accumulation of hepatic free fatty acids and triglycerides, thus patients with SS or at risk may have impaired free fatty acid metabolism that predisposes to pancreatitis with asparaginase use. Limitations of this study include a small sample size, partial availability of baseline imaging, and non-standardized radiographic interpretations of the degree of steatosis. However, our findings suggest further investigation is warranted and a multi-center study is in progress. Our study highlights the need for closer monitoring of Hispanic patients to mitigate the risk of serious liver disease with the use of curative pediatric regimens for ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Open-Label Bendamustine for Pediatric Patients with Relapsed or Refractory Acute Leukemia: Safety and Efficacy Outcomes,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3602-3602 ◽  
Author(s):  
Christopher Fraser ◽  
Patrick A. Brown ◽  
Gail C. Megason ◽  
Hyo Seop Ahn ◽  
Bin Cho ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Stable Disease ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Cell Transplant ◽  
Phase 2 ◽  
Platelet Recovery ◽  
Duration Of Response ◽  
Grade 3

Abstract Abstract 3602 Background: Acute leukemias, consisting of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), are the most common form of childhood cancers. New treatments are needed for patients whose disease progresses or recurs following established therapies. Bendamustine is an alkylating agent that has demonstrated activity in adults with chronic lymphoblastic leukemia and rituximab-refractory non-Hodgkin lymphoma (NHL). Bendamustine has antileukemic activity in adults with AML and myelodysplastic syndrome; however, there are few data regarding bendamustine in children or in childhood acute leukemia specifically. This study is a single-arm, phase 1/2 dose-escalating trial to determine the recommended phase 2 dose (RP2D), schedule, pharmacokinetics, and safety profile of bendamustine in pediatric patients with relapsed and refractory acute leukemia. Methods: Subjects were children aged 1–20 years with relapsed or refractory ALL or AML and without the opportunity for curative therapy. Acute toxic effects of prior therapy (ended ≥2 weeks prior to first dose of study drug) had resolved to grade 2 or less. Bendamustine was infused IV over 60 minutes on days 1 and 2 of each 21-day cycle, with delays allowed up to 2 weeks for neutrophil and platelet recovery. The starting dose was 90 mg/m2/dose with planned escalation to 120 and 150 mg/m2 in cohorts of 3. The dose of 150 mg/m2 was to be implemented only if 120 mg/m2 was safe, but produced subtherapeutic plasma levels compared with data from adults. In phase 2, patients were enrolled at the RP2D in phase 1. Patients were followed until disease progression, withdrawal due to safety or other reasons, loss to follow-up, or a maximum of 12 cycles. After the end of treatment, patients were evaluated every 3 months for 12 months after the last dose, or until progression, death, or start of new cancer treatment. Overall response rate was assessed in all recipients and defined as complete response (CR) or CR without platelet recovery (CRp). Duration of response was assessed in patients who achieved CR or CRp. Biologic activity (≥ partial response [PR]) was also recorded. Safety assessments included adverse events (AEs), concomitant medication throughout treatment, vital signs, and clinical laboratory values. Results: Eleven patients were treated in phase 1 and 32 patients in phase 2. There were 27 patients with ALL and 16 with AML. Twenty-five patients had received >3 chemotherapy regimens and 20 patients had received prior hematopoietic cell transplant in addition to chemotherapy regimens. In phase 1, 5 patients received 90 mg/m2/dose, and 6 received 120 mg/m2/dose. Because no dose-limiting toxicities were observed and therapeutic levels were obtained at 120 mg/m2, the RP2D was determined to be 120 mg/m2. In phase 2, 32 patients received 120 mg/m2. Responses in patients with ALL included 2 patients with CR at 90 mg/m2, 1 had PR, and 7 had stable disease at 120 mg/m2. Two patients with AML had stable disease at 120 mg/m2. Duration of response ranged from 1–8 months with one patient still in remission after unrelated stem cell transplant. Three deaths due to progressive disease occurred in phase 1 and 13 in phase 2. None were considered treatment-related. Thirty-seven patients had at least one grade 3 AE and 19 had at least one grade 4 AE. Twenty patients had grade 3/4 thrombocytopenia (47%), 20 had grade 3/4 anemia (46.5%), and 15 had grade 3/4 febrile neutropenia (35%). Most frequent grade 3/4 non-hematologic AEs were hyperkalemia (21%), dyspnea (9.3%), and tumor lysis syndrome (9.3%). No patients withdrew due to AEs. Conclusions: In pediatric patients with multiple relapsed and refractory ALL and AML, preliminary data suggest that bendamustine has an acceptable safety profile. The RP2D was established as 120 mg/m2, which is identical to that used to treat adults with rituximab-refractory NHL. Response data for the study population suggest that bendamustine has minimal activity in heavily pretreated patients with relapsed and refractory ALL, but not in AML. Further studies will be required to evaluate the role of this agent in combination with regimens that are the backbone of current leukemia therapy in children. This research was sponsored by and conducted by Cephalon, Inc., Frazer, PA. Disclosures: Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Frankel:PPD-PharmacoVigilance: Employment, PPD-PharmacoVigilance received funding from Cephalon, Inc. to perform the described analysis. Bensen-Kennedy:Cephalon, Inc.: Employment during the execution of the study. Munteanu:Cephalon, Inc.: Employment. Weaver:Cephalon, Inc.: Employment.

Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a pediatric oncology group study

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1709-1715 ◽  
Author(s):  
Thomas C. Abshire ◽  
Brad H. Pollock ◽  
Amy L. Billett ◽  
Patricia Bradley ◽  
George R. Buchanan
Keyword(s):  
Polyethylene Glycol ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
High Antibody ◽  
Significant Difference ◽  
Extramedullary Relapse ◽  
Antibody Titers ◽  
Pediatric Oncology Group ◽  
First Relapse ◽  
Grade 3

The relapse rate in childhood acute lymphoblastic leukemia (ALL) is approximately 30% but few reinduction regimens have investigated the intensive use of polyethylene glycol Escherichia coliasparaginase (PEG-Asp). Therefore, we assessed the pharmocokinetics and efficacy of PEG-Asp in this setting. Children with B-precursor ALL, in first marrow and/or extramedullary relapse were eligible. Reinduction included doxorubicin on day 1, prednisone for 28 days, vincristine weekly for 4 weeks, and PEG-Asp either weekly or biweekly by randomization. Asparaginase levels and antibody to both E coli asparaginase and PEG-asp were measured weekly just before each PEG-asp dose. Overall, 129 of 144 patients (pts) (90%) achieved a complete remission (CR). There was a highly significant difference in CR rates between weekly (69 of 71; 97%) and biweekly (60 of 73; 82%) PEG-Asp dosing (P = .003). Grade 3 or 4 infectious toxicity was common (50%), but only 4 pts died of sepsis during induction. Other toxicities were infrequent and hypersensitivity was rare (6 of 144; 4%). Low asparaginase levels were associated with high antibody titers to either native (P = .024) or PEG asp (P = .0013). The CR rate was significantly associated with higher levels of asparaginase (P = .012). Patients with ALL in first relapse receiving weekly PEG-Asp had a higher rate of second remission compared with biweekly dosing. Low levels of asparaginase were associated with high antibody titers. Increased asparaginase levels may correlate with an improved CR rate. The use of intensive PEG-Asp should be explored further in the treatment of ALL.

scholarly journals Impact of Ethnicity on Toxicities Associated with Dose Escalating Methotrexate in Pediatric Patients with Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5074-5074
Author(s):  
Ashley Siryk ◽  
Haley Grunwald ◽  
Amanda Brahim ◽  
Frank Gentile ◽  
Faina Shenderov ◽  
...  
Keyword(s):  
Sample Size ◽  
Primary Outcome ◽  
Lymphoblastic Leukemia ◽  
Hispanic Patients ◽  
Pediatric All ◽  
Grade 3 ◽  
The Impact ◽  
Dose Escalating ◽  
Hispanic White ◽  
White Patients

Background: Epidemiologic studies in pediatric oncology have demonstrated disparities in Acute Lymphoblastic Leukemia (ALL) outcomes and survival for various ethnic minorities including Hispanic patients. While differences between outcomes and survival of different racial/ethnic groups in pediatric ALL is well documented, the impact of race/ethnicity on the incidence of methotrexate related toxicities in this population has not been fully described. Methotrexate, a mainstay of pediatric ALL regimens, has the potential to cause a variety of toxicities including myelosuppression, hepatic injury, acute kidney injury (AKI), mucositis, and central nervous system (CNS) injury. Recent literature suggests that Hispanic ethnicity may be associated with an increased risk of methotrexate toxicity, specifically neurotoxicity (Giordano (2017)). This project evaluated ethnicity associated with the incidence of methotrexate toxicities that could lead to dose reduction or delays in therapy such as grade 3 or 4 myelosuppression, hepatic injury, nephrotoxicity, and mucositis in patients receiving dose escalating methotrexate. Methods: A single-center, retrospective chart review was conducted at a 224 bed pediatric hospital. Patients were eligible for inclusion if they had a diagnosis of ALL and received intravenous (IV) dose escalating methotrexate between August 1, 2011 and March 31, 2019. Electronic medical records were used to identify eligible patients using medication identification numbers cross referenced with diagnosis codes. Toxicity data was collected to evaluate interruption in dose escalation of IV methotrexate due to grade 3 or 4 liver dysfunction, nephrotoxicity, mucositis, neutropenia, or thrombocytopenia. The primary outcome was percentage of doses which resulted in a dose-limiting toxicity. A two-sample t-test was performed for the primary outcome between Hispanic white and non-Hispanic white patients. Results: Of the 64 patients initially identified, 60 patients were included for final analysis. Two patients were excluded due to a diagnosis of Acute Biphenotypic Leukemia, one patient did not receive IV methotrexate per protocol due to delay in therapy and was subsequently ineligible, and one patient did not receive dose escalating methotrexate per protocol for unspecified reasons. A total of 460 doses were given to 60 patients. The sample size consisted of 22 non-Hispanic white, 21 Hispanic white, 9 Black, 3 Hispanic black, 1 Asian, 1 multi-racial, and 3 patients with unspecified ethnicity. The percentage of patients who experienced at least one toxicity was 58.3% (35 patients). The most common grade 3 or 4 toxicity experienced per dose was thrombocytopenia (6.5%), followed by neutropenia (6.3%), mucositis (1.3%), liver dysfunction (0.22%), and no patient experienced nephrotoxicity. When comparing the rate of toxicity between Hispanic and non-Hispanic patients, Hispanic patients experienced toxicity at a rate of 17.4% per dose compared to non-Hispanic patients at 12.2% per dose, although this was not a statistical significant difference (p = 0.61). Hispanic white and non-Hispanic white patients received the same amount of doses at 165 doses of IV methotrexate. Hispanic white patients experienced a toxicity rate of 19.4% per dose compared to 12.1% per dose in the non-Hispanic white patients. Hispanic white patients experience more thrombocytopenia, where as non-Hispanic white patients experienced more neutropenia. Although not statistically significant possibly due to small sample size, Hispanic ethnicity was associated with higher rates of methotrexate toxicities. Understanding the impact of methotrexate toxicity in respect to ethnicity is important to improving treatment outcomes for pediatric patients with ALL. More robust studies with a larger sample size are warranted to explore the potential impact of ethnicity on tolerability of this regimen. Disclosures No relevant conflicts of interest to declare.

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