Background and Aims

Asparaginase-associated toxicities (AAT) often preclude planned chemotherapy for the treatment of acute lymphoblastic leukemia (ALL). As conflicting practices exist for dose modifications with older age, obesity and/or large body surface area (BSA), our objective was to examine the association of AAT with these risk factors.

Methods

We examined Induction data from patients ages 1-30 years enrolled in the Children’s Oncology Group ALL trials AALL0232 and AALL0434. Pegaspargase (2,500 IU/m²) was administered without prescribed dose-capping. Prospectively evaluated AATs included hyperbilirubinemia, elevated alanine aminotransferase (ALT), thrombosis, and pancreatitis. Obesity was classified using body mass index (BMI) ≥30 (or ≥95th percentile). BSA was analyzed continuously and dichotomized at 1.5m² (equivalent to pegaspargase 3,750 IU, the threshold for permissible dose-capping). The association of AAT with end-Induction minimal residual disease (MRD) ≥0.01% was assessed.

Results

Using data from 4,925 patients, multivariable logistic regression analyses found increased risk for any AAT in all age groups ≥10 years (p=0.002) and in patients with both obesity and high BSA (>1.5m²) (p<0.0001). Risks for hyperbilirubinemia, ALT elevations, and thrombosis were increased in patients with high BSA and obesity (OR 3.5, 95% confidence interval [CI] 2.2-5.7), OR 3.3, 95%CI 1.7-6.6, and OR 3.1 95%CI 1.5-6.5, respectively), but not in those with high BSA alone. Age was not associated with thrombosis or ALT elevation; risk for pancreatitis was associated with Hispanic ethnicity, but not with other factors. AAT were not associated with MRD ≥0.01%.

Conclusions

We report the largest dataset of AAT during ALL induction. Risk for AAT was increased in patients ≥10 years and in those with both obesity and high BSA, but not high BSA alone. Dose-capping may not be necessary for patients with high BSA without obesity.

©2022 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was previously presented at the 2022 ASCO Annual Meeting. All rights reserved.

Background and Aims

The outcomes of Stage I-II Low Risk (LR) Favorable Histology Wilms Tumor (FHWT) patients enrolled to COG trials and the impact of single segmental chromosomal aberrations on outcome has not been previously reported but may inform risk stratification and therapy assignment in future therapeutic studies.

Methods

We report event-free survival (EFS) of all Stage I and II LR FHWT patients who enrolled to the COG Renal Tumors Classification, Biology and Banking study, AREN03B2 who were treated with standard-of-care EE4A and assess the impact of single LOH 1p, or LOH 16q, and/or 1q gain on EFS. Patients meeting criteria for Very Low Risk (nephrectomy only) or Standard Risk (combined LOH 1p and 16q) were excluded. Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards models were used to evaluate biomarker effects.

Results

In the overall cohort of LR FHWT patients treated with EE4A, 4-year EFS was 95% for Stage I (CI: 93-98%; n=319) and 87% for Stage II (95% CI: 84-90%; n=555, p=0.0003). While no adverse biological factor was significantly associated with EFS among Stage I LR patients, in the subset of stage II LR patients, 4-year EFS with and without LOH 1p were 79% (95% CI: 67-94%) and 87% (95% CI:84-90%, HR=1.64, p=0.21); 4-year EFS with and without LOH 16q were 75% (95% CI: 65-86%) and 89% (95% CI:86-92%, HR=2.51, p=0.0004); and 4-year EFS with and without 1q gain were 63% (95% CI: 44-89%) and 90% (95% CI:82-99%, HR=4.4, p=0.006).

Conclusions

Outcomes of Stage I FHWT LR patients were better than for Stage II LR patients. Adverse biologic factors were associated with poorer prognosis in Stage II but not Stage I FHWT patients. These results support new risk stratification and treatment strategies that we plan to assess in a prospective clinical trial.

Background and Aims

WT1 disorder is characterized by combinations of glomerulopathy, urogenital anomalies and Wilms tumor. There is bias towards description of patients with variants in the DNA-binding/Zinc-finger domain of WT1 (exon 8/9). We observed an enrichment of variants outside this region in children with Wilms tumor and found it challenging to predict their glomerulopathy risk. This prompted us to study phenotype-genotype correlations in a national cohort of individuals with WT1-variants.

Methods

We approached all Dutch genetic laboratories and requested pseudoanonymized data of all patients with germline WT1-variants.

Results

We identified 36 patients with (likely) pathogenic WT1-variants (median age at inclusion 13.3 years, range 2.8-58). Seventeen patients had truncating variants, 12 of which located outside the DNA-binding/Zinc-finger domain. All 17 patients had Wilms tumors (median age 12 months, range: 6-35), two developed glomerulopathy leading to kidney failure (age 26 and 40 years). Nine patients had missense variants, all in the DNA-binding/Zinc-finger domain. Of those, two developed Wilms tumors (age 12 and 18 months), 9/9 glomerulopathy (median age 1 month, range: 0 months-54 years) and 8/9 kidney failure (median age 1 month, range: 0-23). Three patients had splice-site variants (introns 1, 6, 7). Two developed Wilms tumor (intron 6-7) and 3/3 kidney failure (median age 33 months, range: 10-333). Three patients had intron 9 splice variants, none developed Wilms tumor, all had kidney failure (median age 173 months, range: 24-240). Four patients had a (partial) WT1 deletion, all had Wilms tumor and none glomerulopathy. Four patients experienced WT1-related glomerulopathy onset after Wilms tumor (median age 26.5 years, range: 2-40).

Conclusions

We observed remarkable few patients with infantile/childhood glomerulopathy onset when the WT1-variant is outside the DNA-binding/Zinc-finger domain. These patients can however be at risk for glomerulopathy later in life. Therefore, we suggest life-long surveillance for glomerulopathy for these patients and kidney-preserving treatment when affected by Wilms tumor.

Background and Aims

Malignant renal neoplasms are rare before age 45. Age, gender, and genetic risk factors can influence the risk of these neoplasms. However, the risk in survivors of childhood cancer is not well established. This study aims to report the incidence of renal subsequent malignant neoplasms (SMNs) after treatment of a childhood primary malignancy.

Methods

Using the Surveillance, Epidemiology, and End Results (SEER) registry, we identified survivors of childhood cancer who developed a renal SMN. Survivors were under 20 years old at the time of primary cancer diagnosis and diagnosed between 1975-2016. We excluded survivors with a primary renal cell carcinoma or adenocarcinoma, and the SMN had to occur at least 13 months after the primary cancer diagnosis. The clinical characteristics of the survivors with SMNs of the kidney (including renal pelvis) were evaluated and standardized incidence ratios (SIRs[observed/expected]) were calculated. Kaplan-Meier estimates were performed to assess survival after renal SMN.

Results

Of 1,477 survivors of childhood cancer with SMNs, 53 developed a renal SMN (54 total cases). Of the 54 cases, 47 were a second cancer (43 carcinomas, 3 Wilms, and 1 Ewing sarcoma), 6 carcinomas were a third cancer and 1 carcinoma was a fourth cancer. Among these, there were 29 female (54.7%), 47 white (88.7%) and 7 Hispanic (13.2%) survivors. The most common primary cancers were Hodgkins lymphoma (n=9) and neuroblastoma (n=7). The mean ages of primary malignancy and renal SMN occurrence were 10.1 years and 31.1 years, respectively. The SIR of developing any renal SMN was 4.52 (p<0.05; 95%CI 3.39-5.89). The 5-year overall survival after a renal SMN was 71% (95%CI: 55%-82%).

Conclusions

Renal SMNs are rare but occur ~4.5 times more frequently in survivors of childhood cancer compared to the general population. This increased risk should be considered when providing long-term care for survivors of childhood cancer.