Faculty Bibliography

BACKGROUND:Optimal chemotherapy for treating mixed-phenotype acute leukemia (MPAL) and the role of hematopoietic stem cell transplantation (HSCT) remain uncertain. Major limitations in interpreting available data are MPAL's rarity and the use of definitions other than the currently widely accepted criteria: the World Health Organization 2016 (WHO2016) classification. METHODS:To assess the relative efficacy of chemotherapy types for treating pediatric MPAL, the Children's Oncology Group (COG) Acute Leukemia of Ambiguous Lineage Task Force assembled a retrospective cohort of centrally reviewed WHO2016 MPAL cases selected from banking studies for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Patients were not treated in COG trials; treatment and outcome data were captured separately. The findings were then integrated with the available, mixed literature to develop a prospective trial in pediatric MPAL. RESULTS:The central review confirmed that 54 of 70 cases fulfilled WHO2016 criteria for MPAL. ALL induction regimens achieved remission in 72% of the cases (28 of 39), whereas AML regimens achieved remission in 69% (9 of 13). The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 72% ± 8% and 77% ± 7%, respectively. EFS and OS were 75% ± 13% and 84% ± 11%, respectively, for those receiving ALL chemotherapy alone without HSCT (n = 21). CONCLUSIONS:The results of the COG MPAL cohort and a literature review suggest that ALL chemotherapy without HSCT may be the preferred initial therapy. A prospective trial within the COG is proposed to investigate this approach; AML chemotherapy and/or HSCT will be reserved for those with treatment failure as assessed by minimal residual disease. Embedded biology studies will provide further insight into MPAL genomics.

Rationale: We showed that PEG is the primary epitope associated with hypersensitivity to polyethylene-glycol (PEG) conjugated asparaginase (pegaspargase), and asparaginase itself was the epitope in unconjugated asparaginase (L-ASP; PMID, ). A prior study of cohorts treated with either L-ASP or pegaspargase showed that HLA-DRB1*07:01 was associated with hypersensitivity (PMID ); whether this is true for reactions after pegaspargase only is unknown.
Method(s): This study included three cohorts of pediatric leukemia patients treated upfront with pegaspargase: St. Jude Children's Research Hospital's Total XVI (TXVI, n = 596), Children's Oncology Group AALL0232 (n = 2275) and AALL0434 (n = 1026). Germline DNA was genotyped using either Illumina or Affymetrix SNP-chip platforms. Genetic ancestry was inferred using iAdmix. HLA alleles were imputed using SNP2HLA for those with > 90% European ancestry. Genetic variants not genotyped directly were imputed using the Michigan Imputation Server. Analyses between genetic variants and hypersensitivity were performed in each cohort first using cohort-specific covariates and then combined using meta-analyses.
Result(s): Fewer intrathecal injections (P = 2.7x10^-5 in TXVI) and male gender (P = 0.025 in AALL0232) were associated with hypersensitivity. HLA alleles DQB1*02:02, DRB1*07:01, and DQA1*02:01 were associated with PEG-ASP hypersensitivity (P < 6.2x10^-6). The three alleles were in the same haplotype. All genome-wide significant (P < 5x10^-8) variants fell in the HLA loci on chromosome 6. The top hit rs28383330 (Pmeta = 1.6x10^-12) is located 5' of the HLA-DQA1 gene.
Conclusion(s): Although hypersensitivity reactions to L-ASP and pegaspargase are due to different epitopes, they share the same HLA risk alleles.
Copyright

PURPOSE/OBJECTIVE:Children's Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL. PATIENTS AND METHODS/METHODS:AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases. RESULTS:= .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively. CONCLUSION/CONCLUSIONS:The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.

BACKGROUND:Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. METHODS:We performed a genome-wide association study (GWAS) in 1,191 children with T-ALL and 12,178 control subjects, with independent replication using 117 cases and 5,518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two-sided. RESULTS:A novel risk locus in the USP7 gene (rs74010351, odds ratio = 1.44, 95% CI = 1.27-1.65, P = 4.51 x 10-8) reached genome-wide significance in the discovery cohort, with independent validation (odds ratio = 1.51, 95% CI: 1.03-2.22, P = .04). The USP7 risk allele was over-represented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs. B-ALL pointed to distinctive etiology of these leukemias. CONCLUSIONS:These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs. T-ALL).

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subset of B-cell ALL with a spectrum of underlying genetic alterations that activate kinase or cytokine receptor signaling. Ph-like ALL occurs at all ages but is most common in adolescents and young adults and is postulated to be a factor in the inferior outcomes in this age group. Ph-like ALL confers a poor prognosis with conventional chemotherapy and the pediatric and adult oncology communities are conducting trials utilizing molecularly targeted approaches. In parallel, the role of immunotherapy is being assessed for this unique and biologically diverse ALL subgroup.

There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10^-8), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10^-8) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10^-8), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10^-8). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and demonstrate distinct somatic features, including CRLF2 rearrangement in approximately 50% of cases; however, the role of inherited genetic variation in ALL susceptibility among children with DS is unknown. Here, we report the first genome-wide association study of DS-ALL, comprising a meta-analysis of four independent studies, with 542 DS-ALL cases and 1,192 DS controls. We identified four susceptibility loci at genome-wide statistical significance: single nucleotide polymorphisms rs58923657 near IKZF1 (odds ratio [OR]=2.02, P_meta =5.32x10^-15), rs3731249 in CDKN2A (OR=3.63, P_meta =3.91x10^-10), rs7090445 in ARID5B (OR=1.60, P_meta =8.44x10^-9), and rs3781093 in GATA3 (OR=1.73, P_meta =2.89x10^-8). We performed DS-ALL versus non-DS ALL case-case analyses, comparing possible associations at these and three other established ALL susceptibility loci (BMI1, PIP4K2A, CEBPE) and found significant association with DS status for CDKN2A (OR=1.58, P_meta =4.1x10^-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression, high hyperdiploidy, ETV6-RUNX1, and B-other subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 susceptibility locus. It maps to a B-cell super-enhancer, and the risk allele is associated with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation rates in Down syndrome- than non-Down syndrome lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of a known ALL risk locus in children with DS and serve as a basis for further biological insights into the etiology of this disease.