ALL: Genetics Providing New Insights Into Signaling Pathways and Treatment Targets

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Those frustrated with low long-term remission rates in adult acute lymphocytic leukemia (ALL) can find hope in the superior outcomes associated with treatment for pediatric ALL. Overall survival with therapy reaches 85% in children but lags at 45% in adults. Targeting specific pathways and adding novel agents to standard therapy should improve outcomes in adult ALL.

“To achieve the goal of curing all patients with ALL and reducing toxicity, there is a need for new therapies to target underlying molecular pathology of the disease, which forms the crux of leukemia research at this time,� said Christine Harrison, PhD, professor of childhood cancer cytogenetics, Newcastle University Leukaemia Research Cytogenetics Group, UK.

Advances in sequencing technology will identify genes and pathways that are consistently altered in high-risk ALL, which should yield novel targets, she said.

Although virtually all chromosomal abnormalities occur in both adult and childhood ALL, there is a significant difference in the incidence of most cytogenetic subgroups according to age, she said. For example, the good-risk cytogenetic subgroups characterized by ETV6-RUNX1 and high hyperdiploidy are seen almost exclusively in young children, whereas the incidence of BCR-ABL1 increases dramatically with age.

Gene expression profiling has identified a subgroup of BCR-ABL1–like ALL that accounts for 10% to 15% of childhood and 25% of adult precursor B-cell ALL, “and there is evidence for sensitivity to tyrosine kinase inhibitors when incorporated into therapy,� she said.

A recently identified abnormality is intrachromosomal amplification of chromosome 21 (iAMP21). It defines a distinct cytogenetic subgroup of older children (median age 9 years) with precursor B-cell ALL and is “associated with a dismal outcome� and a high risk of early and late relapse. When standard therapy is used, prognosis is poor, but modified treatment with high-risk regimens significantly improves outcomes.

Looking Into Pharmacogenomics

Relapse of childhood ALL is unacceptably high for some subgroups. Inherited genomic variation contributes to the risk of relapse and to adverse effects of therapy, said Mary Relling, PharmD, chair, Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN.
Her laboratory is using candidate gene interrogation and is applying genome-wide approaches such as gene expression profiling, genome-wide single nucleotide polymorphism (SNP) analyses, and whole exome/genome sequencing of patients undergoing uniform treatment to identify genes and genome variations that determine the disposition and effects of antileukemic agents. The goal is to elucidate the genomic determinants of toxicity and efficacy of antileukemic agents.

In scanning the genomes of children with ALL and controls, 6 of 18 SNPs that differed in frequency between the 2 groups were associated with 1 of the 4 main subtypes of ALL. Two SNPs were linked to the ARID5B gene.

Polymorphisms in ARID5B are highest among Hispanics and lowest in blacks, “which mimics the frequency of childhood ALL in these racial groups,� she said. They could account for some of the racial disparities in outcome of ALL therapy due to the higher frequency of variants associated with relapse in Hispanics, she said. Inherited variations in ARID5B were found to influence the response to methotrexate and to be associated with enhanced accumulation in leukemia cells, allowing for lower doses.

They have also found evidence that ALL subtypes differ in their responsiveness to asparaginase. Using a genome-wide approach, they discovered that both inherited and acquired genomic interindividual variation in the aspartate metabolic pathway contribute to resistance to asparaginase in ALL.

At present, genetic testing of thiopurine methyltransferase (TPMT) is being conducted before initiation of thiopurines to minimize acute myelosuppression, said Relling. Acute myelosuppression can be prevented by adjusting doses of thiopurines based on TPMT phenotype or genotype without compromising these agents’ effectiveness.

Antibody-Based Therapies

New antibody therapies that target cell surface antigens were reviewed by Anjali Advani, MD, staff physician, Hematologic Oncology and Blood Disorders, Cleveland Clinic, Cleveland, OH.

Rituximab, a naked antibody, targets CD20. Although only half of precursor B-cell ALL cases express CD20 on 20% or more lymphoblasts, CD20 expression is associated with a shorter duration of remission and worse overall survival in adult ALL, making CD20 an attractive target to combine with chemotherapy.

Epratuzumab is a humanized monoclonal antibody that targets CD22, a regulator of B-cell activation and the interaction of B cells with T cells, said Advani. In a phase 1 study, surface CD22 was not detected on flow cytometry on peripheral blood leukemic blasts within 24 hours of epratuzumab administration. Later-phase clinical trials showed a higher rate of complete molecular remission (CMR) when epratuzumab was combined with backbone chemotherapy compared with chemotherapy alone.

Bispecific single-chain T-cell engaging (BiTE) antibodies retarget cytotoxic T-cell lymphocytes at preselected surface antigens on tumor cells. Blinatumomab is the first member of the class of BiTE antibodies; it combines a CD3 binding site for T cells and a CD19 binding site for B cells, thereby creating the opportunity for T cells to destroy B cells. In a small 4-week study, infusions of blinatumomab led to B-cell depletion, an 80% CMR, and a relapse-free survival rate of 61% at 3 months of follow-up.

Inotuzumab ozogamicin is a promising monoclonal antibody against CD22 bound to calicheamicin for the treatment of relapsed/refractory ALL. A response rate of 57% was obtained in a phase 1/2 trial of heavily pretreated adults with refractory CD22-positive ALL.

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