Genetics Providing New Insights into Signaling Pathways and Treatment Targets in ALL
New Orleans, LA—Those frustrated with low long-term remission rates in adult patients with acute lymphocytic leukemia (ALL) can find hope in the superior outcomes associated with treatment for pediatric ALL. Overall survival (OS) with therapy reaches 85% in children but lags in adults at 45%. Targeting specific pathways and adding novel agents to standard therapy should improve outcomes in adult patients.
Identifying Cytogenetic Subgroups
“To achieve the goal of curing all patients with ALL and reducing toxicity, there is a need for new therapies to target the underlying molecular pathology of the disease, which forms the crux of leukemia research at this time,” said Christine J. Harrison, PhD, Professor of Childhood Cancer Cytogenetics, Newcastle University Leukemia Research Cytogenetics Group, Newcastle upon Tyne, United Kingdom.
Advances in sequencing technology will identify genes and pathways that are consistently altered in high-risk patients with ALL, which should yield novel targets, Dr Harrison said.
Although virtually all chromosomal abnormalities occur in adult and in childhood ALL, there is a significant difference in the incidence rate of most cytogenetic subgroups according to age, Dr Harrison said. For example, the low-risk cytogenetic subgroups characterized by ETV6-RUNX1 and high hyperdiploidy are seen almost exclusively in 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 B-cell precursor ALL, “and there is evidence for sensitivity to tyrosine kinase inhibitors when incorporated into therapy,” Dr Harrison said.
A recently identified abnormality is intrachromosomal amplification of chromosome 21. It defines a distinct cytogenetic subgroup of older children (median age, 9 years) with B-cell precursor ALL, and is “associated with a dismal outcome” and a high risk for early and late relapse. When standard therapy is used, the prognosis is poor, but modified treatment with high-risk regimens significantly improves outcomes.
The Promise of Pharmacogenomics
Relapse of childhood ALL is unacceptably high for some subgroups. Inherited genomic variation contributes to the risk of relapse and to the adverse effect of therapy, said Mary V. Relling, PharmD, Chair, Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN.
Dr Relling’s 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 antileukemia agents. The goal is to elucidate the genomic determinants of toxicity and efficacy of drugs to fight leukemia.
Overall, 6 of 18 SNPs that differed in frequency between the genomes of children with ALL and of controls were associated with 1 of the 4 main subtypes of ALL, and 2 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,” Dr Relling said. They could account for some of the racial disparities in outcome of ALL therapy because of 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.
There is also evidence that ALL subtypes differ in their responsiveness to asparaginase. Using a genome-wide approach, the investigators discovered that 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 the initiation of thiopurines to minimize acute myelosuppression, said Dr Relling. Acute myelosuppression can be prevented by adjusting the doses of thiopurines based on TPMT phenotype or genotype, without compromising these agents’ effectiveness.
Exciting New Antibody-Based Therapies
New antibody therapies that target cell-surface antigens were reviewed by Anjali S. Advani, MD, Staff Physician, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic, OH.
The older agent rituximab, a naked antibody, targets CD20. Although only half of the cases of pre–B-cell ALL express CD20 on 20% or more lymphoblasts, CD20 expression is associated with a shorter duration of remission and worse OS in adult patients with 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 Dr Advani. In a phase 1 clinical trial, 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 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 new 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 with blinatumomab led to B-cell depletion, an 80% complete molecular remission, and a relapse-free survival rate of 61% by 3 months of follow-up.
Inotuzumab ozogamicin is a promising monoclonal anti-CD22 antibody that is bound to calicheamicin for the treatment of patients with relapsed or refractory ALL. A response rate of 57% was obtained in a phase 1/2 clinical trial of heavily pretreated adult patients with refractory CD22-positive ALL.