Can Genetics Help Unlock the Mysteries Surrounding Adult ALL?

In recent years, overall progress in treating acute lymphoblastic leukemia (ALL), in which malignant white cells multiply in the bone marrow, has been tempered by this fact: Survival rates among children far outstrip those of adults, with childhood rates reaching 85%¹ and adults registering at 45%.²

What accounts for the disparity? In short, it’s in the genes. Presenters Christine J. Harrison, PhD, FRCPath, and Mary V. Relling, PharmD, peeled away at the layers of the relationship between the genetics of ALL and its pharmacology, at an education session during the 55^th American Society of Hematology Annual Meeting and Exposition in New Orleans.

Dr Harrison, of the Northern Institute for Cancer Research at Newcastle University, UK, offered an overview of the known genetic changes that affect treatment decisions, and offered hope that the advances in sequencing technology will yield more novel targets and, in turn, therapies to take aim at them in fighting ALL.

Not every patient ends up with ALL for the same reason, Dr Harrison explained. Some subgroups of the disease present better genetic risks than others for targeted treatment, and knowledge in this area is growing, she explained. For example, it is well-known that ETV6-RUNX-1 positive patients are considered what Dr Harrison called a “good risk” for treatment, while those with the Philadelphia (Ph) chromosome translocation are “poor risk.”³ Thus, treating ALL is about more than going after bad cells. “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,” she said.

What is becoming known, according to Dr Harrison, is that even though virtually all chromosomal abnormalities occur in both adult and childhood ALL, most abnormalities, and in turn forms of the disease, have distinct differences by age.³ At the start of an upcoming clinical trial, screening will be carried out routinely, “to identify patients with abnormalities at the time of diagnosis,” Dr Harrison said. For those who show an abnormality, more intensive treatment is recommended; for adults, a bone marrow transplant is called for as soon as remission occurs.

Much of Dr Harrison’s presentation involved evaluating the features of recently identified abnormalities, starting with an introduction to iAMP21, which is characterized by a highly abnormal chromosome 21; it is associated with children who are at least 9 years old and has a “dismal outcome,” Dr Harrison wrote in a companion paper for her presentation. The abnormality, she said during the talk, “has a high incidence of early relapse, but also a high incidence of late relapses.”

Researchers don’t precisely understand the mechanism behind iAMP21, Dr Harrison said, “but we have a few hunches.”

She also spent considerable time discussing BCR-ABL1, which has a distinct age differential: the abnormality accounts for just 10%-15% of childhood B-cell precursor ALL, but among adults, it accounts for 25%.

While Dr Harrison looked at cytogenetics and age, Dr Relling, with St. Jude’s in Tennessee, followed with a discussion of differences in therapy response and relapse in ALL by ethnic group. “Many inherited DNA variants differ in frequency among racial/ancestral groups,” Dr Relling wrote in her companion paper to her presentation.⁴ “Although discovered in Europeans, the frequency of ARID5B polymorphisms is highest among Hispanics and lowest in blacks, which mimics the frequency of childhood ALL in these racial groups.”

More pharmacogenomics research can close these gaps, but clinicians must proceed with caution, as ALL drugs are highly toxic. Still, Dr Relling said the field is ripe for advancement as the drugs involved have narrow therapeutic indexes, making them ideal for research. Clinicians are increasingly accustomed to using genetics to adjust therapy, and the question have progressed to a point of asking: What’s more important for relapse, an inherited or acquired genomic variation?

“We don’t know now, but we’re making progress,” Dr Relling said.

Another question facing clinicians is how long they should wait between the discovery of an apparent link between a gene and behavior of ALL and treatment that targets that link. “If genotypes are going to be more and more available, which are so strongly associated with drug prescribing, should they be used now?” she asked.

Finally, she said, comes the question plagues all of genetics: What is the relative importance of rare variants, versus common variants?

Among the movements to answer these questions — and create treatment standards – is the Clinical Pharmacogenetics Implementation Consortium (CPIC), of which Dr Relling is a part. The group has 109 members, covering 14 countries, and includes observers from the US Food and Drug Administration (FDA) and the National Institutes of Health (NIH).

So far, Dr Relling said, “Thirteen genes are the subject of CPIC guidelines, covering about 60 mediations. Of the 13, 3 are routinely important with ALL. They are TMPT, G6PD, and CYP2D6.”

References

1. Pui CH, Mullinghan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120(6):1165-1174.
2. Larson, S, Stock W. Progress in the treatment of adults with acute lymphoblastic Leukemia. Currr Opin Hematol. 2008;15(4):400-407.
3. Harrison CJ. Targeting signaling pathways in acute lymphoblastic leukemia: new insights. Hematology Am Soc Hematol Edu Program, 2013; 2013.118-125
4. Relling, MV. Pharmacogenomics of acute lymphoid leukemia: new insights into treatment toxicity and efficacy. Hematology Am Soc Hematol Edu Program, 2013; 2013.126-130.