ASH 2015

Genetic variant that signifies higher risk for avascular necrosis in children with acute leukaemia

Dr Peter D. Cole - Albert Einstein College of Medicine, New York, USA

Now, you were looking at children with acute lymphoblastic lymphoma, can you tell me what you were looking at, particularly what you were investigating here?

The project came about because most children with acute lymphoblastic leukaemia are cured but many experience severe side effects from therapy. This project had to do with bony toxicity of therapy. The start of the project came from a question, we didn’t understand why it is that if we’re giving all the treatment with leukaemia the same therapy why were some developing toxicity and not others. We knew that bony toxicity is related to age but within age categories we weren’t able to pick out why some kids were having this toxicity and not others.

So you thought genes might be involved, what did you home in on and why?

What we did was we thought we were smart, we came up with a list of 19 genes that we thought might play a critical role in the pathogenesis of bony toxicity among leukaemia patients. Then, going through the literature we identified genetic variants that are common, that are present in more than 15% of the general population, that change the function of these genes. So we very simply asked if we looked at all of our kids with leukaemia do those who happen to have these genetic variants have a greater risk of bony toxicity.

In particular you noted thymidylate synthase, what’s that and what’s its role in acute lymphoblastic leukaemia?

That was the biggest hit out of the 19 variants that we investigated. Thymidylate synthase is a gene that’s necessary for the formation of one of the DNA precursors, thymidylate is one of the four nucleotide bases incorporated into DNA. Anti-cancer drugs like methotrexate, which is a key component of leukaemia therapy, work by preventing cancer cells from replicating their DNA. So methotrexate inhibits directly and indirectly thymidylate synthase. We knew that methotrexate may play a role in causing bony toxicity so we weren’t terribly surprised to see that this particular variant which affects thymidylate synthase showed up as one increasing risk for bony toxicity.

So you found that in these children with leukaemia there was a relationship between this gene. What usefulness has that turned out to have?

We don’t know yet but we think it may be useful in predicting which children will be at greater risk. What we found was in our analysis of over 600 kids treated the same way for leukaemia, the 20% of kids who had this particular variant had a much higher risk of developing either osteonecrosis if they were below the age of 10 or bony fractures if they were above the age of 10. So we think that going forward children, when they start treatment for leukaemia, can be tested for this variant and if they have this variant we, as clinicians, should probably pay closer attention to them and surveil them for signs of bony toxicity.

But they do need the chemotherapy.

Absolutely. We can’t take away the chemotherapy.

So what are you offering them?

We can monitor them closely and at the earliest signs of bony toxicity, at that point, we might need to modify their therapy. Interestingly, this gene product, thymidylate synthase requires the vitamin folic acid to function. So we suspect that those children who have the genetic variant and happen to be deficient in folate may be at increased risk of many toxicities, including bony toxicity. So that would suggest a dietary intervention for children who have this particular gene variant.

Are there any drugs you could add to compensate for the bony toxicities?

That would be tricky. There are some new strategies that may help protect bones against toxicity but they need to be tested in clinical trials first. Our biggest fear is that we’re right now curing most children of leukaemia, our biggest fear is that any change we make to therapy to decrease toxicity might increase the risk of relapse and that would be tragic, of course.

So what do you think doctors should be doing about their patients with acute lymphoblastic leukaemia in the light of your findings now?

I think that they should be aware of this increased risk and talk with their patients. Any patient who has symptoms of bony toxicity, particularly the young ones, we don’t think of looking for osteonecrosis in the younger patients because it’s less common in the younger patients. But any young patients who are experiencing bony pain should be examined carefully for signs of osteonecrosis. If it can be picked up early a change in therapy, for example a decrease in corticosteroid use, might prevent further progression of osteonecrosis, avoiding more drastic interventions like surgical joint replacement.

But you could make changes of dose and changes of things like steroids?

Yes.

So what’s the bottom line for doctors, then, coming out of this topic here at ASH?

The bottom line is that even though we’re treating our patients all the same and giving them the same curative therapy for leukaemia, our patients are not all the same. They differ in many ways, among them genetically, and we should be aware that some of that genetic variation may make some patients more at risk for some toxicities and other genetic variants may increase risk for other toxicities. We should be aware to this emerging body of knowledge that will eventually help us tailor and individualise therapy to maximise cure rates and minimise toxicity of therapy.