The underlying issue was that Nico was now hypermetabolizing the staple chemotherapeutic agent, a drug called 6MP. This was diagnosed by drawing Nico’s blood levels of 6MP metabolites. Metabolite testing is expensive, but Nico’s stubborn numbers and increasing symptoms of liver toxicity justified the cost. 6MP is metabolized into either 6MMP or 6TGN. The last year of treatment, Nico’s body started to metabolize 6MP into 6MMP preferentially. 6MMP is not only not anti-leukemic, it is very toxic to the liver. So Jeff and I were knowingly administering a daily medication to our child that was not only not benefitting him as it should, it was actually making him measurably sick (raising liver enzymes). Our oncologists would say there was still some benefit of 6MP administration in Nico’s case, just not the desired level of benefit. But based upon the level of 6MMP versus 6TGN in Nico’s bloodstream, that benefit was slight. That was a dark time. I was consumed trying to find a fix (was it the time or the way we were administering the drug?). I also felt like we were up against the clock (another month without adequate suppression might lessen Nico’s ability to stay in remission).
Jeff and I and our oncologist all agreed that we needed to pull Nico out of his current protocol (the standard high-risk arm of a large clinical trial) in lieu of another pediatric leukemia trial specific to hypermetabolizers. This second, smaller trial was in its nascent stage, still in development by a team at our clinic. The trial-in-design intended to investigate an old medication for a new purpose. This purpose was to correct 6MP hypermetabolism. 6MP is not only a staple in treatment protocols for childhood leukemia, it is also used to treat Crohn’s disease and ulcerative colitis in adults. Adults, just like children, can have issues with drug metabolism. Years ago, studies were done with adult patients with ulcerative colitis who, like Nico, were metabolizing 6MP preferentially to 6MMP (which is a bad thing for those patients too). Scientists with an understanding of the complexities of drug metabolism theorized that a drug that could correct these 6MP metabolism issues already existed and was being used widely for another condition. Allopurinol is an older medication that has been used for many years to treat gouty arthritis. Allopurinol’s mechanism of action made it a potential antidote for 6MP hypermetabolism. So doctors tested this theory in the adult Crohn’s and ulcerative colitis patient populations, and were extremely successful. These adult studies concluded that Allopurinol shunted metabolism of 6MP away from 6MMP towards the desired pathway of the therapeutic 6TGN metabolite. With this data, some pediatric oncologists started prescribing Allopurinol to patients like Nico. Prescribing Allopurinol for pediatric leukemia patients is off-label, meaning there are no large clinical trials showing Allopurinol’s efficacy in children. And children do not necessarily metabolize drugs the same way that adults do. But considering the alternative, which was to do nothing, I think prescribing Allopurinol was a reasonable gamble. Nico's oncologist was one of doctors that was comfortably using Allopurinol in pediatric patients. Coincidentally, the period that Nico became a hypermetabolizer was also when our clinic launched a clinical study specific to Allopurinol in the pediatric leukemia population. The goal is to show that Allopurinol will work in pediatric leukemia patients the same way it did in adult Crohn’s and ulcerative colitis patients. Ultimately, the hope is that Allopurinol will be indicated (labeled) for use in pediatric patients.
Per the new protocol, which was really still being designed, there were several steps in the ramp up before Nico could sign on. One of these steps included increasing Nico’s dose of 6MP to one that he never tolerated in the past. As his parents, Jeff and I were reticent about this step though we understood the rationale. The doctors needed to demonstate that Nico was a good candidate for the study before pulling him out of what is a tried-and-true treatment protocol for the vast majority of children with leukemia (i.e., prove Nico has toxic levels of 6MMP at X dose). The ramp up seemed to take an excruciatingly long time, again we felt the treatment clock running down. Then just as Nico was slated to start the trial drug, he had another blood count crash that required a chemo-hold and hospitalization. I knew the moment his temperature spiked what it meant - he would not meet the criteria essential to start the second trial. We were so discouraged. Thankfully, our oncologist was as fed up with this cycle as we were, and after Nico recovered we all opted to unofficially start the trial without being technically enrolled. Because Nico did not meet the study parameters when he started, his data will not officially count in the study results. But I know that Nico’s case inspired in a change in the trial’s enrollment criteria; so I like to think that Nico’s case still indirectly furthered this research.
The new trial required that we spent a lot of time at clinic. Nico has to be closely monitored because the experimental drug was known to shunt, or at least alter, 6MP metabolism. There was a risk of over-correction. The dosages of all of his oral chemo had to be dropped and slowly titrated. We started going to clinic once a week for blood draws and exams. Our oncologists were not just looking at blood counts anymore, they were drawing the actual metabolite levels in Nico’s bloodstream on a weekly basis. Somehow this did not end up being that bad. We have spent so much time in clinic, it became a second home. We know everyone. Everyone knows us. Everyone is really nice. It just became our routine. Tuesday was clinic day.
Nico could have been the poster child for this drug. His counts immediately shifted. We were able to titrate his doses of both 6MP and Allopurinol very quickly (a matter of a couple of weeks), and Nico remained in a therapeutic range for the duration of treatment. It is important to note that he was not just in the therapeutic range related to the ANC (absolute neutrophil count), which is the indicator used by pediatric oncologists to gauge adequate marrow suppression. Nico’s actual drug metabolites were measured, plotted and graphed. His 6TGN levels were perfect, in the high end of what is considered therapeutic, while his 6MMP levels remained at a safe level (and subsequently his liver enzymes remained in normal levels as well). The Allopurinol allowed Nico to achieve adequate bone marrow suppression at a much lower dose of both 6MP and the other staple of maintenance therapy, Methotrexate. Nico went from 150% dosing to 75% dosing of both because of the Allopurinol, and he maintained a steady level of suppression within the desired range for months.
This was a game-changer for us. All of the symptoms that Nico experienced related to liver toxicity diminished. They were not eliminated, but they were not as worrisome. For example, Nico had terrible bouts of hypoglycemia related to the 6MP. He had to drink milk every night around 3:00 a.m., or he would be symptomatic by morning. If he slept in, I was convinced he had slipped into a coma. I was nervous all of the time. On the Allopurinol, Nico still needed to eat ASAP upon rising, but we were able to sleep through the night for the first time in many years. The Allopurinol also eliminated our anxiety about the administration guidelines of 6MP. When we started treatment in 2013, 6MP had to be taken on an empty stomach - 1 hour before or 2 hours after food. It was also suggested that it should be taken in the evening. Try that with a toddler. It meant he either had to finish dinner no later than 5:30 pm everyday or we had to wake him up in the night to take medicine. Combine these rules with the worry over his blood sugar, and this was a real quality of life killer, I promise you.
So, there is it. That is a wrap-up of the last six moths. There are more updates, but I thought this one was overdue. I wanted to write about our experience because the focus on metabolites is really new. Many clinics do not test metabolites at all. Many clinics that do test metabolites do not consider using Allopurinol. I do not know how difficult it is to get insurance companies to pay for metabolite testing. But it seems likely there might be pushback by some. I want other parents with kids like Nico to know about this possible solution. This is a real thing, and something can be done.
The last six months were humbling. We became very aware of how lucky we were to both be where we are and have the doctor that we have. Whatever happens, we know that Nico got the best possible care that we were capable of getting for him. We have done everything we can, and that is all we can do. Now we just hope it was enough.