Pediatric AML: Starting with the science
Thanks to Dr. Soheil Meshinchi MD, PhD and Julie A. Guillot for their input and for sharing content for this article. Much gratitude for their tireless efforts in furthering cures for children affected by Pediatric AML.
Acute Myeloid Leukemia (AML) is a blood cancer that is a disease of the elderly. It affects kids too, and is a rare cancer. Less than 1000 kids/year will be diagnosed with it. It represents 6% of all childhood cancers and 20% of all childhood leukemias but is a leading cause of pediatric cancer deaths.
Amongst all pediatric cancers, AML is considered to have the most intense chemotherapy and side effects are intense, requiring hospitalization. There are long term effects because of the toxicity of the therapy. 50% of children will relapse, and about 30% will receive a stem cell transplant (SCT). Five year survival is about 65–70%. Survival rates after a relapse are low. The faster the patient relapses, the worse the prognosis.
While there has been some improvement in outcomes over the last 40 years, mostly due to better supportive care, there has not been a fundamental change in therapeutics.
So why has it been so difficult to improve survival for Peds AML? Let’s start with the science
Dr.Soheil Meshinchi, MD PhD has studied Pediatric AML and treated children at Fred Hutchinson Cancer Center for over 25 years. He shared his insight with me.
Pediatric and Adult AML are different diseases and present differently
We know that AML is caused by underlying genetic changes. These changes can be simple (mutations) or complex and structural (chromosomal events like fusions).
There are genetic differences between adult and pediatric AML. Adults have many mutations. Kids’ genomes reveal complex structural changes.
Analogy 1: Understand this as the difference between making a spelling error in a word (mutation), which might or might not be material individually, to words in a sentence being reversed or re-arranged (fusions), which are certainly material to sentence comprehension.
In the graph above (Tarlock, et. al), we see that genetic fusions (in blue) are prevalent in children and young adults. These decrease in older patients. Parallelly, mutations/patient (in green) have a higher prevalence in adults.
- Adult AML develops over time. Pediatric AML is acute.
Many mutations are required for progression to adult AML. These mutations are acquired across a period of time, perhaps even environmentally triggered. Adults also tend to have diseases that are ‘precursors’ to full-blown AML. This is when their bodies are still ‘acquiring’ mutations.
Kids with AML have fewer mutations but more structural changes associated with their disease. These tend to be more potent events that can cause AML at once.
Analogy 2: Genetic variations in kids tend to get ‘nuclear’ fast. Adult disease tends to smolder, sometimes undetected for years before morphing to a full-blown disease.
In the graph above, we see that the incidence of the precursor to AML (MDS — Myelodysplastic Syndrome) is virtually absent in children and young adults.
Other scientific facts..
Pediatric AML is a heterogenous disease. There are many types and subtypes. Research has found that some of the disease targets (receptors) can be shared between cancerous and healthy cells and so, preferentially targeting these receptors can affect both diseased and healthy cells. Biology is complex and cells can mutate and evade treatment. It is thus very unlikely that we get a “one size fits all” cure.
Standard of care for children is ‘hand-me-down’ adult therapies
Most drugs and therapies used for kids are decades old, toxic and have long-term effects.
Predominantly, the drugs and protocols used have been designed and developed for adults which have “trickled down” for use on kids, usually with a 6.5 year lag time. Kids are not “little adults” and the drugs and trials approved for adults don’t necessarily “fit” kids. Kids are also resilient and respond differently to adult drugs.
Today’s treatments’ long term effects can be as life-threatening as the cancer itself. Children who survive the cancer and treatment can have long term effects like organ failure, infertility and cognitive issues.
- Big pharma has so far not been keen on investing in pediatric AML
Most of big pharma’s budget goes toward adult therapeutics. Taking a drug to market costs $2.5B of investment and up to 14 years to take what was a potential pre-clinical drug candidate through the R&D, clinical, regulatory and commercial process. Developing drugs for children has a set of additional challenges. There are many safety, ethical and regulatory issues to grapple with. Additionally, pediatric cancers like AML are rare. The financial incentives are just not enough to garner the R&D investment. Pharma companies are understandably wary. Therefore, there is a heavy reliance on government and philanthropy to support research in academic environments.
Pediatric cancer just ends up being in a less than favorable position even with government funding. The NCI, for example, allocates 4% of its funding toward 12 pediatric cancers (and this is a heterogenous set of over a 100 cancers). Grants tend to be small. Progressing the science, is therefore slower than we’d want it to be.
Unfortunately, the net result is that kids with AML and their families are being left with few options.
There are challenges but many opportunities
The future is bright for precision treatments for Pediatric AML. From a scientific perspective, advances in the use of genomics, proteomics and modern immunotherapies have shown successes with other blood cancers. Targeted therapies may be less toxic thereby helping children thrive after cancer therapies.
We have a lot of work to do, starting with clearly defining subsets of patients for whom targeted and personalized therapies can work. This would require collecting genetic biomarkers for every patient and investing in analytic tools. Rare cancers need a rethink of the clinical trial process, incentives from the FDA as well as more collaboration and data sharing between academic children’s hospitals. And yes, targeted funding for Pediatric AML would definitely help!
In subsequent posts, I’ll share some early success stories/state of the art for precision therapeutics for Peds AML as well as the challenges and opportunities.
Thanks for reading!
