Chemotherapy treatment might induce leukemia relapse

Chemotherapy drugs, the first line of defense for a common form of adult leukemia, could actually be contributing to the disease’s rate of relapse in patients.

The findings are part of a study out of the Washington University School of Medicine in St. Louis, published Wednesday in the advance online edition of Nature.  The researchers took samples from eight patients diagnosed with acute myeloid leukemia (AML).  Patients with AML who don’t receive chemotherapy usually die within a few months.

But out of the patients who do receive chemotherapy treatment and go into remission, about 80 percent relapse and die within the next five years.

“The purpose of this study was to try to begin to understand what happens at relapse,” Dr. Timothy Ley, co-author the study, told FoxNews.com.  “Does the tumor change? Does it evolve? Is it even the same tumor coming back?”

To obtain their results, Ley and his team had to do quite a bit of genome sequencing – constructing the complete DNA sequence of a person’s genome.  They sequenced three distinct genomes of each patient: Normal healthy genomes from the patient’s skin, genomes after they presented with leukemia, and genomes after the patient received chemotherapy drugs and eventually relapsed.

“Every time the tumor comes back, it’s got a few new mutations added on to the original tumor.  Not a huge number, only a few dozen new mutations that are tacked on.  We think a tiny handful of those might be relevant for the tumor’s ability to come back and be resistant to treatment.”

— Dr. Timothy J. Ley, co-author the study

The researchers sequenced the genomes of the cancer cells nearly 600 times each, significantly increasing the accuracy of their findings.  They eventually were able to create a timeline of how the cells mutated over the course of the patient’s diagnosis.

“What we found surprised us.  For one thing, the same tumor always comes back - always with a twist,” Ley said.  “Every time the tumor comes back, it’s got a few new mutations added on to the original tumor.  Not a huge number, only a few dozen new mutations that are tacked on.  We think a tiny handful of those might be relevant for the tumor’s ability to come back and be resistant to treatment.”

And those handfuls of new mutations were linked to the patient’s treatment.  In order to combat AML, chemotherapy drugs cause damage to DNA of both cancerous and healthy cells.  The researchers discovered that of the new mutations that surfaced with the return of the tumor, many contained DNA damage.

These alterations, known as transversions, were much higher in patients who relapsed than those with the original tumor—meaning the chemotherapy drugs the patients received to combat their original cancer were very possibly bringing about those patients’ relapses.

Another major finding from the team was that there were differing patterns of evolution of the cancer cells linked to AML relapse.

“Some of the tumors really only had one major population of tumor cells.  Others had a single major one and minor ones that were derived from it—they’re called subclones,” Ley said.  “And the behavior of these subclones was surprising.  Some of them were eliminated by the therapy but sometimes a very small one would be the one that would come back, that relapsed, and be lethal to the patient.”

No matter what, the chemotherapy drugs were unable to kill the founding clone that established the original tumor and all of the patients relapsed.  While the results of their research are staggering, Ley doesn’t want patients to quit seeking chemotherapy treatment.

“Without the initial chemotherapy, all of these patients would be dead in a few months.  We know that from history,” Ley said.  “So the therapy that we use, even though it has problems, it’s necessary at this point.  But we need to improve it because it’s contributing to the relapse.”

Instead of swaying patients against getting chemotherapy, Ley and his colleagues hope to use these results as further evidence for the need for targeted therapy for cancer treatment— formulating specific treatments for each unique mutation that causes every different kind of cancer.

“It’s just a reminder I think to everybody what the focus needs to be on,” Ley said.  “Step one is to find all the targets, step two is to develop thoughtful approaches to hit those targets. Because therein lies the ultimate solution.”