AML NCCN GUIDELINESS

March 15, 2010 (Hollywood, Florida) — In patients with acute myeloid leukemia (AML), determining the presence or absence of the molecular markers NPM1, CEBPα, and c-KIT, as well as the more commonly studied FLT3-ITD mutation, can lead to a better understanding of patient survival and relapse risk, according to an update of the AML guidelines presented here at the National Comprehensive Cancer Network (NCCN) 15th Annual Conference.

"I think our biggest story this year is that we're making small advances in the molecular characterization of this disease," said B. Douglas Smith, MD, associate professor at the Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine in Baltimore, Maryland, during his presentation on AML.

"From my standpoint, the way we're understanding biology is really improving." Dr. Smith told Medscape Oncology.

Other highlights from the guidelines include strategies for improving survival rates for acute promyelocytic leukemia (APL) — which Dr. Smith called "our most curable subtype of AML" — and treatment options for AML patients over the age of 60 years.

"This is a disease that is getting older," said Dr. Smith, who reported that the median age for these patients is now 70 years. In fact, "1 in 5,000 people at the age of 70 will come down with [AML], compared with 1 in 50,000 for those at the age of 50."

"Our clinical challenges are that most adults with acute leukemia will die from their disease, and advances in therapy have not been as dramatic as we would have hoped," he said, adding "but we are making inroads."

Molecular Reclassifications

Although it is common for patients with AML to have activating FLT3 mutations, it is the FLT3-ITD mutation that is associated with a poor prognosis, with increased risk for relapse and decreased survival. However, a newly added footnote in the guidelines states that "there is controversy as to whether FLT3-TKD mutations carry an equally poor prognosis."

Dr. Smith said that FLT3 is the mutation "that we know the most about." However, "over the past 5 years, we've discovered other mutations that are the opposite, such as NPM1 and CEBPα, which actually carry better prognoses."

Many patients with FLT3 also have the NPM1 mutation. In a recent study, patients with mutated NPM1 and wildtype FLT3 had a 59% survival rate, compared with 15% for those with wildtype NPM1 and mutated FLT3.

The c-KIT mutation also acts as a prognosticator, predicting poorer outcomes if patients also have core binding-factor proteins.

"Overall, it boils down to this: patients with the NPM1 or isolated CEBPα mutations in the absence of the FLT3 mutation have a better risk status, whereas those with the c-KIT mutation have an intermediate risk, and those with the FLT3-ITD mutation in the absence of NPM1 have poorer risk," explained Dr. Smith.

"I think this gives our patients very valuable information. If we're at a point where we don't have a leukemia that is curable with traditional approaches, then we need to be exploring other options to say, 'these are good candidates for clinical trials, while some may be good for transplants and other interventions'."

Expanding Care for Those Older Than 60

Older patients with AML experience increased DNA damage and toxin exposure, and decreased detoxifying enzyme activity and immune surveillance, reported Dr. Smith. "Frankly, they're just tougher to treat," he admitted.

However, treatment options are not as limited as in the past. "We no longer need to think that if an older person comes in with leukemia, it's just full induction with [athracycline and cytarbine or] nothing," Dr. Smith noted.

"There are other drugs with activity that need to be used carefully and thoughtfully but that do offer the chance to impact survival. Having drugs that are biologically active is incredibly important to expanding our options to patients who otherwise might not get therapy," he added.

Drugs worth considering, based on recent trials, include the DNA methyltransferase inhibitors decitabine and azacitidine. However, Dr. Smith said that more studies are needed to determine the long-term benefit beyond improved marrow function.

He also urged caution with clofarabine, which showed "reasonable response rates" in a recent clinical trial, but also had significant toxicity and adverse events.

"Overall, there are some patients that, despite their age, will benefit from therapy, and maybe as many as 50% will benefit from induction chemotherapy. But for others, it will do more harm. So it's important to evaluate each patient to find out what they'll best tolerate," said Dr. Smith.

Updated APL Treatment Plans

In looking to improve upon successes in APL, the panel focused on reducing toxicity and improving upfront mortality and relapse.

Although traditional oncology approaches have often been based on the idea that more chemotherapy is better, "lessons from pediatrics have shown that it's possible to build success with less," said Dr. Smith.

The new guidelines suggest exploring the possibility of using less cytogenic medications and less intensive therapy for lower-risk patients, "which may translate into less toxicity over time," he noted.

The strongest message, however, was that clinicians should not mix and match protocols.

"When we look at outcomes for APL, it's truly based on a whole schema of several years of therapy," explained Dr. Smith. "So we suggest that you develop a paradigm for your center based on one of the treatment plans laid out and then stick to it."

Exciting Time for AML

"It is a really exciting time for this field," said William Vaughan, MD, professor of medicine and director of the Bone Marrow Transplantation Program at the University of Alabama in Birmingham, and past chair of the NCCN board of directors.

Dr. Vaughn noted that he wrote an article for the Journal of Clinical Oncology a few years ago that stated that nothing much had changed in AML treatment for more than 25 years. However, that's no longer the case.

"It has been a very, very good year for AML, which is well reflected in the guidelines," said Dr. Vaughan. "The ability to subdivide this disease so precisely to determine prognosis is already leading to improvements in therapy, including FLT-3 inhibitors, although that's all preliminary data."

"We're very excited about the ability to select patients for therapy based upon these characteristics," he added. "It also has downstream applications for whether or not to do bone marrow transplants and, if so, when they should be done."

"Overall, it's really paying off for patients with leukemia across the spectrum of age and stage. Clinicians need to be collecting these marker data so they can take advantage of these advances," concluded Dr. Smith.

Dr. Smith reports receiving clinical research support from Bayer HealthCare, Cephalon, Genzyme, and Novartis. He also reports being a consultant to or being on the advisory board or speaker's bureau of Bristol-Myers Squibb, Celgene, ImClone, and Novartis.

National Comprehensive Cancer Network (NCCN) 15th Annual Conference: Presented March 12, 2010.