NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).
Genetics and cytogenetics
Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.
He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.
“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.
He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.
“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”
Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.
“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”
The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.
“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.
“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.
“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”
Quantitation techniques and MRD
The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.
The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10-4).
NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10-4.
In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.
MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.
“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”
The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.
A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.
The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.
Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”