Mark R. Litzow, MD: The treatment of adult acute lymphoblastic leukemia [ALL] remains a clinical challenge. The strongest predictor of relapse is minimal or measurable residual disease, known as MRD, and ALL is now the first hematologic neoplasm for which assessment of early response to therapy by MRD monitoring has proven to be a fundamental tool for guiding therapy. In this OncLive Peer Exchange® panel discussion, I am joined by a panel of experts in adult leukemia. We will discuss the latest advances in the treatment of ALL and MRD testing as a key component in individualizing care for each patient.

I am Dr Mark Litzow, professor of medicine at Mayo Clinic’s campus in Rochester, Minnesota, and chair of the ECOG-ACRIN Leukemia Committee. Joining me today are Dr Ryan Cassaday, associate professor in the Division of Hematology at the University of Washington School of Medicine, and assistant member in the Clinical Research Division at Fred Hutchinson Cancer Research Center in Seattle, Washington; Dr Jae Park, associate attending physician in the Division of Hematologic Oncology, and the director of the Adult Acute Lymphoblastic Leukemia Division at Memorial Sloan Kettering Cancer Center in New York, New York; and Dr Rachel Rau, assistant professor in the Department of Pediatrics, Section of Hematology-Oncology, at Baylor College of Medicine in Houston, Texas. Thank you for joining us. Let us begin.

Ryan, can we start off and would you describe the complexity of ALL management and the heterogeneity of the disease based on some of the factors we know, such as age, disease, biology, and prognosis, and maybe touch on what some of the most prognostic factors are?

Ryan D. Cassaday, MD: Regarding prognostic factors in ALL, there are several that have been around and stood the test of time over the years: older age, if you’re a pediatrician, your patient could be age 10 or higher; for those who treat adult leukemia, obviously that’s not the most practical prognostic tool. So there, 35 years old and up has historically been considered starting to be a high-risk factor. But certainly, as you get into older ages, 60 years old, 65 years old, and over, that’s a particularly challenging population to treat. Biologic factors like cytogenetics and more and more genomic molecular data are coming to be understood more as prognostic features of ALL.

Immunophenotype, particularly the early thymic precursors subtype of T-cell ALL, is a prognostic feature. And the Philadelphia [Ph] chromosome, of course, is an important factor as well, primarily in B-cell ALL. So oftentimes we use a lot of these tools to try to prognosticate how likely a certain treatment is going to work, and to a certain extent can help predict a particular treatment path as well.

Mark R. Litzow, MD: Rachel, could you comment from a pediatric standpoint about what some of the most important factors in this area are?

Rachel E. Rau, MD: Yes. Our prognostic capacity is quite well defined, I feel. And it has been further refined over the past several years. The primary feature we base our initial frontline therapy on would be the patient’s National Cancer Institute [NCI]—Rome risk criteria. And that is based on the patient’s age at diagnosis. If you’re between the ages of 1 and 10, and if you’re presenting a white blood cell count of less than 50,000/μl at the time of time of diagnosis, you’re considered NCI standard risk.

Patients who are older than the age of 10 at the time of diagnosis, or who have a white cell count greater than 50,000/μl are considered NCI high risk. So that, at least in the Children’s Oncology Group, is what we use to determine what our initial induction therapy will be comprised of. An additional poor risk factor determined by age are infants, which is a particularly challenging group of patients to manage, with very poor outcomes. Beyond that we also rely heavily on cytogenetic features, as well as the Ph-positive and the Ph-likes, which are now categorized differently and treated differently. And then MRD, of course. We incorporate an early MRD time point in the peripheral blood as well as in induction time points and later time points of therapy, which are now being incorporated as well.

Mark R. Litzow, MD: Well thank you. Ryan, you mentioned the Philadelphia chromosome; Rachel, you mentioned Ph-like. Those are somewhat confusing. Jake, could you elaborate a little bit on what those terms mean.

Jae Park, MD: The Philadelphia chromosome is the translocation of the chromosome 9 and 22 portions, 9;22 translocation with BCR-ABL translocations. So there are two different transcripts, type P190 and P210, both of which can occur in patients with ALL, P190 being more common in adult patients, whereas about 20% of the time, it’s the P210 transcript. So those are true Philadelphia chromosomes, that particular translocation. And the incidence increases with age. So older age patients can have the frequency of 30% to 40% at all times; they can be Ph-positive. It is very important because treatment is actually different for those patients. In particular, tyrosine kinase inhibitors [TKI] can be used and added to the line of a therapy. So especially for older patients, but for patients who are newly diagnosed with ALL, the testing for those particular mutations is very important at the beginning because, again, it can change prognosis and more commonly, the management at the time.

Ph-like or Philadelphia chromosome-like are more recent, although it’s not well established, and the incidence of those also increases with age until it starts to plateau once you get to young adults at the level of about 20% percent. It could be up to 20% of the time that it’s Ph-like. And it gets its name because the gene expression profile of the patients, even though they do not have a 9;22 translocation with BCR-ABL, can have a similar gene expression profile pattern as those patients who have the Philadelphia chromosome.

I think importantly some of the Ph-like subtypes can also be sensitive potentially to TKIs because they may involve translocation involving ABL or JAK-STAT pathways, and there are targetable agents. Obviously, we’re investigating whether those patients should be treated differently. I think that’s one of the areas in adult patients, and I was interested to hear what Rachel said about the pediatric patients. Knowing that information doesn’t really change what we do. We test a lot and there are a whole bunch of ways to test, which is not quite standardized and that makes it a little bit challenging in some of the adult settings to look for this mutation while the Philadelphia chromosome is very easy. The 9;22 translocation could easily be detected by fluorescence in situ hybridization [FISH], but with the Ph-like, FISH could detect a number of them, the CRLF2 translocation about 50% of the time, but the rest of them may not be easy to detect.

Again, the question is, does it change the management of patients with ALL at this time?

Mark R. Litzow, MD: It is a more heterogeneous group than the Philadelphia-chromosome, which is monolithic in some sense, although there’s some heterogeneity there as well.

Transcript Edited for Clarity