Transcript:Ruben A. Mesa, MD, FACP: I think we’ve really been hitting these key points as for how we’re thinking about prognosis in this group of patients. Why don’t we use that as a segue to turn our attention to the actual treatment of these acute leukemia patients. Let’s first start with the discussion of induction. You’ve got that patient in front of you, they’ve been diagnosed with acute leukemia, and we’re deciding how we’re going to be treating them initially. We know that’s a very different scenario from our end as opposed to the patient that’s already further down the journey. Clearly it can be a complex journey. Have they relapsed? Are they refractory? Are they going to transplant?
But let’s start with the induction part. Elias, from your perspective, first let’s think about the prognostic factors. We’ve discussed a bunch of them. But in terms of that first time we’re seeing that patient, what are the key prognostic factors you want to know about and that you’re going to really have back in a short amount of time to act on for therapy?
Elias Jabbour, MD: Let’s start with what’s urgent to do and then we can go from there. First, I get the referral of somebody with acute leukemia. Rule out APL [acute promyelocytic leukemia]. That is emergent DIC [disseminated intravascular coagulopathy]. You have to get a blood test, ATRA, 15;17 translocation, and PML-RARA; you’ve done that. Five hours later, the blood test is negative. You don’t have the feature of DIC. You get the karyotype done, CBF leukemia, 8;21 inversion 16 or something else: induction high-dose ara-C [cytarabine]. Studies have shown high-dose ara-C must be given. We discuss Mylotarg (gemtuzumab ozogamicin). Gemtuzumab ozogamicin is not on the market, but in this subset of patients, using Mylotarg has been helpful. So, therefore, high-dose ara-C is a must for this patient.
Treatment-wise, there are no implications for therapy to add a tyrosine kinase inhibitor up-front, maybe in a relapse. Transplant? Have a donor? Keep a close eye on that. And then you get to the vast majority of patients where you have either the diploid karyotype or bad features. Rafael eloquently mentioned the NPM1 and other classifications. We have to do the molecular panel and gene sequencing, and get in mind what you have for these patients.
But then you define them by fit for chemotherapy, unfit for chemotherapy. Fit for chemotherapy are 60 years and younger, they don’t have renal failure, they’re in good shape. Usually, we try them for transplant and to find a donor. And you go for high-dose ara-C induction. Now, the question in the USA: 7+3 chemotherapy or high-dose ara-C? I come from MD Anderson where we published multiple papers and meta-analyses showing high-dose ara-C is to be given for diploid, good feature patients. So, for somebody with bad features, high-dose ara-C may not play a good role. And then consolidation plus or minus transplantation if they have a donor. Bad feature, responding or not responding? For unfit patients, regarding chemotherapy? In the randomized trial, at least for decitabine and azacitidine, we don’t have a great CR rate. And it’s changing the dogma of leukemia treatment where CR is the best to get survival. We’re not killing them by chemotherapy, but decitabine has been a standard of care in the US and in Europe for these patients.
It’s not enough. We know at this point, despite the best treatments we have today, relapses are still happening. And I think as you mentioned in the beginning, these patients should be referred to people with expertise, where clinical trials are available, with the aim to improve the overall survival and the response rate for these patients.
Ruben A. Mesa, MD, FACP: So let’s break it into different pieces. You raise a variety of key parts. First, that key decision point regarding: am I really going to go down an induction path or am I going to go through a lower-intensity path? And realize that all of our institutions may have very specific protocols that affect that. But thinking more to the standard approach for individuals who don’t have access to studies: Rafael, at your center, in your experience, if you’re trying to have that sort of litmus test, are you going down an induction path or noninduction path? What are the features you consider? Are there any hard stops you have in between them?
Rafael Bejar MD, PhD: It’s really individualized. I think Elias mentioned all the risk factors that put people into different categories. So, for the most part, patients with AML get treated with 7+3. What we do down the road, depending on their response, is where things begin to diverge. The clinical trial piece is very important and not only in relapsed/refractory patients or patients with difficult features, but really at any level. I think our treatments for AML aren’t so great that we can’t find newer, better ones.
Ruben A. Mesa, MD, FACP: Rami?
Rami Komrokji, MD: I think the first thing we always look at is the age. Although, as we learn more about this, it is really age as function. It’s really a good, almost a geriatric assessment for the patient, their performance status, their activities of daily living, presence of any geriatric syndromes. In younger patients, I think it’s very clear that almost all the patients, unless there is really a major comorbidity, will get intensive chemotherapy.
I think the challenge is more in older patients. What do you define as “older”? I think most of the studies, when they look at AML outcome, look at the age of 60 or 65. But we know in practice that that’s changing. We see patients in their 70s that are very fit. So I think you look at the patient, their comorbidities, their performance status, and those are keys in deciding intensive chemotherapy or not.
I’d like to say that patients with AML, even older patients, definitely do benefit from treatment, and it has been shown in several studies that a treatment is better than no treatment. The question we are looking at is what type of treatment. I think realistically, if we don’t have a clinical trial, we are looking at an intensive chemotherapy approach versus a hypomethylating agent as a standard treatment for those patients. So if patients are fit with no major comorbidities, I think intensive chemotherapy, even in older patients, offers them benefit.
If patients have comorbidities or are unfit, I think nowadays we go for less-intensive chemotherapy. Sometimes the disease features like the cytogenetics may also dictate that choice. So an older patient that has poor risk cytogenetics, with the current standard available therapy like 7+3, the chances of going into remission are very low. And especially if they’re not going to be eligible for allogeneic stem cell transplant, one would question the value of intensive chemotherapy. So, if somebody is older, with poor risk cytogenetics, one may go for less-intense chemotherapy because of that.
Transcript Edited for Clarity