Acute Lymphoblastic Leukemia Patient Population

Transcript:Stefan Faderl, MD: The question is about complexity of management of acute lymphoblastic leukemia and age-based differences in terms of prognosis and management by extension. Now, acute lymphoblastic leukemia is a disease that really spans all age groups from infancy through childhood, the group of the adolescents and young adults, and then, obviously, adult patients—and not least of the patients, the elderly patients, maybe patients over 60 years which may form a special group of patients.

But clearly, the major incidence of acute lymphoblastic leukemia is in childhood. But lo and behold, once you get to 55 or 60 years, you do have a second—smaller, but second—peak incidence of the diagnosis of acute lymphoblastic leukemia. Now, interesting, I think, in acute lymphoblastic leukemia, as you go through the age groups from infancy up to the elderly, the biology of the disease seems to change as well.

As some examples, for instance: infant acute lymphoblastic leukemias have a very high incidence of MLL gene rearrangements which are actually associated with a rather poor prognosis, very much in contrast with the experience in childhood acute lymphoblastic leukemia where the prognosis is actually very good, characterized by high response rates and very good long-term survivals. And children actually also have a high incidence of favorable or good prognosis, cytogenetic or karyotype abnormalities which, among other things, makes the disease just very responsive to treatment.

Once you kind of turn into the adult area, it sort of kind of switches and changes. You have a higher incidence of more unfavorable cytogenetic abnormalities: in particular, most notably, obviously, the incidence of the Philadelphia abnormality that increases with age but also a more recently described subtype BCR-ABL—like acute lymphoblastic leukemias, the incidence of which also increases with age.

A very particular group is the adults, adolescents, and young adult groups of patients, a heavy focus nowadays in terms of approaching them somewhat differently from adult protocols with more pediatric-inspired protocols. And that seems to also achieve better responses. Another sort of biological, I guess, the complexity of acute lymphoblastic leukemia, is the fact that those cells may survive and protect anatomic spaces, like testes in young boys or particular central nervous systems. We may have completely different relapse scenarios where the bone marrow and blood may be clean but we have a very isolated relapse in some of those areas which poses its own challenges in management of those patients in terms of treatment, as well.

I think a lot of complexity in acute lymphoblastic leukemia also comes down to histology. You use, all the time, very complex regimens with lots of drugs involved and very prolonged treatment regimens, plus/minus a lot of stem cell transplant that differs from, say, acute myeloid leukemia. You have differences in tolerability of chemotherapy between children and adults and many differences in drug metabolism, as well, so a lot of things that make acute lymphoblastic leukemia a little bit of a special disease, I think.

Bijal D. Shah, MD: Risk stratification in acute lymphoblastic leukemia is absolutely the next most important thing we can do to improve outcomes. Now, risk stratification involves, I think, fundamentally two components. The first is moving beyond things like white blood cell count or LDH and moving towards both a better characterization of the patient at presentation; so looking more specifically at comorbidities, looking at the performance status, looking at those features which we think are going to show this is not an individual who will tolerate the intensity of the therapy that we’re outlining.

The second component is looking at the disease itself, so the macroenvironment to the microenvironment, asking what is the genetics of this leukemia. Is it Philadelphia positive? Is it a Philadelphia-like ALL? Are there other high-risk genomic translocations that will predict for inferior outcome? The last component is using that information and coupling it to minimal residual disease assessments. Asking after we approach this patient with molecularly targeted or molecularly-based therapy, then moving forward to say did we achieve the outcome we set out to achieve. And, if we didn’t, developing a platform for either adding additional agents, changing agents, or intensifying therapy in some way, shape, or form; for example, allogeneic transplant.

Raoul Tibes, MD, PhD: So one question that comes up often is, what is the upper age limit for adult patients treated with pediatric-inspired regimen? The most recent large CALGB trial included an age limit of 40, or below the age of 40. However, I can tell you from our experience in our institution, sometimes we even go higher to the age of 50.

Why is this important? Because the pediatric-inspired regimen[s] have different drugs, less myelosuppressive drugs, and, importantly, they incorporate asparaginase in the treatment for adult ALL patients. Why is this important? Because the addition of asparaginase in the treatment of ALL protocols has shown, over the years and over many trials, that it improves the outcome for patients with ALL.

A question that comes up is, who are the patients that are fit or unfit for a more intensive regimen? As I mentioned earlier, several of the trials incorporated patients up to the age of 40. I would say some of the academic institutions go past the age of 40 for incorporating asparaginase or pediatric regimens to very fit patients. Fitness is a relative term. As everybody is getting older, many patients are in better shape when they come to us.

There are formal comorbidity scores that we can use to try to get an idea how fit patients are. However, those scores are sometimes cumbersome to calculate, and I think a general assessment based on a physician’s experience or comorbidities of patients should not necessarily prevent treating patients with the appropriate, more intensive, and therapy-including asparaginase.

Transcript Edited for Clarity