Leukemia Awareness Month: Improving Outcomes Over the Past Decade

Jeffrey R. Schriber, MD

After a long period of no change in the treatment paradigm for leukemias, updates in our understanding of disease pathology and molecular targeting have changed the outlook for many patients. Both acute and chronic types of leukemia have undergone evolutions in treatment approaches that have offered better survival outcomes and more tolerable regimens.

“All of the changes in leukemia therapy, and in fact, in most hematologic [malignancies], have been occurring at a dramatic rate over the last 5 to 10 years,” Jeffrey R. Schriber, MD, said in an interview with Targeted Oncology^TM.

Studying the underlying molecular factors associated with different types of leukemia, including acute myelocytic leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia (CLL), has enabled physicians to make more informed decisions on how aggressively to treat individuals with leukemia. This includes which targeted treatments can be employed and whether chemotherapy or hematopoietic stem cell transplant (HSCT) can be avoided.

Schriber, director of hematologic malignancies at Cancer Treatment Centers of America (CTCA) in Phoenix, Arizona, discussed the successes in the treatment landscape of leukemias and what challenges remain for oncologists.

Targeted Oncology^TM: What are the most significant changes you have seen in the treatment of AML over the past 10 years?

SCHRIBER: Leukemia changed the most when we started to understand that there are molecular abnormalities present in some of these leukemias. We've known for a long time that FLT3 overexpression means a bad prognosis in AML and those patients don't do as well. We knew that allogeneic HSCT would work better for them. But what we didn't have is anything we could do about it. It was a little frustrating.

So investigators developed the FLT3 inhibitors. The first was midostaurin [Rydapt, Tauritmo]. There was a large randomized clinical trial [CALGB-10603; NCT00651261] where half of patients got it with standard chemotherapy, half of patients got [chemotherapy alone]. There was an impressive progression-free survival [PFS] and overall survival [OS] advantage to the group that received midostaurin.¹ That was the first major change in leukemic therapy in over 20 years from an AML standpoint. Now, what you want to do immediately is test to see if the patient is FLT3 positive. If they are, midostaurin is added, or there are at least 2 other agents that target FLT3 as well.

But this recognition has led to other therapies. Now there is [ivosidenib; Tibsovo] for IDH1 mutations and [Enasidenib; Idhifa] for IDH2 mutations. We recognized that IDH1 and IDH2 carried the worst prognosis, and we now have inhibitors for both of those. The recognition that we have targeted therapies that can alter how we're treating the disease is probably the first huge thing that has happened [in this setting].

The average age of patients with AML is somewhere around 65 years. This type of therapy is pretty intense, and many of these patients, especially ones with FLT3-positive or harder diseases, would be looking at an allogeneic HSCT, and often they're very sick. Venetoclax [Venclexta] is an oral [inhibitor that] targets BCL-2. It has been used in combination with some of the agents that we commonly use that are well tolerated, like azacitidine [Vidaza], or decitabine [Dacogen]. Studies that are all 2 to 3 years old have shown even in these older patients who are not felt to be suitable for more aggressive therapy, that they are able to tolerate this and have an excellent complete remission rate.^2,3 [Though it is oral], it’s still tough therapy. These patients drop [blood cell] counts and they can get sick. But that is a major advancement as well.

When I used to see patients with leukemia, I wanted to get them in, get their bone marrow [biopsy], make their diagnosis, know whether they had AML or ALL and [which] subtype, and I wanted to get them on therapy as soon as possible. That was always felt to be the mantra. But 2 years ago, there was a study done on the German Study Alliance Leukemia–Acute Myeloid Leukemia registry that showed that you don't have to do it right away, and if you wait and see if they're FLT3-, IDH1-, or IDH2-positive, you can tailor your therapy.⁴ That was another big thing that gave us a little sense of relief because we [learned] we don't have to [give treatment] right this second.

What improvements have been made in the treatment of ALL?

ALL is a disease that's much less common in adults. In adults, 80% of patients with leukemia have AML and maybe 20% or 30% have ALL. For children it's reversed. Children do very well with ALL, because [most patients] go on studies where they intensify the regimens. Those regimens can be very tough for some of the older adults to manage. But there's been a bit of a shift for adult patients under the age of 50. It’s not the majority of adults with ALL, but in those patients, we've shifted towards a [pediatric-inspired] regimen. And if they can tolerate it, [patients receiving] those regimens seem to do a little bit better.⁵

In ALL, we usually see if patients are Philadelphia positive or Philadelphia negative. The Philadelphia chromosome is a translocation between chromosomes 9 and 22. It can cause CML, but it is also classic for ALL. They have a slightly different version of the genetic information that gets exchanged. Tyrosine kinase inhibitor [TKI] therapy blocks the tyrosine kinase that is responsible for this problem. For years, we've used those medicines to treat adults. But recently, there were data that as we get better TKIs, we may no longer have to give HSCT for all those patients.⁶ That became quite relevant in the COVID-19 era when we didn't want to take a patient through an allogeneic HSCT. One of the challenges we face is how do we know who [needs HSCT], because it is very effective, but it’s a tough thing to do. Are there patients we can cure? Traditionally, with Philadelphia-positive ALL, we always want to transplant. Recent data from The University of Texas MD Anderson Cancer Center group have shown with a better TKI, you may be able to avoid doing HSCT.⁷

We now use molecular testing [for minimal residual disease (MRD)] in both AML and ALL to determine whether there is still evidence of disease at very minute amounts. We've done this for years in CML.⁸ Being able to find minute amounts of disease is become very important because if we are able to get patients to these molecular responses with the regular therapies, they may not need an HSCT. It appears that some of these patients do just as well. The ability to [avoid] this very toxic therapy that is expensive and keeps patients in the hospital is a big advancement as well.

We now know in ALL that a patient may get into remission but they haven't achieved a molecular response. Molecular testing allows us to have a better 'camera' that gets a view of everything and says we may be able to avoid more intensive regimens for patients who are MRD negative. For patients who are MRD positive, there's a new medicine called blinatumomab [Blincyto], which is a bispecific T-cell engager. It takes CD19, a marker on ALL, and brings it together with the effector T cells. We can take patients who are molecularly positive and shift them to molecularly negative.⁹

Chimeric antigen receptor [CAR] T cells have changed what we do, particularly in young patients with ALL. I remember the first patient I had who I treated for relapsed leukemia [who received CAR T-cell therapy]. I had given her an allogeneic HSCT, and she did well for a period of time, but came back somewhere about 6 or 7 months after and that's usually a death sentence. At the time, there was a clinical trial of CAR T-cell therapy being done at The University of Texas MD Anderson Cancer Center. She did great for 2 years, and that was unheard of. The changes we’ve seen in ALL, particularly for CAR T, has been very gratifying. We can salvage patients that we couldn't have [before]. A lot of these patients are children because that's where the disease is more common.

The problem with CAR T cells is we're seeing failures now because we [are able to] follow up with patients. I think ALL is a little bit different, but in the lymphomas, [where we thought] this is going to cure patients, it's starting to come back, and we're seeing the same thing happening with multiple myeloma. The duration of this will be important to see whether we are going to continue [using] allogeneic HSCT. You can cure patients [with allogeneic HSCT], but it's tough therapy so we would like to have a replacement for if it's at all possible.

Have there been any recent changes in targeted therapy for CML?

In CML, we are building on [past efforts]. We have a brand-new medication for CML called asciminib [Scemblix], that targets different areas. In CML with the t(9;22) translocation, most TKIs target tyrosine kinases in one area, while this one targets the other. So in those rare patients that failed [other TKIs], this drug is more effective than some of the other drugs that we [compared it with] in a large randomized trial.¹⁰ So now we have a whole new target that we can go after. We usually think CML is an easy disease to deal with, and now we have something for when it [is harder to treat].

What are the most important new approaches to treating CLL?

CLL is the most common type of leukemia. Chronic leukemias usually go for many years, whereas the acute leukemias are the ones we need to treat right away. There are still many patients with CLL who we don't have to treat. We’ve been able to identify biomarkers such as TP53, [which shows the disease will] be more aggressive. We look to see if patients have a mutation in the immunoglobulin gene, [which has] a favorable prognosis.

The biggest change has been the shift from chemotherapy, which we used to do 10 years ago, to immunotherapy. We have 2 different options. Venetoclax can be used with an antibody therapy and is very effective, but it can knock the [blood cell] counts down a little which makes patients sick. With COVID-19, we had to be careful about that.

The other set of agents are Bruton tyrosine kinase [BTK] inhibitors. BTKs are involved in how [malignant] cells are generated and proliferate. There are a variety of BTK inhibitors that have been effective, and they are now used up front in many patients. They were getting therapy with either ibrutinib [Imbruvica] or acalabrutinib [Calquence], and now there is a new one, zanubrutinib [Brukinsa].

[Due to these regimens], patients with CLL no longer get chemotherapy. What I think we will see soon is the combination of [venetoclax and BTK inhibitors] together, and we may even start talking about CLL as something that's going to stay away for a long period of time. Maybe we can talk about curing CLL down the road.

What are the most significant unmet needs in these types of leukemia?

The hardest thing is, what happens when the patients have failed therapies? That's where we spend a lot of our energy, and lot of the dollars in healthcare go towards that. We still need to be able to adjust quickly and [discover] how we can combine as many of these drugs as possible to get our best shot up front. That has been very hard because the way clinical trials work, for the most part, is you test 1 drug. What frustrates us sometimes is you can't do the study that you'd like to do. For instance, in CLL, we have [at least] 3 different drugs, and it would be nice to know that one is better than the other.

I think that's been tough because we can never move fast enough for [relapsed patients]. We’ve made tremendous progress, but we still don't understand why some patients blow through regimens, and that is frustrating. The FLT3 [inhibitor] is standard; I think in time we will say, “We used the IDH1 and IDH2 inhibitors; are there other therapies we can use?” It's starting to happen, but it's not as well defined as I think it needs to be.

What is the most important piece of advice you would give to someone who is less familiar with recent developments in leukemia treatment?

My advice is to go to a center that [treats leukemia] a lot. One of the reasons I came to CTCA was to start a hematologic malignancies program, because like the changes I've talked about for leukemia, there are similar changes in lymphoma, in Hodgkin disease, and multiple myeloma. [Treatment for] these diseases continue to change on an ongoing basis, and it's hard to keep up.

If you're a general oncologist who mostly sees breast cancer, lung cancer, colon cancer, etc, it’s important to have someone who is an expert in immunological disorders. Go spend time at your center of excellence and learn the new therapies and the principles because the drugs will change. I would think about going to a center that does this. That's the way you learn. If I were a patient, I would want to go to a place where this is what they do primarily.

_References:

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_{7. Short NJ, Kantarjian HM, Konopleva M, et al. Combination of ponatinib and blinatumomab in Philadelphia chromosome-positive acute lymphoblastic leukemia: Early results from a phase II study. J Clin Oncol. 2021;39(suppl_15):7001. doi: 10.1200/JCO.2021.39.15_suppl.7001}

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_{9. Franquiz MJ, Short NJ. Blinatumomab for the treatment of adult b-cell acute lymphoblastic leukemia: toward a new era of targeted immunotherapy. Biologics. 2020;14:23-34. Published 2020 Feb 14. doi:10.2147/BTT.S202746}

_{10. Réa D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021;138(21):2031-2041. doi:10.1182/blood.2020009984}