Managing Patients in the Changing Treatment Landscape of ALL

Mark R. Litzow, MD

For patients with acute lymphoblastic leukemia (ALL), many new agents are being developed, leading the field away from standard chemotherapy treatments and towards new combinations.

In the ALL space chimeric antigen receptor (CAR) T cell products including brexucabtagene autoleucel (Tecartus) and tisagenlecleucel (Kymriah) have been approved by the FDA and have offered better survival and remission rates for patients. Agents such as blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and ponatinib (Iclusig), have also been approved in this space over previous years.

However, while there have been several advances for patients with ALL, most apply within the B-cell ALL space. This has left patients with the T-cell subtype of ALL with a major unmet need for more treatment options.

According to Mark R. Litzow, MD, CAR T cell products that are effective against T-cell ALL are being developed and evaluated in both the United States and China. Until then, venetoclax (Venclexta) is a good option for this patient population.

“Ultimately, we would love to be able to do away with bone marrow transplant because although it's a very effective treatment, it also has a lot of complications and risks associated with it. We continue to need to find both new drugs and immunotherapies to treat both B-cell and T-cell ALL,” said Litzow, chair, professor of medicine, Division of Hematology, Mayo Clinic, in an interview with Targeted Oncology^TM.

In the interview, Litzow discussed managing patients with different subtypes of ALL and the session he was a part of during the National Comprehensive Cancer Network 2022 Annual Congress: Hematologic Malignancies.

Targeted Oncology: Can you give a brief overview of the session you were a part of at NCCN this year?

Litzow: We had a session on acute lymphoblastic leukemia treatment options for the different types of leukemia and approaches to patients with relapsed and refractory disease. That was followed by some case presentations which was part of a panel of 4 physicians, including Michelle Shaw, MD, from Moffitt Cancer Center, Aaron Logan, MD, from the University of California, San Francisco, and Nick Short, MD, from The University of Texas MD Anderson Cancer Center.

My talk focused on initial treatment options for patients with acute lymphoblastic leukemia and risk stratification. Some of the new developments in ALL, and there have been many that have been very exciting for us after many years of stagnation where we did not have a lot of new treatments, one of the important things we learned is that in younger adults with ALL, they can tolerate treatment programs that have been used in children, so pediatric regimens. These regimens contain more drugs like vincristine, asparaginase, and corticosteroids.

It seems that additional doses of those drugs have helped improve the outcomes in children and now we have found in young adults. Young adults include patients up to 40 and in some circumstances, up to 50 or 55. They can tolerate these intensive regimens and we see better outcomes, so better survival, and less relapse. We have been incorporating those types of regimens into the treatment of younger patients with acute lymphoblastic leukemia.

What recent developments have been seen in this space?

An important development is the use of testing for small amounts of leukemia in the bone marrow, the blood. We call it minimal or more accurately, measurable residual disease [MRD]. These are patients that we would have traditionally felt were in remission, they have less than 5% blasts in their bone marrow, but then we found that they can have small amounts of leukemia. If they do, they're at increased risk for relapse of their disease. We can now re-stratify patients based on their MRD status. That helps us to determine whether they need to have a bone marrow transplant or not.

We've also discovered, as in other diseases, a lot of the gene mutations that are important in the development of leukemia, and we have found that some of these gene mutations can increase the risk of relapse after they get their initial treatment. I sometimes tell my patients that their leukemia is more stubborn and it's going to be harder for us to keep them in remission. Having that information available to us has also helped us to determine who might need or not need a bone marrow transplant as part of their treatment.

The third big development, which has been very big in cancer and oncology, is immunotherapy, so adapting the immune system to help to fight the disease. There are some new major developments in acute lymphoblastic leukemia that have also greatly enhanced our ability to treat patients and keep them in remission. Some of them are based on antibodies, which are proteins that are used by our immune system to fight infection but can also be developed to attack cells.

What are some new treatments being developed or used for patients with ALL?

There's one called inotuzumab, which binds to a protein called CD22 and it's linked to a chemotherapy drug. It delivers a chemotherapy drug to the leukemic blast and helps kill it. There's also a new agent called blinatumomab. It's been around for a few years now, but we're still finding new ways to use it. This brings a T-cell or the thymus site close to the leukemic blast and helps to kill it. We're using the immune system again in these ways. The biggest development has been the CAR T cells and they have also been a huge development in treating patients who have leukemia that has come back and who have run out of options for being able to get back in remission. CAR T cells put an antibody into a T-cell so that the T-cell also then binds to the leukemic blasts and kills it. It seems to be more potent than the blinatumomab. We're still learning new ways to use CAR T cells and we have now 2 different CAR T cells available.

The first 1 we had tisagenlecleucel [Kymriah]] was only approved for use in people under the age of 25, so it didn't apply to a lot of our patients, but the new CAR T-cell product has been very encouraging to see this new agent and the treatment of ALL. There's another subset of ALL that we call Philadelphia chromosome positive ALL or BCR-ABL-positive ALL. This is where 2 genes come tog,ether and 1 gene gets activated and contributes to the development of leukemia. Some years ago, we developed drugs called tyrosine kinase inhibitors that can react against these BCR-ABL-positive cells. There's another leukemia called chronic myeloid leukemia where these were first developed, and they also have the Philadelphia chromosome. Then we thought, let's try them with pH-positive ALL and see if they work and we found they're very effective.

Combining those with chemotherapy has also been very effective in proving the outcome of this type of ALL which has traditionally been thought to have a poor prognosis. The prognosis is improved considerably now that we have these tyrosine kinase inhibitors with chemotherapy. Now, we're combining them also with the blinatumomab and inotuzumab which are also showing excellent results. It looks like in the future, we may be able to limit the amount of chemotherapy that we need to give by using these tyrosine kinase inhibitors and immunotherapy to treat BCR-ABL-positive ALL, and that's a major advance.

What can you discuss about managing patients with relapsed/refractory ALL?

[At NCCN] Nicholas Short, MD, talked about managing relapsed and refractory ALL. In that setting, we also use some of these agents, including inotuzumab, blinatumomab, and the CAR T cells. There's also an exciting new drug called venetoclax that seems to work in every leukemia. We've seen it work in chronic lymphocytic leukemia, and that's where it was first developed, and in acute myeloid leukemia. Now, we're seeing that it can also work in acute lymphoblastic leukemia. It's being combined with chemotherapy and some of these immunotherapies. It looks like that may be helpful in treating patients with relapsed and refractory disease, and I suspect we'll be using it more even in the frontline setting with newly diagnosed patients.

What unmet needs still exist in this space?

There are 2 broad forms of acute lymphoblastic leukemia. A lot of what I've been talking about, especially with immunotherapy, applies to B-cell ALL The other type is called T-cell. T cells are also called thymocytes and they develop in the thymus gland in our chest. We don't have as many advances in T-cell ALL, so an unmet need. We need new agents in that setting. Now, some CAR T cell constructs are being developed to treat T-cell ALL, but it's a little ironic because we're using a normal T-cell to try to kill a malignant T-cell. Because of that, there's been some problems in developing CAR T cells for T-cell ALL. Some of our Chinese colleagues have developed some innovative ways to try to address that.

There are some new CAR T-cell products that look like they're going to be effective against T-cell ALL, some coming from China and some now in the United States. I think that's going to be a major advance. Venetoclax also does work in T-cell ALL, so I think that will be helpful as we incorporate that more into treatment regimens, but we continue to need new agents in T-cell ALL. Ultimately, we would love to be able to do away with bone marrow transplant because although it's a very effective treatment, it also has a lot of complications and risks associated with it. We continue to need to find both new drugs and new immunotherapies to treat both B-cell and T-cell ALL.

What advice do you have for community oncologists when recommending treatment options for patients with ALL?

Attend meetings and read more about the management of these leukemias. The treatment regimens for AML are quite complicated and many community oncologists don't see many of these patients. I would also respectfully suggest that they partner with a larger, academic medical center where more of these patients are seen and worked with to help manage the patients and take the advice of people that have the good fortune like myself to be able to focus on leukemia and not have to worry about breast cancer, lung cancer, and all the other types that community oncologists have to worry about. Because the treatment regimens for these patients are long, they can last several years, it's not often possible for them to stay close to the academic medical center where they might start their treatment. Partnership between the community oncologist and the academic oncologist or hematologist is very important. I would encourage them to reach out for help and advice from experts that see this disease more often and can help them with the management of it.

What advancements do you think will soon be seen in the ALL field?

All these things that I've just talked about have been very exciting. I think they've been real advances. They've been breakthroughs in the treatment, and I think we're going to continue to see more breakthroughs. As we identify more of these genes that are abnormal, I think we'll be able to develop drugs that target these genes. We're already seeing that somewhat in ALL and we've seen that in acute myeloid leukemia, so I think that will continue to develop. The genomic revolution has been seminal in the development of new treatments for these patients.