Relapsed/Refractory ALL Paradigm Rapidly Evolving With Novel Agents

Jonathan E. Brammer, MD

The introduction of multiple agents including CAR T-cell therapy, bispecific T-cell engagers (BiTEs), and antibody-drug conjugates has revolutionized the treatment landscape of relapsed/refractory acute lymphoblastic leukemia (ALL), said Jonathan E. Brammer, MD.

"The field of ALL is rapidly changing," said Brammer. "When I was in training, we were giving chemotherapy after chemotherapy to patients with relapsed disease. Their only hope was a bone marrow transplant to try and cure them. Now, the future is looking bright for these patients."

Notably, the March 2018 approval of blinatumomab (Blincyto) marked the first agent indicated to treat adult and pediatric patients with minimal residual disease (MRD)—positive B-cell precursor ALL.

"MRD is the most important predictor of outcome for both B-cell and T-cell ALL," explained Brammer. "The majority of patients who have detectable MRD after induction chemotherapy or at the end of treatment will relapse."

Although the introduction of these new therapies has affected the need for stem cell transplant (SCT) in some patients, Brammer believes transplant will retain a role in ALL, particularly for those who have "relapsed/refractory disease or who have MRD-positive disease," he explained.

However, the addition of CAR T-cell therapy to this space may eliminate the need for transplant completely, said Brammer. In August 2017, the FDA approved tisagenlecleucel (Kymriah) for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

In an interview during the 2019 OncLive State of the Science Summit on Hematologic Malignancies, Brammer, an assistant professor in internal medicine at The Ohio State University Comprehensive Cancer Center—James, discussed the role of MRD and transplant in ALL, as well as the introduction of CAR T-cell therapy and other novel agents to the armamentarium.

OncLive: Could you discuss the BLAST study and the importance of assessing MRD in ALL?

Brammer: The BLAST study sought to utilize the BiTE blinatumomab to introduce T cells to the leukemia cells and activate an immune response. Researchers were able to effectively eradicate MRD in patients who had MRD following at least 3 rounds of treatment. Additionally, many of those patients were able to undergo transplant.

Is it important to achieve MRD negativity earlier in the disease course rather than later?

It is always important to attain MRD negativity as early as possible. The patients who had detectable MRD after 3 cycles of treatment or at the very end of treatment were able to receive blinatumomab. The goal was to determine if MRD could be eradicated. Blinatumomab was used primarily as a bridge to transplant because [blinatumomab] is not thought to be a curative therapy.

What is the utility of transplant in ALL?

The role of transplant has evolved in ALL. Traditionally, SCT was indicated for patients who had Philadelphia chromosome—positive disease or for those who failed to attain a remission.

However, this has changed dramatically over time, especially because we have identified differentiated subtypes, high-risk groups, and more effective therapies that make transplant less necessary.

Patients who have MRD-positive disease after induction or at the end of treatment appear [to derive more benefit] from transplant whether or not they receive salvage therapy. Without transplant, those patients will likely relapse.

SCT should also be considered in patients with high-risk ALL, including early thymic precursor T-cell ALL, mixed-lineage ALL, and Philadelphia-like ALL.

How has the role of transplant evolved in ALL?

The ability to perform SCT has improved over time. In the past, transplant was reserved for patients under the age of 60.

Currently, we can transplant patients 75 years old and younger using reduced-intensity conditioning. Also, we have new techniques to use a mismatched donor for patients who do not have a fully matched donor. The availability of transplant, as well as our ability to perform transplant safely and effectively has improved, thus making it an effective modality in ALL.

What pivotal studies have evaluated varying approaches with transplant in ALL?

Many people have wondered whether doing a bone marrow transplant improves survival for patients with ALL. There was a study that looked at patients who had MRD positivity at the end of treatment compared with patients who are MRD negative.

Across all subtypes, that trial showed that SCT did not benefit patients with MRD-negative status, but it did substantially benefit those who had MRD positivity. This finding established the role of transplant for patients who are MRD positive. Patients with high-risk disease who go through chemotherapy and achieve MRD negativity can likely avoid transplant, but it should always be discussed with the patient to determine the optimal course of action.

What data have been reported with inotuzumab ozogamicin (Besponsa)?

Inotuzumab ozogamicin is an antibody-drug conjugate that targets CD22, which is present on B-cell ALL cells.

The INO-VATE study [demonstrated] that 80% of patients who received inotuzumab ozogamicin attained remissions compared with 30% of those who received standard chemotherapy. These were patients with truly refractory ALL.

However, those remissions are typically short-lived. It is an effective agent, but it should be considered a bridge to transplant.

Inotuzumab ozogamicin is associated with veno-occlusive disease, as is SCT. In the INO-VATE trial, 14% of patients had veno-occlusive disease. I would strongly consider avoiding chemotherapy agents known to induce veno-occlusive disease, such as busulfan with transplant when using this drug.

For this reason, blinatumomab could be used in this situation to avoid the potential complication of busulfan; however, both drugs are recommended by the National Comprehensive Cancer Network as bridges to transplant.

Is CAR T-cell therapy appropriate for patients who progress on those modalities?

Yes. CAR T-cell therapy has been revolutionary, particularly in the pediatric population.

At [the State of the Science Summit], we discussed the long-term results of a study that showed an 83% hematologic complete remission rate with CAR T cells in patients who had relapsed at least twice. Importantly, most of these patients had already undergone transplant, making the results even more remarkable.

It is highly effective; however, it is only approved for patients who are 25 years old or younger. We cannot use this therapy outside of a clinical trial for older patients.

Could CAR T-cell therapy replace transplant?

That is a great question that a lot of people are considering at this point. I do believe CAR T-cell therapy could replace transplant. The data from the University of Pennsylvania showed that CAR T cells can persist for years after being infused. Many of the pediatric patients who were initially treated remain in remission. In other lymphoid diseases, such as diffuse large B-cell lymphoma, a substantial fraction of patients can remain in remission after CAR T-cell therapy without transplant.

In the future, CAR T-cell therapy could be a curative therapy alone, but more data are needed. For now, CAR T-cell therapy will be utilized after transplant as part of a salvage mechanism in most patients.

What is your anecdotal experience working with CAR T-cell therapy?

I don't typically treat pediatric patients, but I have quite a bit of experience with adult patients with lymphomas who are treated with CAR T cells. The toxicities appear to be similar.

Often, we see cytokine release syndrome that can cause high fever, flu-like symptoms, aches, chills, hemodynamic instability, hypotension, and abnormal heart rhythms.

We also see neurologic toxicities including confusion, “sundowning-like” symptoms, and stroke-like symptoms in adults and children treated with CAR T cells. Although these adverse events almost always resolve, most studies demonstrate that approximately 30% to 40% of patients develop these neurologic toxicities.

There are algorithms to treat patients with these complications, and they are almost always transient. Very few patients will die from CAR T-cell therapy itself, but it is something to closely monitor. As such, the majority of patients are kept in the hospital for at least 1 week to monitor for these complications, as they typically occur within 2 weeks of infusion.

What does future treatment look like in this disease?

Although we have seen a lot of advancement in B-cell ALL, the 25% of patients who have T-cell ALL have not seen the same advances. T-cell ALL does not have the same target as B-cell ALL. We need more research and clinical trials for T-cell ALL.