Novel Agents, CAR T Cells Reinvigorate ALL Landscape

Jae H. Park, MD

The field of acute lymphoblastic leukemia (ALL) has experienced a wave of new agents, with the approval of 3 novel therapies in the past year alone.

In July 2017, the FDA granted a full approval to blinatumomab (Blincyto) for the treatment of adults and children with relapsed/refractory B-cell precursor ALL, regardless of Philadelphia chromosome (Ph) status. Blinatumomab was then granted an accelerated approval in March 2018 for the treatment of adult and pediatric patients with B-cell precursor ALL who are in remission but still have minimal residual disease (MRD).

Inotuzumab ozogamicin (Besponsa) was approved in August 2017 for the treatment of adults with relapsed/refractory B-cell precursor ALL, and a milestone moment also came in August 2017, when the FDA issued an approval for the first chimeric antigen receptor (CAR) T-cell therapy—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.

OncLive: Please provide an overview of your presentation.

During his presentation at the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Jae H. Park, MD, an assistant attending physician in the Leukemia Service at Memorial Sloan Kettering Cancer Center, discussed novel therapies for patients with ALL. In an interview during the meeting, Park shared his insight on the impact of agents such as blinatumomab, inotuzumab ozogamicin, and tisagenlecleucel.Park: I spoke about some of the novel therapy options for adult patents with ALL. I reviewed some of the data published in the last couple years using immunotherapy, such as bispecific antibodies like blinatumomab; antibody-drug conjugates, such as inotuzumab ozogamicin; and CD19-targeted CAR T cells.

How has the success of CAR T-cell therapy impacted the landscape?

I also reviewed some additional data from the 2017 ASH Annual Meeting. There were not a lot of updated clinical trial data, but since the meeting, there have been new publications proving the efficacy and long-term durability of using CD19-targeted CAR T cells. I ended the lecture on where the field is going using these novel therapeutic approaches in the treatment of patients with ALL.CAR T-cell therapy has transformed the therapeutic options for patients with ALL, but there is still lot more work that needs to be done. However, what has been proven and confirmed through multiple clinical trials is the high efficacy and achieving initial CR rates in the range of 80% to 90% in previously heavily treated patients who are chemorefractory, relapsed, or have undergone transplant. This is what led to the approval of tisagenlecleucel for patients with ALL. These patients would typically not have a lot of options in terms of getting into a remission.

Can you highlight the data surrounding CD19-directed therapies?

It is not perfect; we are still dealing with side effects and what to do after relapse. There is a lot of work to be done to reduce the rate of relapse and engage long-term remission rates for these patients. The role of transplant in the setting of CAR T cells is up for question. Is transplant necessary for some of these patients? It appears so. Some patients benefit from CAR T cells as a definitive therapy, but we don't know who those patients are yet. There is ongoing work to figure out how to select patients who might not need a subsequent therapy after receiving CAR T-cell therapy.CD19-targeted CAR T cells have been generating a lot of good data for patients with ALL, both pediatrics and adults. They have been in several publications. Earlier this year, the New England Journal of Medicine (NEJM) published the ELIANA trial, which reported impressive outcomes, such as high response rates that were seen in the phase II single-center studies and confirmed in multicenter global studies. [ELIANA] proved that this type of study can be done in a large-scale global trial and can replicate the data similarly to what was observed before.

Additionally, the durability of remission is similar to what has been presented previously. It is a short-term follow-up in the large scale, so we still need to see what happens to these patients after attaining remission. Relapse continues to be an issue, but not as much as compared with relapse after chemotherapy, or other available therapies such as inotuzumab ozogamicin or blinatumomab.

In adult patients, we still do not have a CD19-targeted CAR T-cell product approved for ALL. However, many clinical trials have proven efficacy in these patients. Toxicity continues to be a problem in adult patients with ALL—more so than pediatric ALL. Nonetheless, this therapy has shown to be effective. As we modify the therapy and optimize the safety and efficacy, we believe that this therapy should be approved in adult patients, as well.

Where are we with combination regimens with CAR T-cell therapy?

Our group from Memorial Sloan Kettering Cancer Center published data in the same NEJM issue as the ELIANA trial. This was phase I long-term data that showed that adult patients with low disease burden at the time of CD19 CAR T-cell infusion benefited the most with little toxicity, and a significantly better overall survival benefit than patients with a high tumor burden at the time of T-cell infusion. We are still working out why this is the case, but we have at least figured out the factors that determine long-term survival in these adult patients with ALL.Combination therapy with other immune modulators is happening in other diseases such as chronic lymphocytic leukemia (CLL) and large cell lymphoma. In ALL, we are dealing with a high relapse rate and high toxicities, more so than the other 2 diseases. The combination approach that we are seeing in ALL right now is moving the therapy earlier in the treatment before the patient becomes morphologically relapsed with a high tumor burden. After undergoing several cycles of chemotherapy and they have residual disease, it may be beneficial to give CAR T-cell therapy before a bone marrow transplant, where we know the efficacy is likely going to be higher and toxicity lower.

In what other hematologic malignancies will we see CAR T-cell therapy being used?

In the relapse setting, combinations with other chemotherapeutic approaches—whether it is cytoreduction first followed by the CAR T cells as a more consolidative approach, or in combination with another immunotherapy—are being worked on. The concern is that once you combine with the other immunomodulators, it is highly potent. Therefore, we need to optimize safety of CAR T-cell therapy alone before we combine it with other immunomodulatory agents.We are already seeing CD19-targeted CAR T-cell therapy in lymphoma and CLL and targeting BCMA is big in myeloma now. The next wave of CAR T-cell therapy in hematologic malignancies is acute myeloid leukemia (AML). We don't have a great target yet.

Looking ahead, what would you like seen addressed in ALL?

For AML, we have several clinical trials ongoing targeting different antigens. We do not have much data yet to see how effective or safe they are. These data will come out in the next couple years.One thing that I would like to see is the cure rate for pediatric patients go from 60% to 100%. It is a rare disease and clinical trials are hard to do, so more collaboration needs to happen between groups. Small trials are still worth doing to get safety signals.

Is there anything else that you would like to add?

The goal is to shorten the duration of total therapy for frontline ALL; right now, these patients get about 3 years of chemotherapy. With the emergence of these 3 new novel therapies—inotuzumab ozogamicin, blinatumomab, and CAR T cells—and the potential of moving them earlier, the majority of these patients will not need 3 years of chemotherapy. I would like to see the shortening of duration of chemotherapy, as well improved quality of life for our patients. If we can spare bone marrow transplant in some of them, that would be ideal, as well.MRD testing is a critical component of managing patients with ALL. It is the single most prognostic indicator for ALL, and I would like to emphasize that MRD testing should be done on these patients. Earlier detection of these rising ALL cells by pathologic complete response or flow cytometry is important to know so that the clinician can discuss options with their patients.