Novel Therapies Show Significant Activity in Relapsed/Refractory ALL

Jae H. Park, MD

Bispecific T-cell engagers (BiTEs), antibody-drug conjugates (ADCs), and CAR T-cell therapy are all novel treatment modalities that are emerging for patients with relapsed/refractory acute lymphoblastic leukemia (ALL), according to Jae H. Park, MD.

“We have good therapies for patients with relapsed/refractory B-cell ALL that we know are better than chemotherapy, including blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and CAR T-cell therapy,” said Park. “Instead of giving repeated courses of chemotherapy, we should be considering these novel therapies.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Park, hematologic oncologist and attending physician at the Leukemia Service and Cellular Therapeutics Center of Memorial Sloan Kettering Cancer Center, discussed how emerging agents across several treatment modalities are demonstrating great potential in ALL.

OncLive^®: What have longer follow-up data shown with regard to CAR T-cell therapy?

Park: It's encouraging that we have seen high response rates and complete response (CR) rates of approximately 80%. However, we have also seen early relapses in approximately 40% of adult patients with ALL. Nonetheless, durable remissions have been observed, which is what has kept the excitement going. We're seeing remissions lasting up to 5 years.

We also have a better understanding of which patients may benefit the most from this type of therapy. Specifically, we believe patients with a lower burden of disease [will experience the most benefit].

Furthermore, ongoing trials are investigating ways to reduce the toxicity of CD19-directed CAR T-cell therapies. We have gotten better at managing toxicities associated with CAR T-cell therapy, but we want to prevent these events completely without comprising efficacy. Some of those approaches include targeting different cytokines; that research is ongoing.

Are other antigens being evaluated besides CD19?

Yes; CD19-targeted CAR T-cell therapy was developed for patients with B-cell malignancies. Other B-cell antigens could be targeted, including CD22. We have seen preliminary data showcasing their efficacy, but the remission durations don’t appear to be as long [as what we have seen with CD19-targeted products]. Bispecific CAR T cells are also targeting CD19 and CD22. There are a couple of different ways to target antigens at the same time; those studies are ongoing.

How is measurable residual disease (MRD) being tested in ALL?

MRD is one of the best prognostic indicators we have in ALL; it's something we should all be aware of and monitor during treatment. MRD assessment is important, especially now that we have a directed therapy for patients who are MRD-positive. MRD is a prognostic indicator that can inform us how likely a patient is to need subsequent therapy and whether earlier allogeneic transplant can help a patient avoid subsequent lines of therapy after relapse. MRD-negative remissions are the goal of therapy, especially in the frontline setting. Now, we have blinatumomab, specifically for patients with MRD-positive disease. Blinatumomab is a CD19-targeted BiTE, which brings CD19 and CD3 together.

The BLAST trial was a large confirmatory study for blinatumomab in adult patients with MRD-positive B-cell ALL. Patients were either in their first or second CR. We saw a CR rate of 80%, which is quite impressive in that setting. Some of the remissions were durable, although most patients ended up proceeding to bone marrow transplant afterward. It’s clear that blinatumomab is effective in this setting. However, questions remain, such as whether all patients need to undergo transplant afterward. Hopefully we'll get more data with other therapies in this setting in the future.

Could you shed light on the long-term analysis of the INO-VATE trial?

The trial evaluated the CD22-targeted ADC inotuzumab ozogamicin compared with standard chemotherapy in the relapsed setting. The initial data showed a higher combined CR and CR with incomplete hematology recovery rate of 80% versus chemotherapy. Long-term follow-up confirmed the durability of the remission and the survival benefit of inotuzumab ozogamicin versus chemotherapy. Inotuzumab ozogamicin was used as a bridging therapy to transplant; about half of patients who achieved a CR proceeded to bone marrow transplant. We also saw that patients who had a transplant after receiving inotuzumab ozogamicin had prolonged survival compared with those who did not go on to transplant.

What are the eligibility criteria for transplant?

Transplant eligibility is a moving target; no hard and fast rule exists. Age is 1 factor, but it's not only about biological age; other comorbidities factor in [to this decision], too. It really comes down to the risk-benefit ratio. Transplant may offer the best chance of a cure, but it can also cause the most harm. We also consider the fitness of the patient. We can use some comorbidity indexes, but again, they’re not objective measures. These days, almost everyone will have a donor available, whether it's an unrelated donor or haploidentical. Another factor is patient willingness. Some patients look for alterative therapy, whereas others want transplant because they’ve heard good things about it or have family members who have done very well with it.

Could you discuss some of the agents that are being used in the relapsed/refractory setting?

We now have 2 approved agents that we can use: blinatumomab and inotuzumab ozogamicin. Deciding between these agents depends on several factors. We have to consider patient factors, disease factors, the ultimate goal of the therapy, and whether transplant is an option after receiving these therapies. These agents are quite effective, but they’re still used as a bridge to transplant; they're not curative.

There are adverse events that we have to be kept in mind, such as veno-occlusive disease with inotuzumab, and some of the cytokine release syndrome and neurological toxicities that we see with blinatumomab, although these events tend to be transient and reversible. Careful evaluation is necessary, which is why patients are referred to specialized centers. You want to choose the right therapy. You don’t want the patient going to transplant in bad shape. Genetic factors can also influence your decision one way or another. CAR T-cell therapy is not yet approved [for use in the clinic], but it's available within the context of clinical trials. That could be a third option for these patients. Eventually, we're going to get randomized data comparing CAR T-cell therapy with blinatumomab or inotuzumab ozogamicin in the relapsed setting. Hopefully, once those data become available, we will know which agent should come first.