Integrating Immunotherapy Into Frontline ALL Treatment

Mark R. Litzow, MD

Significant advancements and ongoing research in the B-cell precursor acute lymphoblastic leukemia (ALL) space are aimed at integrating immunotherapies into frontline treatment regimens. At the 2024 Society of Hematologic Oncology Annual Meeting, Mark R. Litzow, MD, highlighted the significant strides made with 2 key immunotherapy agents: blinatumomab (Blincyto) and inotuzumab ozogamicin (Besponsa).

Blinatumomab is a bispecific T-cell engager that combines antibodies targeting CD3 and CD19 to direct T-cells to leukemia cells. Inotuzumab is an antibody-drug conjugate that links a CD22 antibody with a potent DNA-damaging agent. Both treatments, previously approved for relapsed/refractory ALL, are now being evaluated for their effectiveness in earlier treatment stages.

In his presentation, Litzow highlighted the ECOG-ACRIN E1910 trial (NCT02003222) which included 488 patients with Philadelphia chromosome-negative B-cell precursor ALL.¹ Initially, patients enrolled in this trial were treated with 2 months of induction chemotherapy. Patients who achieved a complete remission were then randomized to receive either standard consolidation chemotherapy or a regimen combining chemotherapy with blinatumomab.

Results showed that the combination of blinatumomab and chemotherapy led to a 3-year overall survival (OS) rate of 85% vs 68% with chemotherapy alone. This OS improvement led to a new FDA indication for blinatumomab, with the agent now approved for use in the consolidation phase of treatment.²

In an interview with Targeted Oncology^TM, Mark R. Litzow, MD, professor of medicine in the Division of Hematology at the Mayo Clinic, discussed the incorporation of immunotherapy into upfront ALL treatment.

Targeted Oncology: Can you discuss the topic of your session at the SOHO 2024 Annual Meeting?

Litzow: I spoke about frontline immunotherapy in B-cell precursor acute lymphoblastic leukemia. There have been major advances in the treatment of B-cell precursor acute lymphoblastic leukemia with the incorporation of immunotherapy. It is primarily focused on 2 agents: one is blinatumomab, which is a bispecific T-cell engager molecule. It combines a CD3 antibody and a CD19 antibody and brings a T-cell in proximity to the leukemia cell. The other is inotuzumab, which is an antibody-drug conjugate, a CD22 antibody linked to a DNA damaging agent, calicheamicin. These are both approved in the United States for relapsed/refractory acute lymphoblastic leukemia and have shown significant efficacy. There has been interest in moving it into the frontline setting. Many of the studies have combined these with chemotherapy in different schedules.

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There are also emerging studies using them by themselves without any chemotherapy, either alone or combining them. There was a very interesting study presented giving inotuzumab initially to older patients with B-cell ALL and then, depending on their response, and adding blinatumomab, and this has shown a high complete remission rate and encouraging survival.

Can you discuss the ECOG-ACRIN E1910 trial?

In my presentation, I presented a study that I had the privilege of leading. It is called the E1910 trial through the ECOG-ACRIN Cooperative Group. This was a National Clinical Trials Network

intergroup trial in the United States. We took patients between the ages of 30 and 70 with B-cell precursor ALL, and we enrolled 488 of these patients. These patients were Philadelphia chromosome-negative, and we gave them 2 months of induction chemotherapy. If patients achieved a conventional morphologic complete remission, they stayed on study. If they did not, they went off the study.

We had an 81% complete remission rate. They then got an intensification cycle of chemotherapy for [central nervous system] prophylaxis, and then we assessed their measurable residual disease, or MRD status, by flow cytometry. If they were MRD-negative, we randomized them to get the control arm of 4 cycles of conventional consolidation chemotherapy followed by maintenance therapy, or we gave them the same 4 cycles of consolidation chemotherapy, but added 4 cycles of the blinatumomab, which is given by a continuous [intravenous] infusion for 4 weeks. So, those patients got 2 cycles of blinatumomab when they were randomized, then 3 cycles of chemotherapy, then another cycle of blinatumomab, another cycle of chemotherapy, and then the fourth cycle of the blinatumomab. They then went on to maintenance therapy, and again, either group of patients could go onto an allogeneic transplant if their physician felt that was indicated. About 20% of the patients did go for a transplant.

What were the findings from this study?

We found that from the time of the randomization, the 3-year overall survival in the blinatumomab plus chemotherapy patients was 85% compared with 68% for the patients that got chemotherapy. This was a highly significant difference. The P value was 0.002, so this is encouraging for us to see. Amgen, which is the supplier of blinatumomab, took this data to the FDA and got a new indication for blinatumomab. It is already approved for [patients with] relapsed/refractory and MRD-positive [disease], and now, it is approved in the consolidation phase of chemotherapy. The addition of blinatumomab to chemotherapy in this setting has shown improvement in survival and has been a major advance.

Now, what we did find in the study was that of the 488 patients that we enrolled at the beginning, only 286 patients made it to the randomization phase. Of those 286, 62 were MRD-positive. We were going to randomize those patients, but when the FDA approved blinatumomab for MRD-positive disease, we no longer randomized and assigned them. We had 62 of those patients, and then there were 224 MRD-negative patients, 112 in each arm. The point I make here is that if we can move the immunotherapy up earlier in the course of treatment, we hopefully will be able to increase the response rate and lessen the number of patients that we lose from chemotherapy. That is the trend in the field, to move immunotherapeutic agents up earlier in a treatment course. The hope is that eventually we—and we are already starting to see this—can lower the amount of chemotherapy that we give. Whether we would eventually be able to completely eliminate chemotherapy is not known at this time, but it may be a possibility in the future.

What are the next steps for research in this space?

It is moving immunotherapy up earlier in the course of treatment. That is already starting to be done, particularly in older patients. We have to be more cautious in younger patients, because those patients obviously can have a long lifespan, and we want to make sure we don't compromise their treatment. But the trend is to move the immunotherapy up earlier in the course of treatment, either right after some initial chemotherapy, or to give the immunotherapy upfront, and then follow with some chemotherapy in these younger patients.

The other immunotherapy that I have not talked about is [chimeric antigen receptor (CAR)] T-cell therapy, which is also efficacious in B-cell precursor ALL, and the possibility of moving that up into the earlier phases of therapy. Right now, it is approved for patients [with] relapsed/refractory [disease] and have failed some other treatments. I think moving CAR T-cell [therapy] up early in the course of treatment also has the potential for tremendous benefit.

What are some of the biggest challenges in incorporating immunotherapy into treatment?

There are some unique toxicities with these agents. In the study I described, the E1910 trial, even though the patients were in remission with the blinatumomab, we did see more neuropsychiatric events, some seizures, headaches, confusion. So, monitoring carefully for some of those unique toxicities.

These agents are [also] expensive, so being able to seek reimbursement and make them available to many patients who might not otherwise have the opportunity to get them is also important. The blinatumomab right now is given intravenously by a 4-week infusion, so patients have to wear an infusion pump. There have been some very preliminary studies giving the blinatumomab subcutaneously, and so if those develop in a favorable direction, that might ease the administration of the agent and make it more accessible as well.

How do you determine which patients are most likely to benefit from upfront immunotherapy?

It is looking like most patients will benefit. In my study, we did not see as much benefit for blinatumomab in older [patients]. We are not entirely sure why that is. We did have to give less of the conventional therapy to those patients because of some [adverse] effects that may have influenced things. Older patients tend to have more high-risk features, so that may have impacted things. I do not want to make too much of that fact that we did not see as much benefit in the older patients, but we do need to continue to look at that. Giving these agents by themselves without a lot of chemotherapy does seem to benefit those patients, but

we do have to be sensitive to the age of the patients and their tolerability of these regimens.

For a community oncologist, what is the most important for them to know about this topic?

We have to make sure that they are comfortable with treating ALL. ALL is not the most common leukemia [in adults], so community oncologists may not see it as often. I think if they are comfortable treating it, they are certainly able to do that. They should be hopefully familiar with these agents, so that they know some of the unique [adverse] effects and can do some of the preventive strategies that we have to help lessen the toxicities.

Oftentimes, community oncologists will refer those patients to a tertiary center or an academic medical center and get their therapy started there. Then, they can help with some of the subsequent therapy, because courses of therapy still take many months. Having a partnership with an academic medical center, I think, could optimize the treatment of the patient and allow them to spend more time closer to home as well.

REFERENCES:

1. Litzow MR, Sun Z, Mattison RJ, et al. Blinatumomab for MRD-negative acute lymphoblastic leukemia in adults. N Engl J Med. 2024;391(4):320-333. doi:10.1056/NEJMoa2312948

2. FDA approves blinatumomab as consolidation for CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. News release. FDA. June 14, 2024. Accessed September 12, 2024. https://tinyurl.com/3px58wm4