The Evolving Treatment Landscape for ALL 

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EP: 1.The Evolving Treatment Landscape for ALL 

EP: 2.Using MRD to Monitor Therapeutic Response in  ALL 

EP: 3.The ZUMA-3 Trial: Study Design and Patient Population

EP: 4.The ZUMA-3 Trial: Efficacy and Safety Results

EP: 5.The ZUMA-3 Trial: Clinical Endpoints

EP: 6.The Potential Future Impact of CAR T Cell Therapy in Adult ALL

Eunice Wang, MD: Hello, my name is Dr Eunice Wang. I’m the chief of the leukemia service and professor of oncology at the Roswell Park Comprehensive Cancer Center in Buffalo, New York. I’m here to discuss the results of the ZUMA-3 trial for adult patients with acute lymphocytic leukemia [ALL] in the relapsed and refractory setting.

Over the last few years, the treatment landscape for patients with relapsing/refractory B-ALL [B-cell acute lymphocytic leukemia] has dramatically changed. There have been numerous paradigm-changing treatments and agents, which are now considered standard of care. These include the adoption of immunotherapy; specifically, CAR T cells for treatment of our younger patients between the ages of 1 and 25 with relapsed disease. We’ve also seen the advent of immunotherapy in the form of antibody-based therapies; specifically, inotuzumab, which is a CD22 antibody-drug conjugate, as well as blinatumomab, a CD3/CD19 bispecific antibody, which works by activating the immune system.

These agents have not only been used in the relapsed/refractory setting, but are now entering the arena for treatment in the upfront as well as consolidation realm. Blinatumomab has also been shown to be highly effective for treatment of ALL patients with minimal or measurable residual disease [MRD]. Another transformation in the field has been the adoption of MRD positivity as a new, and potentially most important, prognostic indicator of treatment response and overall clinical outcomes in B-ALL.

Bijal Shah, MD, MS: There’s no question that therapy for relapsed B-ALL is rapidly evolving. We now have the introduction of blinatumomab and inotuzumab into the space. As I’ll share with you later, I hope there will be an approval for CAR T-cell immunotherapy for adults with a relapsed B-ALL. The introduction of these agents into the relapsed space, and their effectiveness in this space, has necessitated trying to bring them into earlier lines of therapy. We’ve seen that with blinatumomab having been integrated in the ECOG [Eastern Cooperative Oncology Group] 1910 study. We’re waiting for that readout.

We also have Nicola Goekbuget [MD’s] data showing that blinatumomab can now be used for patients who fail to clear MRD, after some component of their frontline chemotherapy. Then, they would take patients through 3 phases of therapy, and if they still had some residual MRD, they could be considered for blinatumomab as a salvage. This was with levels of disease well below the standard 5% blast threshold that we have used for decades and was a major step forward.

We’re now similarly trying to understand how inotuzumab will perform in these settings. What will it do in the context of MRD? What will it do in the context of frontline chemoimmunotherapy? All of these approaches will hopefully allow us to reduce the intensity and the duration of chemotherapy as we go forward. If we’re still talking about 3 years of chemotherapy for all adult patients with ALL 5 or 10 years from now, I’d worry that we’d made a mistake and hadn’t landed where we need to land. We must find a way to simplify this for our patients.

We’re starting to see—not just in these studies, but through studies done at The University of Texas MD Anderson Cancer Center—an idea of what this might look like. I’m specifically referring to data presented by Elias Jabbour, MD, Nicholas Short, MD, and others looking at the mini-CVD/inotuzumab combination followed by blinatumomab consolidation. It’s an attempt to dramatically reduce the intensity of hyper-CVAD, shorten the total duration of hyper-CVAD, and use the novel agents to help carry us through the process so that patients can achieve durable remission without multiple years of therapy.

In terms of unmet medical needs, the big question is how we push beyond where we’ve been. When we talk about survival in adult ALL, if we go to the SEER index [Surveillance, Epidemiology, and End Results Program], we’re still talking about roughly 40% survival for adults; 20% and above with newly diagnosed acute lymphoblastic leukemia. This is where I’m hoping the promise of these novel agents will allow us to redefine this number, but I don’t think we can look at that number and say we’ve been wildly successful. We haven’t. We were around that number in the early 2000s, and likely before that, as hyper-CVAD was first developing, as CALGB [Cancer and Leukemia Group B] through successive iterations was performed. We’ve been stuck at this survival estimate for far too long. A major unmet medical need is improving survival for adults with ALL. This is why I come back to the idea of integrating novel agents like inotuzumab and blinatumomab, and hopefully, as we go forward, CAR T-cell immunotherapy to facilitate that.

For the first time, we saw some data that suggested we may be getting there. I’m going to refer to an MD Anderson clinical trial that was presented by Nicholas Short at the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting. This was a combination of ponatinib and blinatumomab that was given to patients both in the relapse and newly diagnosed settings. In some senses, it’s similar to the dasatinib-blinatumomab study that was recently presented by Robin Foà, MD, and colleagues in the New England Journal of Medicine. The stark difference here is the patients did not go on to allogeneic stem cell transplant consolidation as a matter of routine. In fact, this was used as definitive therapy without transplant or Philadelphia [Ph]-positive ALL. This is a major step forward in redefining the intensity of therapy and using our novel agents to get there.

We have, for many years, operated with the assumption that patients with Ph-positive ALL uniformly need allogeneic stem cell transplant consolidation to achieve long-term survival. I’m hopeful that this study will challenge that. As we evolve in the CAR T-cell therapy space, I’m hopeful that we will also begin to use this approach for the non Ph-positive patients and begin to ask critically whether we can adapt regimens for higher-risk patients in particular—be it p53 or Ph-like—so we can also step away from the standard of allogeneic transplant consolidation. For now, the question of transplant remains an experimental one, meaning we’re still trying to learn this from clinical trials. Hopefully, we will have some answers in the years to come.

Transcript Edited for Clarity