Chief of the leukemia service and professor of oncology at the Roswell Park Comprehensive Cancer Center

Eunice Wang, MD

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Videos

Eunice Wang, MD, and Bijal Shah, MD, MS, discussed unmet needs for adult patients with relapsed/refractory ALL and reflect on the current treatment landscape.

The Potential of CAR T-Cell Therapy in Adult ALL

Bijal Shah, MD, MS, and Eunice Wang, MD, discussed the use of clinical endpoints like CR, CRi, and CRh as they relate to the ZUMA-3 trial of CAR T cell therapy.

The Use of Clinical Endpoints in the ZUMA-3 Trial

 Regarding the key efficacy end points, we achieved our primary end point, which was overall response rate. This is a composite of complete remission [CR] and CR with incomplete platelet recovery [CRi]. This specifically was around 70%. The true CR rate was a little over 56%. The CRs were MRD [minimal residual disease]-negative. We weren’t able to get the MRD data from 1 patient, so we reported an MRD negativity rate of 97%. Importantly, the CRs were durable. When we look at duration of remission, this was quite prolonged—around 12 months overall—for all the patients, independent of whether they achieved a CR or CRi.

Importantly, these response data translated into a meaningful duration of remission, relapse-free survival [RFS], and overall survival. Specifically, in patients who achieved a CR or CRi, the median duration of response was a little over 12 months. For those who achieved a true CR—the majority of patients who achieved a response—we saw a median duration of response of almost 15 months. When we look at subsequent therapies, specifically allogeneic transplant, and censor for patients who underwent this procedure following CAR [chimeric antigen receptor] T-cell immunotherapy, we couldn’t show any benefit. In fact, at the data cutoff, 12 of the patients who achieved a CR/CRi were still in ongoing remission without having had a transplant. That speaks to the potential of this therapy as a definitive therapy. We won’t know until we have more data, more patients, and potentially even a randomization, rather than a simple statistical censoring, to help us understand the impact and the magnitude of benefit of transplant after CAR T-cell immunotherapy, but these are very promising.

When we think about the median RFS, there’s one thing I want to stress. We call it relapse-free survival according to this study design, but in terms of terminology, it equates to EFS [event-free survival] if you were to see it in a different study. We did not only study the RFS in responding patients. We studied it in all treated patients. Whether you want to call it RFS or EFS is fine. The median RFS was around 12 months. It was around 14 months in patients who achieved a CR or CRi.

Median overall survival was outstanding. The median was 18.2 months for the group. In those who achieved a CR or CRi, we haven’t yet reached median survival estimate. For the types of patients we enrolled, recognizing many had seen prior inotuzumab or prior blinatumomab, transplant and the like, these data are quite remarkable. I’m hopeful that this is going to be sufficient to merit FDA consideration and approval so we can begin utilizing this for our patients.

 The efficacy shown with this regimen was extremely high, with 71% of the 55 patients experiencing a CR or CRi following a single infusion of Kite CAR T cells. Currently, 31% of these patients remain in remission and are getting ongoing therapy. The median duration of the remission was also remarkable, with patients having responses lasting 12 months. Median relapse-free survival was over 12 months. Median overall survival for the patients was an impressive 18.2 months. To place this in context, our other treatments for relapsed/refractory B-ALL [B-cell acute lymphocytic leukemia], such as inotuzumab or blinatumomab given as single-agent therapies, have been associated with a mean duration of response or median overall survival ranging from 5 to 7 months. In my opinion, an overall survival of 18.2 months with this cohort after a single infusion was impressive. Median duration of the follow-up for these patients was also very reasonable: over 16 months of follow-up.

Adverse events were described for this patient population and may be of particular interest to community physicians and other providers. Half of patients developed anemia or neutropenia. About a quarter of patients developed immunological toxicity; specifically cytokine release syndrome [CRS], a neurological toxicity related to therapy. Immunological CRS and neurotoxicity greater than or equal to grade 3 and above generally occurred on days 5 to 9 of therapy and lasted a median of 7 days. These toxicities were largely reversible with administration of steroids and early administration of inotuzumab. However, there were 2 grade 5 events: 1 patient with a fatal brain herniation and a second patient with a septic syndrome. Overall, 10 out of the 55 patients proceeded on to subsequent allogeneic stem cell transplantation. The data, when censored for allogeneic transplantation, was not altered, with the median overall survival and duration of response remaining 18 months and 12 months, respectively.

When we talk about the potential practical implications of this therapy, a single infusion of this CAR T cell was associated with a significant grade 3 and above cytokine release and neurological toxicity in 25% of patients. The high efficacy rate of 71%, as well as the particularly long durability of these responses—lasting 18 months and, in some cases, has not yet been reached in the responding patients—is very impressive. As mentioned previously, we would anticipate that salvage chemotherapy, particularly for patients who had failed 2 to 3 lines of therapy, would be highly ineffective with only 10% to 20%, or 30% at best, of patients having a response to salvage chemotherapy following upfront chemotherapy.

Blinatumomab has been shown to have high response rates, particularly in patients with low-level disease, but the duration of these responses is only a matter of months. Similarly, with inotuzumab, we see limited durability with high response rates up to 80% in patients with first relapse B-ALL, but durability of response lasting only a matter of 6 months. Therefore, these data are highly encouraging and promising and are likely to set a new landmark in our treatment of relapsed and refractory disease in adult patients for whom CAR T-cell therapy, up until now, has been limited to only individuals younger than 25 years of age.

Bijal Shah, MD, MS, and Eunice Wang, MD, discuss efficacy results of the ZUMA-3 trial of chimeric antigen receptor (CAR) T-cell therapy for acute lymphocytic leukemia (ALL), and review key safety data.

Safety and Efficacy of the ZUMA-3 Trial

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 ZUMA-3 was a phase 1 to 2 multicenter study of the safety tolerability and preliminary efficacy of KTE-X19 CAR T cells for the treatment of patients with relapsing/refractory B-ALL [B-cell acute lymphocytic leukemia] whose cells expressed a CD19 surface marker. This study enrolled patients above the age of 18 who had documented presence of greater than 5% morphologic ALL [acute lymphocytic leukemia] cells following prior therapy. Patients needed to have appropriate ECOG [Eastern Cooperative Oncology Group] performance status and no significant organ toxicity. Patients with multiple lines of therapy, including prior allogeneic stem cell transplantation, were eligible for this study.

The treatment regimen consisted of a single infusion of the Kite CAR T cells. The primary endpoint of the study was obtaining CR [complete remission] vs CR with incomplete count recovery [CRi]. The secondary endpoints were overall survival, event-free survival, and duration of remission. Safety profiles and adverse events, particularly immunological toxicities, were monitored closely and quantified as well. The phase 1 portion of the study as well as the dose escalation and establishment of a phase 2 dose have been reported at prior meetings.

At the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting, Dr Shah and colleagues presented the results of the phase 2 expansion cohort of this multicenter study. This cohort described the outcomes of 55 patients who received at least 1 Kite treatment infusion following conditioning regiment. The end points were CR, CRi, relapse-free survival, median-free survival, and duration of remission. The patients enrolled on this study ranged from 18 to 84 years of age, with a median age of 40 years. 47% of all patients had received 3 or more prior therapies. All of them had greater or equal to 5% per bone marrow blast. ECOG performance status was 0 to 1. All of these patients had received a single infusion. Up to 71 patients had initially been enrolled on this study, but not all 71 eventually received treatment; largely due to interim adverse events or toxicities and disease progression.

 Thanks for inviting me to speak about the ZUMA-3 clinical trial. We were happy to be able to present these data at ASCO and have the data published in the 

. The ZUMA-3 clinical trial is a study of CAR T-cell immunotherapy for adults with relapsed B-cell ALL. This was a multicenter international study and the first of its kind to explore the benefit of CAR T-cell immunotherapy for adult patients. We required patients to have morphologic evidence of disease—greater than 5% blasts—to enroll. The blast burden in enrollment was around 65%. Once patients enrolled, they would undergo prescribed bridging therapy followed by standard fludarabine and cyclophosphamide conditioning, and then the CAR T-cell infusion.

Patients were allowed to come on with central nervous system [CNS] disease, but it needed to be CNS1 or CNS2. We did not allow patients with CNS3 disease to enroll in the study. With that said, we allowed patients with Down syndrome. We allowed patients with Philadelphia-positive and Philadelphia-negative disease. We tried to be as inclusive as we could in terms of eligibility to ensure patients would have the opportunity to receive this therapy.

Regarding prior lines of therapy, patients could come on if they were primary refractory—meaning no response to their initial course of chemotherapy—or if they had 2 or more prior lines of therapy with remission in between. They had to be in the third line or beyond. When we look at the patients we enrolled, we had a median age of 40, with the oldest patient being 84 years of age. Almost half of the patients had prior blinatumomab, which was permitted as long as they had preserved CD19 expression. A similar number of patients had prior allogeneic stem cell transplant. About a quarter of the patients had prior inotuzumab. About a third of the patients came on with primary refractory disease. This was a tough population when we look at those who went on to receive the CAR T-cell infusion.

Eunice Wang, MD, and Bijal Shah, MD, MS, discuss the overall study design and patient population of the ZUMA-3 trial of CAR T-cell therapy in adult patients with R/R ALL.


ZUMA Trial of CAR T-Cell Therapy in R/R ALL

 Today, with the increased surveillance by MRD [minimal residual disease] for the treatment of B-ALL [B-cell acute lymphocytic leukemia], clinicians are increasingly viewing MRD status as opposed to frank morphological disease as potentially an indicator of primary refractoriness. For example, a patient who receives up-front induction chemotherapy and consolidation therapy for B-ALL in the adult and pediatric settings would be expected to have morphological complete remission rates of over 90% with standard chemotherapy options.

However, although those patients have morphologically negative disease, the MRD status is perhaps a better indicator of whether that patient truly has achieved a therapy response. In the setting of somebody achieving a morphological response with standard therapy but remaining MRD-positive, this is increasingly being viewed as equivalent to primary refractory frank morphological disease status in terms of its implications for management and overall prognosis.

 MRD monitoring in acute lymphoblastic leukemia is critical. We now understand that very low levels of disease can culminate in relapse. These levels of disease are well below our standard methods for detection, be they 4-color flow cytometry or morphology. In the United States, we’ve now largely moved toward MRD-based flow. This means a minimum of 6—typically 8—color flow cytometry to allow us to quantitate blast down to the 0.01% threshold.

We’re now seeing new technologies emerge, including the Adaptive clonoSEQ platform that uses next-generation sequencing [NGS], that allows us to get even lower, down to the 0.0001% threshold, or 1 x 10-6. This is extraordinarily powerful. We have data in pediatric ALL presented by Michael Pulsipher, MD, and colleagues showing that detection down to this level can predict who is more likely to relapse in the context of allogeneic stem cell transplant. We’ve known for years that using the quantitative PCR [polymerase chain reaction] and BCR-ABL going down to this level is also predictive of clinical outcome. I have little doubt that we’ll see the same thing emerge with serial studies now of this NGS platform, all the way down to 1 x 10-6.

The nice thing about the NGS platforms is just as we found with the quantitative PCR for BCR-ABL, we can now assess this on peripheral blood. The sensitivity will be lower, but the ease with which we can do this now allows us to more easily monitor for MRD in our B-ALL patients as they’re proceeding through therapy. I hope this will allow for quantitative assessments that capture relapse early.

You heard me say that blinatumomab is now approved for MRD relapse of B-ALL. It’s fascinating. Our pediatricians have beat us on this front. They’ve also found that CAR [chimeric antigen receptor] T-cell immunotherapy is similarly highly effective in the MRD setting. They had patients who had no detectable leukemia presented as part of a multicenter consortium. This is the PRWCC [Pediatric Real World CAR Consortium] for CAR T-cell immunotherapy. Liora Schultz, MD, presented this data at the 2020 ASH [American Society of Hematology] Annual Meeting. They looked at a cohort of around 200 patients. Nearly 50 had no detectable disease by flow cytometry but were simply considered high-risk. These patients benefited tremendously from CAR T-cell immunotherapy. When you look at their outcomes, my recollection is about 70% or 80% of them were still in remission after CAR T-cell immunotherapy with extended follow-up. You might argue, “They were already in remission, they didn't need it.” But as it turns out, they develop B-cell aplasia. When compared with their counterparts who had only 5% or higher blasts, the difference was profound. It was around 35% survival in that subset of patients relative to those who had lower blast burdens.

Putting this together, we now have 2 potent immunotherapy platforms. We have blinatumomab and we’re now seeing with CAR T-cell therapy evolve in the pediatric space, where we can argue that these are highly effective in the low disease burden setting. It emphasizes the need to identify these patients using these sensitive techniques and tools that are now at our disposal. This is unquestionably how we’re going to move the field forward, and how we’re going to ultimately improve that survival benchmark that I referred to earlier.

In terms of how frequently to monitor this, it’s a tough question. I don’t know that anyone has the right answer. Some of this is protocol-dependent. Whether you’re going to do it post-induction or post consolidation—which are more or less the standard—is irrelevant to me. Pick your time point and try to follow the protocol as closely as you can so the data you’re generating equates with the data that were generated on the study. Guidance for monitoring post-consolidation is still largely undefined. There’s value because picking up on the level of disease is something that is now actionable, but trying to identify those optimal time points so you are not running a test unnecessarily is still something we need to learn.

Eunice Wang, MD, and Bijal Shah, MD, MS, discussed the use of MRD status to assess therapeutic response and guide treatment decisions in patients with relapsed/refractory ALL.  

Using MRD to Monitor CAR T Response in ALL

 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.

 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 

. 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.

Eunice Wang, MD and Bijal Shah, MD, MS, discuss novel agents and emerging therapeutic approaches for the treatment of acute lymphoblastic leukemia.  