Bijal Shah, MD, MS, an associate member of the Department of Malignant Hematology at Moffitt Cancer Center, discusses efforts to combat resistance to BTK inhibitors in patients with mantle cell lymphoma (MCL).

Initially, BTK inhibitors made a significant impact on the MCL treatment paradigm, Shah says. This success resulted in an underlying assumption that there was no need to invest further in the space, as nothing could outperform these agents, which was a huge determent to patients, Shah notes.

The majority of patients with MCL who experience a BTK relapse do not do well, Shah adds. This is because the disease takes on a much more aggressive phenotype after relapse on a BTK inhibitor, and the lymph nodes progress rapidly, Shah explains. Additionally, if a patient has a leukemic variant, they could experience a rapidly increasing white blood cell count that is difficult to manage, according to Shah. This is a very proliferative phenotype, and resistance to BTK inhibitors has been reported very early in patients with MCL, Shah says.

Moreover, progress on combatting this resistance has been slow, Shah notes. However, CAR T-cell therapy could be a feasible option if patients can get through the manufacturing phase, which can be challenging, Shah says. Effective bridging therapies are still needed for this patient population, Shah adds. As such, it is beneficial that agents such as venetoclax (Venclexta) can be utilized, despite the lack of a formal label, Shah concludes.

Videos

Bijal Shah, MD, MS, discusses efforts to combat resistance to BTK inhibitors in patients with mantle cell lymphoma.

Dr. Shah on Efforts to Combat Resistance to BTK Inhibitors in MCL

Bijal Shah, MD, MS, associate member, Department of Malignant Hematology, Moffitt Cancer Center, discusses shortcomings with BTK inhibitors in high-risk mantle cell lymphoma (MCL).

Although oral BTK inhibitors, such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), have transformed the treatment paradigm of MCL, some patients with high-risk disease do not respond to these agents, says Shah. In addition, these patients are unlikely to respond to chemotherapy, Shah explains. 

 mutations, high Ki-67 expression over 50%, and blastoid or pleomorphic morphology, Shah says. As BTK inhibitors and chemotherapy are not suitable treatment options for this patient population, novel therapies and combinations strategies are needed, concludes Shah.

Bijal Shah, MD, MS, discusses shortcomings with BTK inhibitors in high-risk mantle cell lymphoma. 



Dr. Shah on Shortcomings With BTK Inhibitors in High-Risk MCL

What are the other investigational CAR [chimeric antigen receptor] T-cell therapies, not necessarily their names, but their mechanisms that are going to be different? 

The one the farthest along or that is beginning to be entering clinical studies is off the shelf, which may make a difference. These are already being investigated and being studied in multiple myeloma and diffuse large B-cell lymphoma. At ASH [the American Society of Hematology annual meeting], we also heard about UCART22, targeting a different antigen, but there is an allogeneic off-the-shelf product and there are many different types out there. 

Regarding off the shelf, without naming one clinical trial, there are different technologies that can modify the T cells, and there are ones with NK [natural killer] cell-based therapies derived from healthy donors, or core blood, or iPSC [induced pluripotent stem cell]-derived, the NK cells and T cells. There is a variety of different immune effector cell therapies, targeting either CD19 or CD22 in the case of B-cell malignancies. The big benefit is the immediate availability of the product, so we do not have to wait for the bridging chemotherapy with the manufacturing, whether it is 3 or 6 weeks. This time is always getting shorter. The bigger question, is it going to deliver as durable an outcome as autologous, the CD19 CAR product? For that, it will take a longer time for the data to read out.

Do you think we have solved the immunogenicity problem with the off-the-shelf product? My view is that they are very short-lived, and we have not fixed that problem yet, even though that was the goal.

Most of these studies are still early, so it is hard to say anything with any real confidence. The prospect of an off-the-shelf product is great in the idea that we can deliver it more quickly. But I have yet to see any data that convince me that the efficacy of these products is on par with the autologous ones.

Within a year we will have brexucabtagene autoleucel. It will be interesting to see how Kite and the FDA negotiate, and what that approval looks like. Will it be for all relapses or will they specify after 2 prior lines? My hope is after that, we start to see something we have never seen, which is exploring CAR T-cell therapy with this Kite product, in the context of the alliance, really bringing it forward. We try to understand now as we approach this in a broader context and then figuring out who is that high-risk patient population. How do we design a trial, in the context of the alliance, to now prioritize the CAR for these very high-risk patient populations, and what are the questions that we want to answer by virtue of doing so? That is where I would like us to see in a year because we will have an approval.

The CD22 autologous CARs are not as durable, but there is some excitement. The reason I am excited about them is in trying to understand where we are going to land in not 1 year, but in 2 or 3 years. Are we going to be doing work like what Rebecca Gardner, MD, has done at the Fred Hutchinson Cancer Research Center, where we are combining a CD19 and a CD22 CAR to try and avoid some of these antigen escape issues? Are we really going to focus on bispecific monoclonal antibodies? What is that CD22 CAR going to look like, and what is it going to teach us in terms of the biology of ALL [acute lymphoblastic leukemia] ...? 

One of the things I was impressed with at ASH was a discussion on CD58 and its impact on CAR T-cell responsiveness and the impact of failing to interact with CD2 on the CAR T cells. They are interesting data, and so much that we must learn still in this CAR T-cell space. As it relates to general allogeneic off-the-shelf CARs, they can be durable. Dr Park and I are part of one trial where we are using this now in patients with aggressive lymphoma and lymphoblastic leukemia. We are seeing some patients achieve deep and durable remissions. It is hard, and not everyone is going to experience that. We still have not put our finger on who is going to be the best responder, and so for now we are doing things like adapting the lymphodepletion to try to understand how we can contribute to the longevity universally and see better outcomes in that context. Allogeneic off-the-shelf CAR delivers at a lower cost point that promise of the patient just needs an MRD CR [minimal residual disease complete response] so they can get to transplant.

ASH Updates for CAR T-Cell Therapy in Acute Lymphoblastic Leukemia

 Let’s assume that brexucabtagene autoleucel [brexu-cel] is going to be approved. It doesn’t look to me like the approval of tisagenlecleucel is going to change, the approved indication. What do you see the field look like in a year or two?

Brexucabtagene autoleucel will ultimately get FDA approved for adults with ALL [acute lymphoblastic leukemia]. The specific details of the FDA label are going to have to be worked out between the manufacturer and the FDA. For those less familiar with some of these nuances, it’s worth stating that this product is, for all intents and purposes, the same as axicabtagene ciloleucel [axi-cel]. There is a different T-cell selection step that occurs on the back end of the manufacturing phase, but in terms of toxicity, hospitalization for a week, etc, if you’re used to giving axi-cel for large cell lymphoma, it’s more or less the same product. It’s also the product that just got approved for mantle cell lymphoma.

Where I hope the field is going is some attempt at collaboration between some of these different organizations and companies to try to understand, whether it’s through the cooperative group setting or some other mechanism, how we could potentially sequence these therapies in an optimal way. We’re on the cusp of having another potent therapeutic for this historically very challenging disease.

Inevitably what’s going to happen is these are going to creep into earlier lines of therapy as we get more data with mini hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] and inotuzumab, and as we get the results of ongoing studies from the cooperative groups using blinatumomab as part of the frontline therapy. Inevitably, CAR [chimeric antigen receptor] T-cell therapies are going to continue to move up earlier. How feasible they would be as a truly frontline therapy is debatable, but I suspect that’s where the field is going to be moving in relatively short order.

 In a year, if you’re a 35-year-old person with relapsed ALL, whether it’s early relapse or late relapse, will there be more than 1 CAR T-cell product for you?

 In a year it will be brexu-cel and only that one, short of investigational strategies. There are many other studies that are ongoing to try to improve upon the gains that have been made so far. At selected centers, as is often the case in modern oncology at particular academic centers, there may be a commercially available product and a clinical trial available that may be preferable, but not yet approved. 

Richard M. Stone, MD: Do you think that the approval of brexu-cel will make it more difficult to do research with other CAR T cells like the candidate from Autolus Therapeutics? If you’re 35 years old and you relapse, you’re going to get brexu-cel, you can’t get tisagenlecleucel. That leaves the newer products, like Autolus, which might have less toxicity. Where does that leave that, the third line?

Once we see the full data from the ZUMA-3 study to understand the toxicity profile, the durability of response, etc, there may be subsets of patients for whom we can know up front that there’s a high chance you could have serious toxicity or a low probability of response with brexu-cel. Even though we don’t know how well this third-generation bispecific CAR, that has a new manufacturing process, works, if we gave you the commercial product, your outcome is probably not going to be very good.

The trials will have to be written carefully to allow people to get these investigational drugs earlier because if we wait until they’re near dead, it’s not going to be good.

 This is the challenge in the field. Most of our protocols exclude prior CAR therapy, independent of the duration of response they had with that prior CAR. That challenges things moving forward because of the concept of clinical equipoise. Do you put a patient on an investigational phase 1/2 clinical trial, even if it has good data behind it, or do you treat them with the commercially approved product where you have a more mature data set? 

That’s like the debate between early use of a CAR T cell versus blinatumomab.

Evolving Field of Acute Lymphoblastic Leukemia 

 Let’s talk about some of the investigational CAR [chimeric antigen receptor] T-cell therapies, and which one is farthest along, perhaps KTE-019 [axicabtagene ciloleucel]?

The Kite product, Tecartus [brexucabtagene autoleucel], is the furthest along in adult ALL [acute lymphoblastic leukemia]. Autolus Therapeutics is on their heels with their product, with a plan to start a multicenter trial in the United States and Europe very soon. That’s the low-affinity CD19 CAR. But right now, Kite is leading in this space. Noelle Frey, [MD, MS,] and the group at the University of Pennsylvania did do a single-center phase 1/2 with the tisagenlecleucel product, which is promising in terms of the data. 

What we have right now are the phase 1 data from the US multicenter trial, and it’s very promising. These are heavily pretreated patients. The median number of cycles was 4. A lot of patients had prior BLIN [blinatumomab] and INO [inotuzumab]. Many of the patients had prior allogeneic transplant. We were still seeing high response rates, upward of 80%, essentially all MRD [minimal residual disease]-negative. We were able to deliver it with a manageable profile for CRS [cytokine release syndrome] and neurotoxicity. It was about 20% for grade 3/4 CRS and about the same once we started giving earlier corticosteroids for the neurotoxicity rates. We were able to push those down and successfully deliver this product even to older adults. I am happy with the data from phase 1, Dr Park and Dr Cassaday were part of that protocol.

What we hope is it joins this therapeutic armamentarium for ALL, so that we can have another option to throw into the mix. Then we can start to sort out these questions of how do you sequence and what’s the optimal place? It’s a powerful therapy.

Tisagenlecleucel is a CD19 CAR. It uses a 4-1BB costimulatory domain. It’s manufactured from bulk PBMCs [peripheral blood mononuclear cells]. Brexucabtagene autoleucel undergoes a process of T-cell selection first prior to manufacture, with the goal of filtering out the blasts. There the costimulatory domain is based on a CD28. What we see as a consequence, we think that the CD28 product expands faster and persists less in comparison to the 4-1BB product, which is going to have a slower expansion but then persist for a longer period.

Richard M. Stone, MD: Will it be more necessary to perform a second allogeneic transplant after the Kite product versus the Novartis product tisagenlecleucel?

 Adult ALL data are less clear. With the tisagenlecleucel in pediatric and young adult ALL, the ELIANA study, in which it got approved for up to the age of 25, the vast majority of those patients didn’t get transplanted and then were able to maintain a durable response, an EFS [event-free survival] of about 60% at the 1- and 2-year marks. Based on those data it doesn’t look like, at least in the pediatric and young adult ALL, you don’t need a 4-1BB now. Whether that’s driven largely by the 4-1BB or the biology of the pediatric and young adult ALL, that’s the part that we don’t know.

The Kite data, and our own Memorial Sloan Kettering Cancer Center data, which are very similar, but not the same manufacturing process…. Although our data showed there’s no overall survival benefit, the durability of remission tends to be higher with the transplant consolidation. It’s less clear with the 4-1BB versus CD28 question in adult ALL because there are conflicting data also from the Seattle Children’s [Hospital], coming from the children and adults. It may not be just about the construct, but the biology of the disease in this different age group also matters just as much.

Investigational CAR T-Cell Therapy in Acute Lymphoblastic Leukemia 

 Is there a concern about somebody who gets blinatumomab, and they respond or they don’t respond, but then they relapse? Now, this patient comes to you for CAR [chimeric antigen receptor] T-cell therapy; is that a problem? 

 It’s not a problem. There are a few points that are worth thinking about. There was the abstract we presented, the ZUMA data, showing that prior blinatumomab, even if patients received blinatumomab as their last line of therapy and were refractory, did not impact the likelihood of response to CAR T-cell immunotherapy using what’s now called the Tecartus [brexucabtagene, autoleucel] product from Kite. There were 2 abstracts at this American Society of Hematology meeting that reached different conclusions, both multicenter, retrospective studies. 

The first from Nirali Shah, MD, MHSc, from the NCI [National Cancer Institute], their consortium of investigators suggested that maybe there is an impact on both CD19 antigen density and the likelihood of response to subsequent CAR T-cell immunotherapy. One of the problems with that is they did not control for how many prior lines of therapy the BLIN [blinatumomab] group had. We’ve seen in now multiple studies, the more heavily pretreated the patient, the less likely even CAR T-cell therapy is going to work, and that may be a reflection of T-cell fitness or other factors that we haven’t assessed. 

The second multicenter paper came from Liora Schultz, MD, from the Stanford University School of Medicine group., It was around 200 patients, all who had received the Kymriah [tisagenlecleucel] product, and there was no association between prior blinatumomab exposure and the likelihood of the outcome. Interestingly, the most powerful feature for both obtaining response and maintaining that response was tumor burden. Anything over 5% blasts or any patient who had extramedullary disease had only about a 35% likelihood of maintaining their remission over time in comparison to the groups who had lower disease burden, where it was about 50%, similar to what was seen on the pivotal ELIANA trial. 

 If somebody uses BLINA [blinatumomab] to reduce the tumor, you’re happy with that.

 One thing to add to Nirali Shah’s abstract about the prior blinatumomab showing the lack of efficacy or the durability of CAR T is that the vast majority of the CAR was using either tisagenlecleucel or the 4-1BB containing CAR in the pediatric, young adult patients. It’s unclear and more difficult to generalize given the kind of controversial data, and Bijal’s data and our data looking at blinatumomab, to assume that prior BLIN [blinatumomab] is all bad. There may be cases that could downregulate and then be bad, but it may also depend on a variety of different disease factors, the type of CAR they will use, and the sensitivity of the CAR and scFv [single-chain variable fragment] to the particular CD19.

 To get CAR T cells after blinatumomab, you have to have both received and had a failure of blinatumomab. While it’s not like blinatumomab is a curative therapy for a high proportion of people, there are some people who derive durable benefit from it. It’s not appropriate to look at those data and say we need to be giving CAR T cells first and not blinatumomab. The margin of benefit wasn’t huge, and you’re ignoring the fact that some people can get blinatumomab and do pretty well long term with that approach and not ever need CAR T cells.

The challenge is trying to pick up on those patients. When we look at the median duration of response with INO [inotuzumab] and BLIN [blinatumomab], we’re talking about 3 to 4 months. It wasn’t a long remission, and so the question is can we deliver a therapeutic that gives us a longer remission safely? There are a lot of pieces to CAR T therapy. There’s apheresis, there’s collection, and there’s infusion. There are the typical pieces of the puzzle that we think about when we think about CAR T. I would not hesitate in using it in the frontline setting. We’ve seen durable remissions with CAR T-cell immunotherapy. Using effective therapy in the relapsed setting is exactly what we should be doing. There’s no reason not to withhold this.

We have to deal with the reality that CAR T-cell therapy is not yet approved in the first-relapse setting. We can debate about this business about relapsing after transplant in CR1 [first complete remission], but it’s not approved. Right now it’s a second-line therapy in people under age 25.

What’s remarkable on that same retrospective view by Dr Schultz, was how many patients received it as their second-line therapy. It was a high percentage.

 They presented similar data last year with a different group, showing in a real-world setting that it depends on how you define the second line because MRD [minimal residual disease] positive…. That’s how some of us are getting it approved.

 I’m talking about a patient who gets chemotherapy, is MRD-positive after some number of cycles of chemotherapy, and receives CAR T-cell therapy next.

CAR T-Cell Therapy Use in Second Line Acute Lymphoblastic Leukemia 

rearranged ALL and gets a transplant in first remission, then relapses. If they’re 25 or below, are they eligible for tisagenlecleucel?

That type of patient is eligible. If they’re first relapse they are and then they’re not primary refractory. When I mention CAR [chimeric antigen receptor] T-cell therapy, I was thinking in my mind about the clinical trial.

We’re going to talk about this first relapsed patient after transplant. Would anybody use a CAR T-cell investigational therapy in first relapse without having had a prior transplant?

If there were a clinical trial that provided that option, I wouldn’t hesitate. However, there are not any to my knowledge.

We have some of our own investigator-initiated CAR T-cell studies at The Fred Hutchinson Cancer Research Center that are fairly broadly written in terms of eligibility criteria. By the letter to the law, we have that option at my center, at least have in the past. Since these are still phase 1/2 trials, where we don’t have a lot of long-term follow-ups, the fact that we have two FDA [Food and Drug Administration]-approved agents with level 1 evidence, not great in terms of long-term efficacy, particularly for someone who hasn’t had a transplant yet, my usual practice would be to try either inotuzumab or blinatumomab initially and reserve the CAR T-cell therapy, be it on a study or as a standard product for subsequent lines of therapy.

If you were the FDA, you wouldn’t allow any studies to go through that allowed that type of patient to go on?

At least not 1 that was on a registrational path.

Do you think that there are some certain first relapse patients after a transplant who should get it, who would be appropriate to get a CAR T-cell therapy? There were post-transplant patients on the upfront, on the original TOWER and INNOVATE trial.

All 3 drugs have been used in all those settings. It’s more of a matter of what is the long-term goal for the patient, what is the subsequent line of therapy to help us choose between all 3 lines there. All of this, including the CAR T-cell therapy, which is under investigation over the age of 25 at this time, could be an option there. In the original study, and some of the ZUMA studies, some of the patients were allowed to not have to have BLINA and inotuzumab, although they almost always did because they had been mostly used in our trials. This is because it’s older, much before the BLINA-9 exposure or approval, that some of these patients actually received a CAR T-cell therapy ahead of that.

It’s a different era, so we have 2 approved drugs there. Theoretically, all 3 could be an option. It is difficult to study in these BLIN/INO-naїve patients because the current era that we are sitting in is at least 1 exposure. They have yet to be exposed to both. It’s hard to deny approved therapy that we know works well, especially in 80% CR [complete response], CRI [complete remission with incomplete hematologic recovery] rate with inotuzumab. We enroll in investigational therapy, especially if it’s an off-the-shelf in other CAR T therapies where we have less experience with those.

CAR T-Cell Therapy After First Relapse of Acute Lymphoblastic Leukemia 

Let’s discuss relapsed ALL, starting with relapsed Philadelphia-negative ALL. We never like to see that, but we have 3 agents approved in relapsed ALL— blinatumomab, inotuzumab, and at least for younger adults, CAR [chimeric antigen receptor] T-cell therapy.

This is something that not everyone is going to agree with me with. Independent of tumor burden, we tend to approach our patients with BLINA [blinatumomab] in the first relapse setting. The main reason for that has been the toxicity that we’ve seen with inotuzumab. Part of that may be a reflection of practice patterns, we’re incorporating INO [inotuzumab] into the later lines of therapy where it’s less likely to be effective and the marrow is more beat up. Because of the low toxicity profile, we tend to favor BLINA for first relapse. If they’re young, CAR T after that. If they’re older, then we’ll end up going down a CVD[cyclophosphamide, vincristine, dacarbazine]/INO or INO-based approach.

I’m less disinclined to consider inotuzumab in first relapse and it speaks in part to the issue of disease burden. Those first relapses are the ones that may come out of the blue with somebody who finished maintenance therapy, only coming in every 2 or 3 months, and all of a sudden their platelets are 6 or their white count is 30. That’s a situation where blinatumomab historically, can work but perhaps not as well and there’s more toxicity. Inotuzumab, on the other hand, works well except on the high ends of disease burden, and is reliable. If you can use it selectively and not expose patients to too many cycles, you can still safely administer that medicine with the goal of getting a patient to a stem cell transplant.

Let’s discuss the trials that might assess if CAR T-cells would be a useful therapy in first relapse.

There was one plan by Novartis, the famous OBERON trial, but it has not taken off yet. It’s a relevant question now as we’re discussing either INO or BLINA, which 1 to use in the second-line setting or the first relapse setting, and among the CAR T-cell therapy, too. We don’t have such an answer. Hopefully, we can get such trials to get going soon. I’m less disinclined to choose inotuzumab being more inclined to use it in the higher burden patients, typically. Even though BLINA can work, the efficacy rate is lower. I’ve been using the mini-CVD/INO combination that allows a slightly lesser dose of inotuzumab, and especially for those who have later relapse, but not on hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone]. In the combination of the chemotherapy and less dose of inotuzumab, we don’t know that for sure, potentially reduce the chance of VOD [veno-occlusive disease] after transplant.

Just because INO beat chemotherapy and BLINA beat chemotherapy doesn’t mean that they’re the best therapy to use. This is why adding chemotherapy to 1 of those regimens, such as mini-hyper-CVD and INO seems to be, there are good responses in the relapsed setting. Let’s address the concerns of using an INO-based regimen, either alone or with mini hyper-CVD for relapse when you’re going to take somebody to transplant.

The biggest concern is a sinusoidal obstructive syndrome or veno-occlusive disease, though there are other forms of hepatotoxicity that can happen with this drug. When it’s been looked at retrospectively, the things that seem to bear out is the highest risks for developing that potentially very serious complication are if you’ve had a prior transplant, if you’re older age, if you’ve had multiple prior lines of therapy, or underlying liver disease. Many of these you can’t do anything about. You can’t undo a patient’s alcoholic cirrhosis or you can’t undo the transplant that they got in first remission.

The things that you can do prospectively to reduce that risk that we know of is less exposure to the drug, avoiding particularly dual alkylator conditioning regimens for the subsequent transplant if the patient goes on to transplant. The data has yet to be borne out for inotuzumab, its related drug gemtuzumab ozogamicin. There’s more experience of providing more of a duration of time from the last treatment to the start of conditioning. Those are the things we typically do to try to mitigate that risk. Fortunately, I would say our experience has fared fairly well in terms of having a low risk of that complication. Ursodiol is another thing that people talk about using, though none of the studies have ever prospectively looked at whether or not that can help.

We use ursodiol. We don’t have any qualms about that. We use the mini-CVD combo because it allows for a lower dose of the inotuzumab. We start at the 0.3/0.3 rather than the 0.6/0.3 approach that was taken on the published study, with the goal of trying to reduce that total exposure. In regards to defibrotide during the transplant, it’s not something we commonly do.

Let’s move on to the difference between first relapse before the transplant or first transplant if someone had a transplant during CR1 [complete remission 1].

When working withpatients with a prior transplant, I’ll be less inclined to use inotuzumab or blinatumomab. I would favor CAR T-cells in that patient. I think INO and BLINA at best is a bridge to transplant. For the patient with a first transplant, it may not always be possible to get a second transplant and the efficacy may not always be good, especially if the CR duration from the first transplant was relatively short. I’m looking for more definitive therapy, not that CAR T-cell therapy has been proven to be a definitive therapy. We have a subset of patients with an INO and BLINA, but the more of those patients, a possibility at least with an autologous anti-CD19 CAR T-cell therapy. I’d be more inclined to use CAR T in the post-relapse transplant patients in the setting, whether there’s a bridge to a second transplant, and we’re hoping not, but hopefully as more of definitive therapy for them.

Approach to Managing Relapsed Acute Lymphoblastic Leukemia 

Let’s discuss older adults with ALL and the decision of transplant. If you have a patient that is 55 or older and you manage to achieve remission, MRD-negative or positive, do you transplant?

If they’ve become MRD-negative, it’s not just based on age factors alone. If they are MRD-negative there are a number of factors in terms of decision making for the transplants, MRD positivity, or the high-risk genetic features, I will consider the transplant.

 We did a retrospective analysis looking at this and transplant doesn’t seem to be a great idea for older patients because of the toxicity.

I generally do not do a transplant for older patients. I still consider it for Ph-positive disease. The Fred Hutchinson Cancer Research Center’s experience with reduced-intensity conditioning for ALL has been primarily, but not exclusively, for Ph-positive disease. The data that we have with that approach is relatively good. The challenge is to be eligible for a reduced intensity transplant, you’ve got to be in deep remission and those are the patients that are going to do well regardless of what you do. Then you have to consider the fact that many of those patients end up on a TKI [tyrosine kinase inhibitor] post-transplant. How much the GVL [graft versus leukemia] effect is truly adding is unclear. For fit and motivated older adults with Ph-positive ALL, I will typically recommend they undergo a transplant in first remission. We would consider giving a myeloablative preparative regimen to someone in their upper 50s if they were in great shape. For Ph-negative patients, unless we could do a myeloablative transplant in the setting of high-risk disease features, I would generally not do it.

Data has shown that Philadelphia-negative ALL is not very responsive to immunological therapies other than the obvious ones like blinatumomab and inotuzumab. But in terms of transplant, that’s a tough one.

We’re going to end up on some level thinking very critically on how we approach ALL in the older adult population. We’re probably going to end up adopting a schema like in DLBCL [diffuse large B-cell lymphoma] where there’s the fit, the unfit, and the frail. We have to decide based on that determination whether we approach them with curative therapy or palliative therapy. For the older adults, more often than not it’s palliative. We’re talking about upwards of a third of those patients who have 

 aberration, there may not be a significant benefit to an allogeneic stem cell transplant in the 

-mutant subgroup. Not to say we don’t do it in a younger patient where we’re worried about possible Li-Fraumeni syndrome … or even just hypodiploid ALL. It’s becoming clearer that those patients are exceptionally at a high risk of relapse after the allogeneic transplant, suggesting that this is just a group of patients for which there’s a strong unmet need.

Role of Transplant in Older Adults With Acute Lymphoblastic Leukemia

Let’s talk about MRD [minimal residual disease]-negative patients and if there any MRD-negative patients that you would think of transplanting in first remission.

0-range ALL [acute lymphoblastic leukemia]. Even if they become MRD-negative we worry, so I’d send them to transplant. Hypodiploid [ALL] is the other [group of patients] that I do [a transplant]. T

 and the Ph [Philadelphia chromosome]-like [patients] are the ones I’m struggling with. But with T

, there is data from [The University of Texas] MD Anderson [Cancer Center] [that] hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone] may not be as bad of a marker for frontline hyper-CVAD in the Ph-like [patients] when they become MRD negative. These are the 2 situations that I usually do send them to transplant, especially if they’re younger because the data is less clear and long-term follow-up is better with a transplant.

Let’s discuss T-cell patients and whether or not to send them to transplant.

In general, I send the early T-cell patients to transplant and those who have persistent MRD.

 When seeing a patient with B-cell ALL walk in the door, what are the factors that go into deciding whether to transplant?

My usual approach is to not recommend a transplant in first remission unless they have some feature about their disease that has demonstrated to be high risk. With Ph-positive patients, typically I’m recommending a transplant in first remission. 

 rearranged patients I’m recommending transplant in first remission, and ETP early T-cell precursor also. Those 3 are the ones if a patient is eligible for transplant, are the ones that I’m sending, irrespective of how early or how deep a remission they’re in.

The others, it ends up being more than an MRD-based decision. The other high-risk groups, like the hypodiploid, which is not a common situation in adults, and high prevalence of

 mutations in that subgroup. While it’s hard to extrapolate this data, there were back-to-back studies published in the 

 a couple of years ago that showed no clear benefit from those patients undergoing transplant in first remission. However, those were pediatric studies. The assumption that transplant is going to absolve all sins and work across subtypes is not true. There are biological subtypes where it isn’t effective and maybe that’s one of them. Beyond those handfuls of situations, those are the ones that I’m generally not recommending transplant unless they have persistent MRD.

I would automatically transplant a Philadelphia chromosome-like ALL patient, even if they’re MRD-negative. The 

s have a high propensity for relapse down the line. The big challenge is, what is MRD-negative? It’s with the sensitivity of the tools that we have in hand, we can get down to 1x10-4 with good flow, 1 x 10-6 with NGS [next-generation sequencing], but there are 6 logs below that that we’re not going to see. My experience has been that these 

s, even when we get them MRD-negative, have a strong propensity for relapse.

We wish we could succeed in transplanting almost everybody, but there are a whole host of psychosocial reasons why they don’t make it to the transplant. We’re probably transplanting around 20% or 30% of the patients that we see. We will succeed in curing around 35% of adults with ALL, and hopefully, we can do better by incorporating multimodality therapy. I consider allogeneic transplant to be part of that.

The Ph-like, not all patients, are going to get transplanted. The one thing is that pediatric regimen, I think the age groups with asparaginase-regimen the cure rate hopefully, at least the CALGB data shows a little bit higher. Depending on the frontline regimen that you may be using … response in terms of transplant. I certainly don’t transplant as many. The majority don’t get transplanted because luckily the majority are able to get MRD-negative with their front-line regimen—just over 50% or so depending on the regimen. So I think they would just count the MRD negativity rate and I think you end up being, well, it’s a minority but still by 30% to 40% of it belong to the high-risk category. Either because they are MRD-positive or because they are presenting with a 

[mutation] or other high-risk. Those are the ones we are considering for transplant, and of those not everybody makes it. They first have to convert and we would like to get to MRD negativity before sending to transplant.

There is a risk of not being able to get a relapsed patient into another remission, to consign everybody to transplant in first remission is a big deal. It’s a disease of younger adults where some of the results with the pediatric-inspired therapy, both from Dana-Farber Cancer Institute and the CALGB [Cancer and Leukemia Group B] study. Most of those patients don’t get transplanted. I tend to reserve it for beyond first remission, but if you miss the boat, you may miss the boat forever. It’s also tough to see somebody succumb to a first remission allogeneic transplant or have major toxicities, which can occur.

Managing MRD-Negative Acute Lymphoblastic Leukemia

MRD [minimal residual disease]—we all measure it, but what do we do with it? We’ll start with Jae this time. We have a young adult with ALL [acute lymphoblastic leukemia]who is given the 10403, and their MRD by flow was 0.04% or a point even higher after the initial therapy. Do you say, “Oh my God, I’ve got to do something different”?

 If they’re MRD positive at the end of induction 1, 2, or 3 months or closer to that mark, or they have hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone], if they have detectable MRD—whether it’s 0.01% or closer around that—I do switch therapy. Because the data are clear: The continuation of the chemotherapy is unlikely to benefit.

 I rarely switch therapy after 1 month. Perhaps with the CALGB induction 1—that’s how the trial was designed there—and our pediatric-inspired regimen we were using for 40- to 60 year-olds. We didn’t make the treatment decisions that would change until induction 2, which roughly falls on the 3-month mark; not after induction 1, but induction 2. I use the 3 months to complete and switch therapy to, in this case, blinatumomab for B-ALL [B-cell ALL] MRD positivity. I do switch therapy at that time and in conjunction with those we’re still working up the donor for a potential consolidative bone marrow transplant, especially for younger patients when they become MRD negative.

 What will you tell them at 3 months MRD positive but otherwise OK?

I would tell them that your disease is acting with the high-risk features with MRD positivity, with first chemotherapy refractoriness; the continuous chemotherapy is not going to reach the MRD negativity. The goal is to cure; we first have to cure MRD negativity. The best way to get there is blinatumomab in this setting. It’s unclear at this time whether blinatumomab continuation could be curative vs allogeneic bone marrow transplant.

Bijal, what would you do for a patient who’s MRD positive after getting chemotherapy?

 You tell them right then and there. How many seconds on blinatumomab [BLIN] do you give, Ryan?

It usually ends up being 2 for practical purposes. I’m not sure more than 1 is necessary, particularly for patients who are going on to a stem cell transplant. From a practical perspective—whether it’s identifying the donor or confirming response, even though around 80% of patients will be MRD negative after 1 cycle based on the BLAST trial—our transplant program wants to confirm that they’re MRD negative before they kick into gear in terms of confirming the donor. The time that it takes to do that, I’m usually starting the second cycle of blinatumomab. They might finish that completely or get a couple of weeks into it before the conditioning starts.

Bijal, what do you do about chemoprophylaxis in people who are going to have fairly early transplants?

The prophylaxis doesn’t stop. We’re giving 1 to 2 doses of intrathecal per cycle depending on where they are.

Let’s say they get a couple of cycles of hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]. They’ve probably gotten 4 doses of intrathecal. This hypothetical patient is going to need blinatumomab. Do you continue? How many total doses do you give before you do the transplant?

I’ll give 1 per cycle. If they’ve already finished 2 cycles and their CNS [central nervous system] is negative on those 4 initial doses of intrathecal, we’ll go for 1 intrathecal with each subsequent one.

So you’ll have a total of about 6 before the transplant?

 I do the same thing. Usually right before BLIN starts and right after BLIN finishes, there usually are about 2 cycles.

Managing MRD-Positive Acute Lymphoblastic Leukemia 

 Do you think this is done in the community, Ryan?

No, not as universally as I think we’d like. There are several barriers to that. Outside of academic practices, it’s not clear who is doing the bone marrow test, who’s ordering the test, and what laboratories are available to perform the test—whether it’s contractual obligations that the clinic has with a hospital or a reference laboratory. Another steep hill that we have to climb as an ALL [acute lymphoblastic leukemia] community is that for every other hematologic malignancy, with a few exceptions like APL [acute promyelocytic leukemia], MRD [minimal residual disease] is still generally a research tool.

While there are interesting and provocative data in CLL [chronic lymphocytic leukemia], myeloma, and to a certain extent AML [acute myeloid leukemia], ALL is the 1 disease where very few would debate about the standard nature of MRD in terms of making treatment decisions because it’s so rare. Many community doctors don’t necessarily see it, so they may just immediately assume MRD is a research test, so they’re not going to order it. It’s not uncommon for me to see a referral from a community practice where MRD is not being assessed at all, or certainly not in the manner that we’ve espoused here.

Do you even see ALL being treated in the community? We see AML. But ALL? What do you think about that?

 I used to think that with ALL therapy, why would anybody treat this if you see only 1 or 2 cases per year? But to my surprise, their first therapy they often get in not super-small communities, small or midsize centers that may see 1 or 2 patients with ALL—less than 10—a year. When you see it that infrequently, MRD is a level of concern because it’s not the standard for AML and any other disease. They don’t think about them. They might not have the equipment. For a disease that’s curable and first-line therapy matters, we’re trying to go out and educate that where you receive your first treatment matters. By the time we see the relapsed patients, it’s often too late. Not that I’m sure that I’m going to make a difference, but there are other things that we could have done.

I don’t see it in small community hospitals. But in midsize places like in northern New England, there are some cities there that will do it. But then when the patient goes bad, they come to Boston and it’s a hassle because they’re ripped away from their community. Maybe if they had started there it would have been better. What do you think, Bijal? Florida is a big state.

What we at Moffitt Cancer Center get is many patients who will receive their induction locally and then get transferred after that for a consultation. I empathize with the local provider. It’s not as if they’re not making the call: “Hey, I’ve got this patient, they’re sick, they need to be sent to a tertiary care center.” But oftentimes they’re young, they’re uninsured, they’re still working on the Medicaid or whatever it may be to support them through that process. Maybe they’re just too sick—their white count is 150,000 per mm3, and they’re trying to do whatever they can to temporize things.

I don’t know the answer. Insurance doesn’t pay for lodging. They sometimes don’t even pay for the medicine. How do you get a patient to your referral center from 600 miles away?

It’s very challenging. It’s part of a larger discussion.

A lot is patient driven too. Patients don’t want to travel long distances to receive treatment. They are ripped away from their social support which is hard for them. They’re looking for therapy that they can get closer to their homes. It’s up to us to develop such therapy that can be easily delivered wherever they are.

Treatment of Acute Lymphoblastic Leukemia in the Community Setting 

 Let’s move on to consolidation. Specifically, we routinely use MRD [minimal residual disease]. Ryan, in general, what technology do you use to measure MRD, and how do you use it?

I have the good fortune of working at the University of Washington Fred Hutchinson Cancer Research Center. Our in-house flow cytometry is 1 of 2 reference labs used by the Children’s Oncology Group, from whom much of our knowledge about risk-adapted therapy for ALL [acute lymphoblastic leukemia]using MRD is based in the United States. I am primarily using that assay. It is available as a reference laboratory for other sites looking for a good reputable place. I will also BCR-ABL, RT-PCR [reverse transcription polymerase chain reaction] for patients who are Ph-positive Philadelphia chromosome–positive as an adjunct. I have not routinely incorporated the next-generation sequencing [NGS] assay, the clonoSEQ assay from Adaptive Biotechnologies, mostly because I’m not quite sure what to do with that result. We saw some nice data from Nick Short, where they have retrospectively looked at how it can risk-stratify patients getting hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]. But I’m still a little unsure how to use that result to make treatment decisions. I have a hard enough time using MRD flow and hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] and other agents in adults to know what to do. I’m not sure that NGS adds to it.

When is the key time to look after the initial therapies?

For me, it’s within a month. If I’m using the C10403, it’s at the end of induction. For hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone], I do it after cycle 1A. We have data from our center and also from The University of Texas MD Anderson Cancer Center. Basically, the earlier you’re MRD negative, the better. Then I’ll check it again about 3 months, the end of remission consolidation for 103, and then after cycle 2B of hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]. I may do it sooner for patients who have a high burden of disease after induction if I’m a little nervous. But those are my standards.

We at Moffitt Cancer Center have adapted the Adaptive clonoSEQ assay for most of the patients. Unless they are transferred to us from another center, and they’ve already had some large burden of their therapy there—meaning hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] or whatever they receive locally. Provided we can get a good diagnostic marrow, and this is the case for most of our patients, we use the clonoSEQ assay.

This occurs at the end of induction, cycle 1A and 1B. There’s about a 10% MRD conversion. Nobody knows what that means yet, but there are some patients who convert after cytarabine, methotrexate based. This may be true among patients with T-ALL [T-cell ALL], so we tend to use post-1A and post-1B for our MRD monitoring.

If I have a very high-risk patient—a Philadelphia chromosome–like for example, or a 

, or someone who has a very low level of MRD postconsolidation, I may repeat that at later phases. But it’s more about what is going to be my approach to get them to the transplant.

I want to ask Ryan about the MRD-based flow. Do you have a cutoff for what you consider positive?

The assay that we have at the University of Washington conservatively estimates the level of sensitivity at 0.01%. That is the threshold I will use. I’m of the opinion that any residual disease is positive. Whether it’s at the very threshold of detection or 0.05 or 0.2%, I’m not sure there are substantial differences in those patients.

If you detect it, you’re saying it’s positive.

I wouldn’t go so far as to say I’d only consider it as a categorical dichotomist result. There’s some nuance in the numbers. But I’m not reassured by somebody who’s 3 months into therapy and their level of disease is 0.002%. That’s still a problem.

Bijal, the clonoSEQ. How do you look at that?

Same.Anything that is positive is positive. We found that even at levels of 10-6, those patients are at high risk of relapse.

Because it’s obviously more sensitive than the flow-based detection. We won’t worry that it’s too sensitive in any way, shape, or form.

The positive predictive value has been exceptional. If it’s positive, it’s real.

We’ll come back to that in a second when we talk about therapy. Jae, what do you do at Memorial Sloan Kettering Cancer Center?

We predominantly use flow cytometry as our MRD assay method, and then we are certified at the lab now. We’ve been fortunate to use them in conjunction. We are also using LymphoTrack, which is different from NGS the Adaptive Biotechnologies is using. But similarly, the sensitivity of 10-6 with an NGS. We struggle between the 10-4 and 10-6 or sometimes below that with a better sensitivity. But I agree with Ryan and Bijal: Any detectable levels certainly makes me nervous. What’s a good therapeutic option is the question that we’re struggling with, but it certainly raises concerns for these patients.

I typically do assess them at the end of the month 1 induction. Month 3 is particularly important because that certainly changes the therapy at that timing with a continuation of their current regimen. The 1 point is that MRD assessments should be done through the consolidation. Just because you’re MRD negative at the end of 3 months doesn’t mean you’re going to stay there. Continued monitoring for that is also important.

Role of MRD Testing in Acute Lymphoblastic Leukemia

A group that doesn’t have good answers is the Philadelphia-negative older adults, who can’t tolerate hyper-CVAD. But there’s some interesting data coming out of The University of Texas MD Anderson Cancer Center and elsewhere. Let’s start with Ryan. Have you changed your approach with older adults with Philadelphia chromosome–negative disease?

This is may be 1 of the most challenging patient populations right now. There are newer approaches coming down the pike, both from MD Anderson and US cooperative group studies. I have not yet routinely incorporated the mini hyper-CVD [cisplatin, vinblastine, dacarbazine]–inotuzumab combination, which has been published and was studied primarily in older adults. With many of these regimens, where these newer agents are being brought into the frontline setting, the incremental gain might be seen relative to added toxicity and potentially losing options down the road for relapses.

One thing we use at our center the University of Washington Fred Hutchinson Cancer Research Center, based on preliminary experience of a study we have going so far, at least for relatively fit older adults with Ph-negative ALL [acute lymphoblastic leukemia], they’re using dose-adjusted EPOCH [etoposide, prednisolone, oncovin, cyclophosphamide, hydroxydaunorubicin], a regimen that is fairly well known to many community oncologists. The study has been open for a few years. This is a group of patients for whom there isn’t a great standard. There have been some good successes, at least initially. It’s still a fairly toxic regimen, with cytopenias and some of the same issues that kind of occur with hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone], but it’s not quite as intense.

Bijal, what about in Tampa, for older adults with ALL?

We tend to use the DFCI [Dana-Farber Cancer Institute] protocol, and that is something that was brought forward. My colleague Julio Chavez wanted to explore its activity in our older adult patients, and we found it to be very effective with a lot of dose modifications.

Is that CVD [cisplatin, vinblastine, dacarbazine] and venetoclax?

No, this is the old pediatric-inspired regimen for older adults, the 1 that uses a dose-deintensified induction followed by consolidation with intensified CNS [central nervous system].

That’s the old Larson regimen that I think you’re referring to. I would think I would know that 1, but I don’t.

 It’s 7 consecutive asparaginase phases in consolidation.

That must be older than me, because I’m really old.

 It’s been well tolerated, and what we learned was the critical importance of deintensifying that induction. That’s where we’re losing a lot of our patients, during that induction phase. We’ve stepped it down. Most patients will receive VINC/DEX [vincristine, dexamethasone] or VINC/DEX [vincristine, dexamethasone] asparaginase as their induction, without the doxorubicin or the methotrexate component, and we’ve been quite pleased.

The mini-CVD [cisplatin, vinblastine, dacarbazine]–inotuzumab data are very interesting. It’s also toxic, and it’s hard for our older patients when they develop cytopenias, particularly when they’re prolonged, to carry them through that phase. It’s been a struggle to push that into the frontline setting for our older patients. The data are really good: I think it’s 70% at 1 year were in remission. But the survival was still only around 50%. They’re still losing a significant proportion of patients because of toxicity with that approach. Dr Hagop Kantarjian mentioned dropping it to 2 cycles instead of 4, and maybe that will be sufficient then to help to mitigate some of that toxicity.

The people over age 70 really can only tolerate, begin the first 2 cycles of mini hyper-CVD [cisplatin, vinblastine, dacarbazine]. It’s really tough. I’ve given it to some people, so I can certainly corroborate that. Jae, how do you approach older adults with Philadelphia [chromosome]–negative ALL?

 We at Memorial Sloan Kettering Cancer Center are using more of an INO [inotuzumab ozogamicin]/mini-CVD [cisplatin, vinblastine, dacarbazine]–based regimen between 60 and 65 [years old] and the 70-to-75 range. I rarely will get them through all 8 cycles of those. We do MRD [minimal residual disease] assessment after 3 cycles and after 3 months of treatment. Depending on the performance status and MRD status, we may convert into the blinatumomab consolidation for some. As Ryan alluded to, we are using a lot of our armamentarium there, but these older patients. We may not be able to consolidate with a transplant. There are some potential concerns, but with these are groups it’s too hard to get hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] and even dose-adjusted asparaginase, which we haven’t explored much. We used to have a protocol, but we have moved to the INO [inotuzumab ozogamicin]/mini-CVD [cisplatin, vinblastine, dacarbazine]–based induction followed by either continuation with chemotherapy or consolidation with the BLIN [blinatumomab].

 The next older-adult trial done by the cooperative groups led by Dr Marlise Luskin is going to be mini hyper-CVD [cisplatin, vinblastine, dacarbazine], INO [inotuzumab ozogamicin], the MD Anderson regimen vs the agreed-upon standard of care, which was dose reduced hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] as a control arm. The venetoclax plus mini hyper-CVD [cisplatin, vinblastine, dacarbazine] has had a very high MRD-negative response rate that was tolerable, but it was not deemed ready for prime time either.

Treating Older Adult Patients With Philadelphia Chromosome-Negative ALL 

 Let us talk about our approach to treating these patients. Let us say there is a Philadelphia chromosome–positive patient who is 30 years old. I would like to go around and see how people would treat that, because there are going to be some huge differences.

 We would call in an old-school approach. The best long-term data I’ve seen from any prospective trial in treating adults with Ph-positive ALL [acute lymphoblastic leukemia] were those from SWOG 0805, where hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] was given in combination with afatinib with a plan to proceed on to a myeloablative transplant in first remission. Outside the context of a clinical trial, that is typically how I will manage a young adult with Ph-positive ALL who was otherwise fit and wants to be aggressive. There are certainly some exceptions to that, but that would be the usual approach.

 We at the Moffitt Cancer Center, have adopted hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]–ponatinib combination especially for young adults in large part because it seemed to equate to a higher rate of MRD [minimal residual disease] negativity and a lower rate of transplant. The hope is to avoid that if possible. As more data are collected, whether that is going to be successful will be discovered. But the early data from the University of Texas MD Anderson Cancer Center group suggest that that was a highly effective mechanism to engender MRD negativity by 3 months.

 This is a little controversial, but for the younger guys, like a 30-year-old, we can do a TKI [tyrosine kinase inhibitor] plus chemotherapy vs dasatinib—or ponatinib later, but dasatinib plus a blinatumomab induction. I struggle to know what the right approach is. These patients are sent to transplant, especially the 30-year-old. I do not know whether they need it. The longest data are with a consolidative bone marrow transplant, although MD Anderson 2011-0030 hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] data have 73. There will be a longer follow-up soon without the transplants.

Because of this study, these patients are sent to transplant. Given the D-ALBA study that was recently published, dasatinib plus blinatumomab with high rates of molecular CR [complete response] rate, which is quite comparable to ponatinib plus hyper-CVAD rate. This spares chemotherapy altogether. The post-transplant outcome may be better in terms of the tolerability of the regimen and the fitness of the patient. Although these are younger patients, so it may not matter as much. These 2 approaches can be used leaning toward a blinatumomab-based approach. In some of these patients the trouble is whether they need a transplant. However, a blinatumomab-based approach is used even in younger patients.

 The D-ALBA approach has been used with the full induction for 85 days (about 3 months) and then giving them blinatumomab, regardless of their MRD status, followed by a stem cell transplant. This was recently used with a Harvard medical student who’s about 24 years old. 

 There was a lot of excitement about that combination. When you get published in the New England Journal of Medicine, you are doing something right. The issue seen from that study was the relative lack of conversion from MRD negativity after the dasatinib and prednisone induction. Whether that is some immunosuppressive effect of the preceding therapy, consider what the German experience has been in chemorefractory MRD with high rates of conversion to MRD negativity. There may not be as much efficacy out of the blinatumomab on the back end of that regimen as maybe otherwise seen.

For patients, because the risk of serious toxicity from chemotherapy in younger patients is quite low, at least in the modern era, there is less worry. The follow-up on that study is short when you consider particularly younger patient population where we have historical paradigms of established ways to treat these patients with a high rate of cure. It is a good option for patients, but not all are ready to wholesale incorporate it to everybody.

Richard M. Stone, MD: ECOG [Eastern Cooperative Oncology Group] will be leading the trial…comparing TKI hyper-CVD to the Italian approach. If people enroll in that trial, someday we will answer that question.

Treating Young Adult Patients With Philadelphia Chromosome-Negative ALL

 Hello, and welcome to this OncLive® Peer Exchange® titled “Integrating Newer Therapies Into Management of Adult Acute Lymphoblastic Leukemia [ALL].” I’m Dr Richard Stone from the Dana-Farber Cancer Institute in Boston, Massachusetts. Joining me in this discussion are my colleagues Dr Ryan Cassady, from the University of Washington Fred Hutchinson Cancer Research Center in Seattle, Washington; Dr Jae Park, from Memorial Sloan Kettering Cancer Center in New York, New York; and Dr Bijal Shah, from the Moffitt Cancer Center in Tampa, Florida. 

Today we’re going to discuss a number of topics pertaining to advancements in the treatment of acute lymphoblastic leukemia. We’ll discuss the latest research in the field and the impact of recent clinical trials, including those described at the ASH [American Society of Hematology] 2020 Annual Meeting. Our first topic is going to be the changing paradigm of initial therapy in the treatment of acute lymphoblastic leukemia. Obviously in this complex disease, we’ve learned a lot about heterogeneity in terms of molecular…and genetic classification.

I was wondering if I could ask Dr Cassady to start. Tell us how you view the complexities of ALL management.

 There are a lot of new data and new techniques coming out. Some of these are still waiting for more prospective validation or more data to mature to understand how to integrate them into routine practice. Right now, beyond establishing a diagnosis in the lineage, cytogenetic abnormalities, particularly the presence of the Philadelphia chromosome, and other cytogenetic abnormalities may have a prognostic significance. To a certain extent, some molecular features through genomic testing can be useful. However, that is still an evolving area. Beyond that, with a few exceptions perhaps, identifying the early T-cell precursor subtype of a T-cell ALL by flow cytometry is the key thing to look at in terms of disease itself when making initial therapy decisions.

 I agree. At the our place, they look at age and Philadelphia chromosome positive or negative, which gives 4 subsets. I’d like to ask Bijal: Do you care if it’s T vs B in the initial setting?

 I do, and in particular early T. There’s a benefit for asparaginase-based therapy in early T subset in particular. There may be benefits to asparaginase even extending beyond that early T subset, relative to more adult-centered protocols like the hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] protocol, asparaginase-based protocols, CALGB 10403, and other protocols like the ones developed by Dana-Farber. There’s an advantage to trying to integrate asparaginase into that treatment paradigm to try to get a better outcome.

 Are you saying you wouldn’t use asparaginase? Or would you use more of it?

 I would use more of it. In particular in the early T cell.

 We have really modeled ourselves on the University of Texas MD Anderson Cancer Center approach to the treatment of leukemia. They use a lot of hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]. The way it was initially done was if started with hyper-CVAD, if there’s MRD [minimal residual disease] by imaging—suggesting there’s still residual mediastinal mass, for example—or by MRD in the marrow, at that point add asparaginase usually on day 5 to the hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] protocol. Now, with the CALGB 10403 data set published, a lot of these cases begin with the CALGB protocol, so we’re integrating this asparaginase into the induction.

 At Dana-Farber, we give everybody asparaginase, so the T versus B, at least initially, doesn’t make a huge difference. Although the CALGB 10403 is used the next generation of CALGB protocol, which involves the randomized addition of inotuzumab, for those patients they have to be pre B-cell. Jae, how about Philadelphia chromosome–like ALL? Do you need to know that before you start therapy?

 You certainly don’t need to know that information before you start the therapy. We do get that information, which takes the different ways of getting. At our institution, we’re getting it by NGS [next-generation sequencing] and Archer FusionPlex with targeted RNA sequencing, flow cytometry, and FISH [fluorescence in situ hybridization]. It’s all a combination of different approaches to get some information. It is fortunate to not have to specify them. These pathology tests will be run automatically, but depending on the type of testing and assays, they can take a few days to a couple of weeks easily. We usually don’t have that information at the beginning of therapy. At this time it does not impact initiation of therapy. We also use ALL asparaginase-based regimen, at least for younger patients. The information is received midway through the therapy, and there are other ongoing trials in the COG [Children’s Oncology Group] and others, looking at the addition of a targeted therapy to see whether they improve the outcome. Maybe not necessarily the CR [complete response] rate, but event-free or the longer duration of remission for those patients. 

Until that data become available there will be no changes at the moment. The biggest struggle is when the patient becomes MRD negative, whether they convert to high risk and should a transplant be considered. This is 1 key area that we are struggling with right now: What are the true prognostic implications, especially with the newer therapy with inotuzumab and blinatumomab in the earlier lines of therapy.

 The issue of whether the MRD status after the first cycle or 2 of therapy trumps the biology is key.

Treating Older Adult Patients With Philadelphia Chromosome-Positive ALL

 Let’s talk about our approach to treating these patients. Let’s say there is a Philadelphia chromosome–positive patient who is 30 years old. I’d like to go around and see how people would treat that, because there are going to be some huge differences.

We, at Moffitt Cancer Center, have adopted hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]–ponatinib combination especially for young adults in large part because it seemed to equate to a higher rate of MRD [minimal residual disease] negativity and a lower rate of transplant. The hope is to avoid that if possible. As more data are collected, whether that’s going to be successful will be discovered. But the early data from the University of Texas MD Anderson Cancer Center group suggest that that was a very effective mechanism to engender MRD negativity by 3 months.

 This is a little controversial, but for the younger guys, like a 30-year-old, we can do a TKI [tyrosine kinase inhibitor] plus chemotherapy vs dasatinib—or ponatinib later on, but dasatinib plus a blinatumomab induction. I struggle to know what the right approach is. Generally, these patients are sent to transplant, especially the 30-year-old. I don’t know whether they need it. The longest data are with a consolidative bone marrow transplant, although MD Anderson 2011-0030 hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] data have 73. There will be a longer follow-up soon without the transplants.

 The D-ALBA approach has been used with the full induction for 85 days and then giving them blinatumomab, regardless of their MRD status, followed by a stem cell transplant. This was recently used with a Harvard medical student who’s about 24 years old.

 There was a lot of excitement about that combination. When you get published in the 

, you’re doing something right. The issue seen from that study was the relative lack of conversion from MRD negativity after the dasatinib and prednisone induction. Whether that’s some sort of immunosuppressive effect of the preceding therapy, consider what the German experience has been in chemorefractory MRD with really high rates of conversion to MRD negativity. There may not be as much efficacy out of the blinatumomab on the back end of that regimen as maybe otherwise seen.

For patients, because the risk of serious toxicity from chemotherapy in younger patients is generally quite low, at least in the modern era, there is less worry. The follow-up on that study is pretty short when you consider particularly younger patient population where we have historical paradigms of established ways to treat these patients with a relatively high rate of cure. It is a good option for patients, but not all are ready to wholesale incorporate it to everybody.

ECOG will be leading the trial comparing TKI hyper-CVD to the Italian approach. If people enroll in that trial, perhaps someday we’ll answer that question.

Bijal Shah, MD, Moffit Cancer Center

Articles