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.

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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.

Treating Young Adult Patients With Philadelphia Chromosome–Positive ALL

® 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.

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 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?

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.

 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 improvethe 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 earlierlines of therapy.

Ryan D. Cassaday, MD, University of Washington/Fred Hutch

Articles

Role of Transplant in Older Adults With Acute Lymphoblastic Leukemia

Managing MRD-Negative Acute Lymphoblastic Leukemia

Managing MRD-Positive Acute Lymphoblastic Leukemia

Treatment of Acute Lymphoblastic Leukemia in the Community Setting

Role of MRD Testing in Acute Lymphoblastic Leukemia

Treating Older Adult Patients With Philadelphia Chromosome-Negative ALL

Treating Young Adult Patients With Philadelphia Chromosome-Negative ALL

Treating Older Adult Patients With Philadelphia Chromosome-Positive ALL

Treating Young Adult Patients With Philadelphia Chromosome–Positive ALL

Prognostic Factors Which Impact ALL Management