How do you handle MRD [minimal residual disease] at your institute? When are you checking? How are you checking it?

MRD is very important in ALL [acute lymphoblastic leukemia] assessments. Typically, every time we do a bone marrow biopsy, we check MRD. We still do more MRD by multicolor flow cytometry because this is the way we used to do it, but MRD can be done by clonoSEQ [assay]. We’re trying to do more of the clonoSEQ using initialization sequencing, but what’s been happening, we’ve been having more difficulty obtaining an original bone marrow biopsy for these cases. But MRD is an important prognostic factor in ALL. It surpasses most of the other prognostic factors, like high white blood cell count, phenotype, all these factors. MRD is the most important thing that determines how the patient’s going to do and if we should do a consolidation with allogeneic stem cell transplant or not. Nowadays we have blinatumomab, which is an FDA-approved drug for patients with persistent MRD. There is controversy over what’s the best timing to have the MRD to determine future outcomes and the need of the consolidation with transplant or not. But there are different studies that show that day-28 bone marrow biopsy MRD is prognostic, like the C10403 [consolidation regimen], that shows day-28, day-29 bone marrow biopsy MRD was prognostic. We do it that day. Then we repeat it after consolidation, which is roughly around…initiating therapy. There is less controversy about that MRD, if that MRD is still positive, then we can give blinatumomab. This patient clearly benefits from allogeneic stem cell transplant based on the GIMEMA study and other studies as well.

 Yes, we have a similar approach, and it’s a struggle in the community. I certainly sympathize because I can’t imagine having a clinic full of patients with lung cancer and breast cancer, and having a patient with ALL walk in. There’s a lot of confusion around MRD. I agree, clonoSEQ, having a test that’s commercially available, hopefully it’s going to help with this because clearly, it has now become standard in ALL. It’s something we should all be doing. Here in Hackensack, New Jersey, we are fortunate enough that we have a standardized multicolor flow cytometry assessment available to us, which we use here. Like your approach, we will give patients up to the first cycle of consolidation before we switch to immunotherapy if patients are still MRD positive. Like we’ve talked about, MRD positivity following consolidation probably is the most important prognostic indicator we have. It’s important to identify those patients who need a transplant and need some salvage regimen in preparation for that.

 There are always debates about the timing of the MRD [testing] to determine whether to go to transplant. What about these patients who are still MRD positive after induction, and they become negative after consolidation? This is the one we struggle with deciding should we transplant or not? They have a late MRD response. What’s your approach, James, for these patients?

 I agree. This is probably the point in a MRD decision-making that is the most challenging, and there’s a lot of heterogeneity between centers. Clearly, we know that an early and deep molecular response, or quick MRD response, is important for the patient. The quicker the better. As we mentioned, we have a goal of cycle 1 of consolidation. There are enough data to support that this is a pretty clear point at which we start to lose some of the good prognostic indications of MRD clearance. Then by the third or second cycle of consolidation, there are more robust data saying that if you remain MRD positive after cycle 2, this is the time in which we should entertain other treatment options, and those patients remain at the highest risk. Most centers will let people go out to a maximum of 3 or 2 cycles of consolidation, which we cut that a little shorter here at cycle 2.

 We a have similar approach. For the patient who is MRD positive after consolidation, we frequently recommend a transplant, and frequently we do it after we give blinatumomab, given the high activity of blinatumomab in this setting. Now, for the patient who’s still MRD positive after induction then become MRD negative after consolidation, we take it case by case. Because we are in California, we see a lot of Ph [Philadelphia chromosome]-like patients; high-risk patients, based on genetics, we tend to take them to transplant, even if they clear MRD after consolidation. Patients who develop asparaginase-associated pancreatitis after the first, second dose of asparaginase, then most likely they would receive an adequate therapy, even if we’ve continued this curative regimen, when we recommend taking them to transplant. Others with good-risk genetics, they’re tolerating chemotherapy well, we try to cure with chemotherapy alone.

There’s one interesting study, James. It’s the COG [Children’s Oncology Group] AALL1131 study that was presented at ASCO [American Society of Clinical Oncology annual meeting], where they looked at patients younger than 30 with very high-risk ALL. They asked the question, if you’re still MRD positive at the end of induction and become MRD negative at the end of consolidation, will this improve the outcomes compared with if you remain MRD positive? They randomized patients to either continue on the control cohort, which is mercaptopurine, Cytoxan, cytarabine, vs experiment 1, where they give Cytoxan and etoposide, or experiment 2, the same regimen but they add clofarabine. They closed the second experiment with the clofarabine early due to toxicity. And they saw no difference based on the control, where they received standard consolidation, versus the experimental consolidation. The patients who achieve early MRD negativity, irrespective of what happens after, they still have a better prognosis and disease-free survival compared to the ones who are positive. Although they didn’t see a difference if they became negative or positive with the experimental arm, at the end of consolidation, the patients who received the control arm and achieved MRD negativity, they did better. It’s an area of debate what to do with these patients, and definitely, we need more studies, especially with the introduction of novel drugs early in the course of the treatment of these patients. We still have a lot to learn.

 I agree completely, and to build on that, just like you said, I think here when we identify those patients who remain MRD positive, we’ve already established a relationship with our transplanters. So as we transition away from chemotherapy and into immunotherapy or blinatumomab, specifically for those MRD-positive patients, we will always offer patients blinatumomab for MRD clearance prior to transplant. That’s our standard, acknowledging that those patients who are MRD negative prior to transplant have better outcomes.

Videos

An overview of the treatment implications of testing for minimal residual disease in pediatric and AYA patients with ALL.

MRD Testing in ALL

Which patients with Philadelphia chromosome-positive [Ph+] acute lymphoblastic leukemia may be safely treated in the community setting versus being referred to tertiary centers? Let’s extend that also to Philadelphia chromosome-negative [Ph-], James. What’s your opinion on that?

 This is always a challenge, right? As leukemia physicians, we would love to be able to see everyone. Especially in New Jersey where we’re a densely populated state, one of the most rewarding things has been establishing a good relationship with local oncologists. When patients can travel, and especially in the era of telemedicine, almost everyone benefits from some interaction with a leukemia specialist. These are still rare diseases. With some of these approaches, patients could still be treated at home but seen with us. Particularly in the Philadelphia chromosome-negative setting and patients receiving pediatric-inspired regimens, my sense is that those patients often do benefit from seeing a physician at a tertiary center. These are often complex regimens with unique toxicities and maintaining dose intensity is important. That can be particularly valuable, but I recognize it’s not always possible for folks to get to us. I think particularly patients with Ph+ disease, receiving steroids and TKIs [tyrosine kinase inhibitors], or TKIs and steroids with dose-reduced chemotherapy, those could be easily managed locally, but there could be a real benefit to having a relationship at a tertiary center for MRD [minimal residual disease] monitoring and assessments along the way.

 Thank you, James. I completely agree with you. Maybe we’re having more of the problem here in California compared to New Jersey, since it’s a large area here. Patients sometimes travel for 3, 4 hours to come to our centers. But I agree, especially Ph- ALL [acute lymphoblastic leukemia] in the AYA [adolescent and young adult] population, where the goal is to cure using pediatric-inspired regimens, which are complex. For general oncologists who rarely treat ALL, these regimens are very complicated for the treating physician in terms of toxicity, the way to administer these drugs. I think that at least the patients benefit from having the induction in the tertiary leukemia centers since induction tends to have the highest risk of treatment mortality. At least they can be treated in the tertiary center at the beginning. Once in the remission, maybe they can move back locally and we can work in conjunction with the community doctor to treat the patient. But also, many times we get patients after induction, they are remission, and we don’t have full genetic assessments of their disease. It’s hard to recommend transplants or not in this setting. They rarely check MRD in the community, I would say. For some patients who end up having high-risk leukemia, there’s a benefit of…the patient in case early transplant is needed. And one advantage is the availability of some of the clinical trials that include novel therapies that can benefit the patient and can advance the science if they presented to the leukemia center rather than a community hospital. And for Ph+, I agree, especially after induction, if the management is with TKIs, the increase in steroids is easily managed in the community. Again, you have to have a good relationship with the community doctor and they can call you any time if they need to co-treat the patient.

Drs Aldoss and McCloskey share their thoughts on treating patients with ALL at community centers versus at tertiary, academic medical centers.

Choosing a Treatment Setting for Patients With ALL

Are your treatment goals different based on age and Ph-negative ALL [acute lymphoblastic leukemia]? And typically, if we're still talking about AYA (adolescent and young adult) versus older adults, or even with the AYA, there's always debate about what the upper age limit is for AYA pediatric regimens. For younger adults, we tend to give pediatric regimens because clearly there is a higher chance of cure with these regimens compared to adult regimens. One of the main barriers for pediatric regimens in older patients or AYA is asparaginase toxicity; clearly there's correlation between asparaginase toxicity and increased age. With other drugs like vincristine, frequently patients suffer from peripheral neuropathy when they are in their 40s and 50s compared with someone in their 20s or younger. There are some limits. What we usually do is try to offer this pediatric regimen up to age 50, sometimes even age 54. And to mitigate some of the adverse effect of asparaginase, we tend to reduce the dose of asparaginase rather than giving 2000 international units per meter squared (iU/m2, we try to reduce the dose to 1000 international units per meter squared as the pharmacokinetics data show actually this dose is adequate and inhibition as per gene can give you results for patients treated with these regimens. And it seems toxicity is better when you use a reduced dose. But as I say, the problem is that even with reducing the dose is the increase associated with more toxicity, so we see more interruption, more discontinuation of these regimens compared to younger patients. And even when patients receive similar pediatric regimens, we see the prognosis is not as good as someone who's younger than 18 years old. There is still a difference even by using these modern pediatric regimens in younger adults with ALL. Is that your approach too, James?

 Yes. It's very similar. I agree that particularly when we consider the pediatric-inspired regimens, the asparaginase is, of all the agents, the one that often causes us a lot of issues and is more likely to cause unpredictable issues, so clotting and bleeding are always a concern. For us, our upper age limit for our pediatric-inspired regimen is really 40 years. That's where we draw the cutoff. We have pushed it up higher than that. And we often find even between the ages of 35 and 40, as you mentioned, we have a lot of difficulty maintaining treatment tensity. For all these patients, our goal is always to cure them if possible. And one big difference for us is that anyone in our center who achieved an MRD [minimal residual disease] negative remission by cycle 1 of consolidation with a pediatric-inspired regimen, we don't recommend transplant for those patients. That is a big bridge, whereas for patients who are older, we will often discuss and highly consider a transplant irrespective of their MRD status. That's certainly one difference as they proceed on through induction and consolidation.

 Yes. We have the same approach. When we see the patient is treated with less curative regimens and they're unable to tolerate the curative agents in the regimen, we tend to recommend transplant. Even if they achieve early MRD, we consider transplant, and it depends on various factors. But a newly evolving thing with older patients, since they don't handle chemotherapy well, is the introduction of these novel agents early like blinatumomab, inotuzumab, this may actually change the outcomes of these patients. But, again, the study's still early, and we have to have a longer follow-up to see if we can avoid transplant and the complications of the transplant if these drugs are introduced early in the regimen.

Ibrahim Aldoss, MD; and James K. McCloskey, MD, discuss how to approach the treatment of a pediatric or AYA patient with ALL who is Philadelphia chromosome-negative (Ph-).

Approaches to Treatment of Ph- ALL

 Dr. McCloskey, since you commented on the ponatinib and blinatumomab studies, do you want to talk more also about the GIMEMA study with dasatinib followed by blinatumomab, briefly?

 Yes. This was a phase 2 study early clinical trial of approximately 60 patients that looked at patients who received dasatinib and steroids followed by consolidation and with BLINCYTO® (blinatumomab), again, sparing patients a lot of chemotherapy that we might otherwise use, even if you're using a chemotherapy-reduced regimen. And again, early nonrandomized, but impressive response rates (RR) with a median overall survival (OS) of close to 90% and disease-free survival (DFS) that was 79%. And within that, we could see that the patients who achieved an MRD [minimal residual response] negative response had a really substantially prolonged disease free-survival, indicating to us that if we look at MRD as a surrogate, that we really might be able to select those patients who need transplant, spare patients a lot of chemotherapy by treating them upfront with BLINCYTO®, and then limit transplant. Especially if we think about younger patients and the issues around fertility and the long-term consequences of some of these therapies, it would be great to reduce the exposure to chemotherapy and transplant.

 Definitely. This study generated a lot of interest using this chemotherapy-free regimen. Chemotherapy is always a challenge in older patients since the chromosome-positive is an older patient disease, so this is the future treatment for this disease. And one more interesting thing with this study is they have seen some MRDs increasing during the dasatinib therapy during induction and developing new mutations in the APL kinase. And with the blinatumomab therapy they’re able to get rid of these mutations and the MRD in these cases, so it can overcome some of the limits of the Philadelphia chromosome-positive treatment with TKI[tyrosine kinase inhibitors].

A review of the design, results, and practical implications of the GIMEMA Trial.

Treating Ph+ ALL: The GIMEMA Trial

Dr. McCloskey, now, moving to the Philadelphia chromosome-positive ALL [acute lymphoblastic leukemia], how did this evolve recently with the introduction of tyrosine kinase inhibitors (TKIs), and does it make a difference if the patient is pH-positive or negative when you choose your initial therapy? And with a focus more on the Ph-positive in this section, we'll talk more about the pH negative later.

 This is a quickly evolving area of ALL. And certainly in adults, it's the Wild West. We haven't established a clear standard. And, it's interesting. You could make the argument for a variety of therapies from steroids and TKIs [tyrosine kinase inhibitors] alone, which certainly is appealing in elderly, less-fit patients—TKIs and steroids in combination with some reduced-intensity chemotherapy and then TKIs with chemotherapy. More recently, this idea of even just TKI with immunotherapy or blinatumomab, which looks impressive. One of the important things to note is that clearly, we have at times, especially early in the disease history, underestimated the heavy lifting that the TKI does. And TKIs are really important to utilize for these patients. And then in the community, particularly in the second lines and later, please remember to look for resistance patterns because I know sometimes we see that patients are continued on TKIs without having resistance testing. And we know those patients, just like in your CML [chronic myeloid leukemia] folks, can develop resistance. For us, we use a combination of these approaches for younger, fit patients. We do use chemotherapy—a hyper-CVAD [cyclophosphamide, vincristine, doxorubicin]-like regimen in combination with TKI as frontline therapy. And then we deescalate from there if patients are less fit or elderly. One of the interesting things I think about where we stand today, especially in children, is the role of transplant, and that's evolving quickly. And starting with some heated discussions between us and the transplant people here, the pendulum is starting to shift back towards potentially not transplanting, particularly young patients who have a quick MRD [minimal residual disease] response with a TKI-based chemotherapy combination approach. And I don't know how you were handling that there, but many of us are looking forward to a time when maybe we won't transplant all these folks with Ph-positive ALL.

 I agree with you. This is the hope eventually. Can we really optimize the frontline setting to avoid a transplant in these patients? As adult oncologists, we continue to recommend transplants. Now there is some evolving data that is very encouraging, and an interesting part of it is early molecular response (EMR), where it seems these patients are doing well and potentially have durable remissions without transplant. The other part, the introduction of ponatinib early in the course of Philadelphia chromosome-positive ALL, at least in single-center data from The University of Texas MD Anderson in Houston, Texas, the introduction of ponatinib to very high molecular response early on, and at least with a shorter follow-up, they haven't seen a difference in patient who went to transplant or not. However, the rule of the transplant in this setting, is it's still early to have a conclusion. We must have more study and know exactly which patient can be spared from the transplant. But as you mentioned, the Ph-positive ALL has evolved significantly with the introduction of TKIs. Previously, the challenge with Ph-positive before the TKIs was to get them into remission and to have durable remission, to blend the transplant. And the majority of patients, they tend to relapse while you try to do the transplant. Now, with the TKI, I would say close to 100% achieving complete remission at spine morphology, molecular response is less frequent, and second-generation TKI. And then the question of the intensity of chemotherapy: How much intensity do you need for chemotherapy? That is a frequent question in this setting. I would say most of us try to avoid giving asparaginase to adults because the concern is you may end up with toxicity that interrupts the more important drug, which is the tyrosine kinase inhibitor. The question of hyper-CVAD is would you use it as a front line or not? And you must remember, in this study, the first cycle was reduced intensity after that patient went to hyper-CVAD after the first cycle. And although medical response was the same, the problem was that more patients had treatment-related mortality with the more intense regimen. And there are other studies, especially in older patients. The approach now, not to intensify the chemotherapy, you can get a very good response just with a TKI and steroids and increase in plus or minus.

 To piggyback on that, there’s also exciting new data looking at adding some of these therapies that we use in relapse and refractory patients earlier on in treatment both in the adult and the pediatric world. You mentioned the MD Anderson Group; they have a lot of experience with ponatinib and many of us have recognized the role of ponatinib for these patients. At ASCO [American Society of Clinical Oncology meeting] this year, we did see data looking at ponatinib and BLINCYTO® [blinatumomab] as first-line therapy in patients with Ph-positive ALL. It’s certainly early and it's a small study and a heterogeneous abstract of patients that also included some relapse and refractory patients. But to your point, the patients who were frontline had 100% response rate, all the CRs were MRD negative and none of those patients proceeded to transplant. We look forward to moving these later line therapies that we use for relapse into the frontline setting and Ph-negative ALL, they have a lot of potential in the frontline setting as well.

A discussion on how to approach the treatment of a pediatric or AYA (adolescent and young adult) patient with ALL (acute lymphoblastic leukemia) who is Philadelphia chromosome positive (Ph+ALL).

Approaches to Treatment of Ph+ ALL

Hello, I'm James McCloskey. I'm the chief of leukemia here at the John Theurer Cancer Center in Hackensack, New Jersey.

I’m Ibrahim Aldoss. I'm an associate professor in the department of hematology and hematopoietic cell transplantation at City of Hope [City of Hope Comprehensive Cancer Center,Duarte, California]. I'm specialized in adults and AYA (adolescent and young adult) acute leukemia and transplant. Today, we'll be discussing acute lymphoblastic leukemia (ALL) with the focus on B-Cell ALL and the treatment approach for children, adolescents, and young adults. And I will start by asking Dr McCloskey about the risk assessment in B-Cell ALL and discuss the classification and how this can impact the treatment, the prognosis, and after-treatment in this patient population.

 The risk assessment strategies have shifted, particularly as we consider the role of MRD [minimal residual disease], which I'm sure we're going to talk about a lot today. Historically, we have often used a variety of techniques to risk-stratify patients, and we know that this is a heterogeneous disease, maybe not so much as AML [acute myelogenous leukemia], but we always attempt to look at a patient's age. Certainly, as we're going to discuss today, age is an important variable in considering a patient's disease biology. We certainly know that adults behave differently than adolescents, and even adolescents are different from the true pediatric population. Historically, we've often used a high white blood cell count. Again, I don't know that that's as important today in the MRD setting. We continue to use sided genetics, and particularly MLL [mixed-lineage leukemia] rearrangements are important to look for and prompt a referral for transplant for us. And then molecular testing, particularly in the AYA population, and identifying those patients with Ph-like ALL (Philadelphia chromosome-like acute lymphoblastic leukemia) is important to identifying those folks and as a higher risk patient population for relapse and considering the role of transplant.

 I agree with you, James. It's an important part when we have a newly diagnosed ALL patient. Genetics continue to play an important role in stratifying patients, even in the presence of the MRD and the MRD assessment. And as you pointed out, Ph-like ALL is an important subtype that is unfortunately still underdiagnosed, especially when the patient is treated outside large academic centers, because truly, there is no consensus on how to diagnose Ph-like. But as you pointed out, it's not uncommon in CT [computed tomography]. What we see is up to 20% of cases with B-Cell ALL. And it has implications because these patients don't do well like other subtypes of B-Cell ALL. And unfortunately, the TKIs [tyrosine kinase inhibitors] that are available for the high-risk Ph-positive ALL doesn't work as well in this subgroup. It is important. And as you mentioned, age is important because part of it is the biology of the disease is different. We see good risk genetics in younger patients or we see more hyperdiploid translocation 1221, while older patients, they tend to have high-risk genetics such as Philadelphia chromosome MLL, as you pointed out. That's part of the age, how this influences the prognosis of ALL. But besides that, besides the biology, older patients tend to tolerate treatment not as well as younger patients, even if they have the same genetics. And this leads to early discontinuation, delaying therapy, in addition to the psychosocial issues in adults compared to pediatric, where they have more frequent instruction in the therapy.

Ibrahim Aldoss, MD, and James K. McCloskey, MD, share their thoughts on different stratification measures used to assess risk in pediatric, adolescent, and young adult patients newly diagnosed with ALL.

Ibrahim Aldoss, MD, City of Hope Comprehensive Cancer Center

Articles

MRD Testing in ALL

Choosing a Treatment Setting for Patients With ALL

Approaches to Treatment of Ph- ALL

Treating Ph+ ALL: The GIMEMA Trial

Approaches to Treatment of Ph+ ALL

Risk Assessment in ALL