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.

Videos

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.

Prognostic Factors Which Impact ALL Management

Bijal Shah, MD, associate professor, Department of Malignant Hematology, Moffitt Cancer Center, discusses the results of the phase I/II ZUMA-3 study, which looked at using KTE-X19, an anti-CD19 CAR T-cell therapy, to treat patients with relapsed/refractory acute lymphoblastic leukemia (ALL).

Currently, 5-year survival rates for patients with ALL are in the range of 5% to 10%, according to Shah. There is an unmet need for additional novel therapies, which led to the introduction of KTE-X19. The therapy is unique because physicians will sort the leukemia cells out, pulling only the T-cells into the manufacturing.

Thus far, the ZUMA-3 trial has treated 45 patients with relapsed/refractory ALL with KTE-X19. Thirty patients (66%) had ≥3 prior therapies. Of the overall 45 patients, 6, 23, and 16 patients received 2, 1, and 0.5 × 10

 cells/kg, respectively. All 41 patients who had ≥2 months of follow-up, the overall response rate was 68%. Of 19 pts with ≥2 of follow-up who were treated with 1 × 10

 cells/kg, the complete response (CR) or CR with incomplete hematology recovery rate was 84% and the median event-free survival was 15 months.

Bijal Shah, MD, discusses the results of the phase I/II ZUMA-3 study, which looked at using KTE-X19, an anti-CD19 CAR T-cell therapy, to treat patients with relapsed/refractory acute lymphoblastic leukemia.

Bijal Shah, MD, Moffit Cancer Center

Articles

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

Dr. Shah on Results of ZUMA-3 Study for ALL