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Effective Novel Agents in Upfront Treatment of ALL

Panelists: Mark R. Litzow, MD, The Mayo Clinic; Jae Park, MD, Memorial Sloan Kettering Cancer Center; Bijal Shah, MD H. Lee Moffitt Cancer Center & Research Institute; Anthony Stein Gehr Family Center for Leukemia Research
Published: Wednesday, Jan 30, 2019



Transcript: 

Mark R. Litzow, MD: I want to touch on some of the novel agents that we’re going to be talking about in a little bit more detail. The thought of bringing them into upfront therapy with the idea of being able to lessen some of the myelosuppressive chemotherapy that we have to give. And there were some presentations at the American Society of Hematology meeting [ASH] that we’re at, and [The University of Texas] MD Anderson [Cancer Center] group tends to be in the forefront of this area.

They had some presentations here using inotuzumab ozogamicin. This is a monoclonal CD22 antibody linked to a cytotoxic agent, calicheamicin, and combining that with low-dose chemotherapy. There are many hyper-CVAD [cyclophosphamide/vincristine/doxorubicin/dexamethasone] or many CVD regimens, and showing some encouraging results with that. What are some of your thoughts? What do you know about that?

Bijal D. Shah, MD: I think this is the future. We have to determine how to integrate these novel agents into our frontline therapeutic regimens, not just for the elderly. I think it’s a place to start.... I want every person I’m seeing to be cured, and I want to maximize their likelihood of cure. But for the average adult, we’re still batting around 40% to 50% long-term cure rates. And I would argue that’s not success. And understanding whether we integrate inotuzumab onto a full chemotherapeutic backbone or onto dose modified chemotherapeutic backbones is one that we’ll continue to explore. But the activity we’re seeing in the elderly population, and in the young adult, and in the other populations with INO [inotuzumab] and BLIN [blinatumomab] combinations [is] very encouraging.

We do have to be wary of toxicity with inotuzumab. And while it’s very encouraging, we do have to recognize that it can induce cytopenia. There is a broader effect on the bone marrow, but by putting calicheamicin, a bystander effect I should say, by putting calicheamicin in the bone marrow, thrombocytopenia is common, but neutropenia can also emerge, and infections can also emerge. And then, of course, we can’t ignore the issue of hepatotoxicity. And both VOD [veno-occlusive disease] and just generalized hepatotoxicity as we’re delivering this calicheamicin-based antibody. And [it is] important to stress that that’s not just while we’re giving the therapy but something may extend well beyond the time that we give this particular drug.

So thinking about how we do transplant, when we do transplant. And by how, I mean avoiding things like double alkylator transplants are incredibly important in this regards.

Mark R. Litzow, MD: Thank you. Jae, could you comment about the trial you were involved with, the SWOG [Southwest Oncology Group] trial that was the Intergroup trial where Dr [Anjali] Advani [MD] utilized upfront blinatumomab in older patients with ALL and what kind of results we saw with that.

Jae Park, MD: As Dr Bijal Shah was saying, I think it’s a very exciting time and all of a sudden that we have a very effective therapy that we can use in older ALL patients. Before … if we were seeing a 70-year-old patient, you’d pray they were Ph [Philadelphia chromosome]-positive. And if the patient [was] minus, what options do we really have? A steroid? Vincristine? Maybe some Cytoxan induction therapy.

But now we have an option of this new and novel and different mechanism of action. I think there have been different approaches. And as Bijal was mentioning before and you’re alluding to, inotuzumab, CD22 targeted antibody drug conjugate in combination with a less dose-intense chemotherapy. The other approach that the Intergroup has taken is looking at blinatumomab, which is a bispecific T-cell engager targeting both CD3 and then CD19. So bringing the T cells closer to the site of the B cells and therefore generating the tumor eradication.

Blinatumomab is approved and has been studied in relapsed refractory settings, but this is the first time [it is being studied] as a single standalone regimen … assessing the single-agent activity, and then the safety in older ALL patients greater than age 60.

These patients are receiving blinatumomab as, again, a single agent, first 1 or 2 cycles, to assess a response. If they’re in complete response [CR], the patients went on to receive consolidation, blinatumomab for 3 additional cycles, and then went on to receive POMP [Purinethol/vincristine/methotrexate/prednisone], a low-dose oral chemotherapy maintenance regimen for 2 or 3 years.

In this setting, this is a very novel approach, and the response rates are certainly very encouraging. The CR rate that we are seeing, and this is early preliminary data that we are presenting at this year’s [2018] ASH meeting, it’s about 60%, 65%. In this age group previously we probably estimated, with the tradition of chemotherapy, about 20% or so. So this is an improvement of CR, CRP [C-reactive protein], and Cri [complete remission with incomplete hematologic recovery], depending on the hematologic recovery of the blinatumomab.

So the responses are very encouraging and toxicity also appears to be favorable. We do see some similar [adverse] effects, the cytokine release syndrome, neurological toxicity, but not any more than what we’re seeing in younger patients in relapsed setting. And also very little grade 3 or 4, the toxicity that we really worry about.

It appears to be tolerable and you’re seeing the better response rate than we were seeing before. Whether we can improve even further from the 65%, to 90% to 100% in this, I think that’s the area that we need to move on to. This was a very good first step as a large effort by the Intergroup to study that. And I’m very excited to see what will happen with this agent’s incorporation by itself or another combination.


Transcript Edited for Clarity

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Transcript: 

Mark R. Litzow, MD: I want to touch on some of the novel agents that we’re going to be talking about in a little bit more detail. The thought of bringing them into upfront therapy with the idea of being able to lessen some of the myelosuppressive chemotherapy that we have to give. And there were some presentations at the American Society of Hematology meeting [ASH] that we’re at, and [The University of Texas] MD Anderson [Cancer Center] group tends to be in the forefront of this area.

They had some presentations here using inotuzumab ozogamicin. This is a monoclonal CD22 antibody linked to a cytotoxic agent, calicheamicin, and combining that with low-dose chemotherapy. There are many hyper-CVAD [cyclophosphamide/vincristine/doxorubicin/dexamethasone] or many CVD regimens, and showing some encouraging results with that. What are some of your thoughts? What do you know about that?

Bijal D. Shah, MD: I think this is the future. We have to determine how to integrate these novel agents into our frontline therapeutic regimens, not just for the elderly. I think it’s a place to start.... I want every person I’m seeing to be cured, and I want to maximize their likelihood of cure. But for the average adult, we’re still batting around 40% to 50% long-term cure rates. And I would argue that’s not success. And understanding whether we integrate inotuzumab onto a full chemotherapeutic backbone or onto dose modified chemotherapeutic backbones is one that we’ll continue to explore. But the activity we’re seeing in the elderly population, and in the young adult, and in the other populations with INO [inotuzumab] and BLIN [blinatumomab] combinations [is] very encouraging.

We do have to be wary of toxicity with inotuzumab. And while it’s very encouraging, we do have to recognize that it can induce cytopenia. There is a broader effect on the bone marrow, but by putting calicheamicin, a bystander effect I should say, by putting calicheamicin in the bone marrow, thrombocytopenia is common, but neutropenia can also emerge, and infections can also emerge. And then, of course, we can’t ignore the issue of hepatotoxicity. And both VOD [veno-occlusive disease] and just generalized hepatotoxicity as we’re delivering this calicheamicin-based antibody. And [it is] important to stress that that’s not just while we’re giving the therapy but something may extend well beyond the time that we give this particular drug.

So thinking about how we do transplant, when we do transplant. And by how, I mean avoiding things like double alkylator transplants are incredibly important in this regards.

Mark R. Litzow, MD: Thank you. Jae, could you comment about the trial you were involved with, the SWOG [Southwest Oncology Group] trial that was the Intergroup trial where Dr [Anjali] Advani [MD] utilized upfront blinatumomab in older patients with ALL and what kind of results we saw with that.

Jae Park, MD: As Dr Bijal Shah was saying, I think it’s a very exciting time and all of a sudden that we have a very effective therapy that we can use in older ALL patients. Before … if we were seeing a 70-year-old patient, you’d pray they were Ph [Philadelphia chromosome]-positive. And if the patient [was] minus, what options do we really have? A steroid? Vincristine? Maybe some Cytoxan induction therapy.

But now we have an option of this new and novel and different mechanism of action. I think there have been different approaches. And as Bijal was mentioning before and you’re alluding to, inotuzumab, CD22 targeted antibody drug conjugate in combination with a less dose-intense chemotherapy. The other approach that the Intergroup has taken is looking at blinatumomab, which is a bispecific T-cell engager targeting both CD3 and then CD19. So bringing the T cells closer to the site of the B cells and therefore generating the tumor eradication.

Blinatumomab is approved and has been studied in relapsed refractory settings, but this is the first time [it is being studied] as a single standalone regimen … assessing the single-agent activity, and then the safety in older ALL patients greater than age 60.

These patients are receiving blinatumomab as, again, a single agent, first 1 or 2 cycles, to assess a response. If they’re in complete response [CR], the patients went on to receive consolidation, blinatumomab for 3 additional cycles, and then went on to receive POMP [Purinethol/vincristine/methotrexate/prednisone], a low-dose oral chemotherapy maintenance regimen for 2 or 3 years.

In this setting, this is a very novel approach, and the response rates are certainly very encouraging. The CR rate that we are seeing, and this is early preliminary data that we are presenting at this year’s [2018] ASH meeting, it’s about 60%, 65%. In this age group previously we probably estimated, with the tradition of chemotherapy, about 20% or so. So this is an improvement of CR, CRP [C-reactive protein], and Cri [complete remission with incomplete hematologic recovery], depending on the hematologic recovery of the blinatumomab.

So the responses are very encouraging and toxicity also appears to be favorable. We do see some similar [adverse] effects, the cytokine release syndrome, neurological toxicity, but not any more than what we’re seeing in younger patients in relapsed setting. And also very little grade 3 or 4, the toxicity that we really worry about.

It appears to be tolerable and you’re seeing the better response rate than we were seeing before. Whether we can improve even further from the 65%, to 90% to 100% in this, I think that’s the area that we need to move on to. This was a very good first step as a large effort by the Intergroup to study that. And I’m very excited to see what will happen with this agent’s incorporation by itself or another combination.


Transcript Edited for Clarity
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