Adjunct Treatment With Uproleselan Could Enhance Effects of Chemotherapy in AML

The novel E-selectin antagonist uproleselan could augment the use of chemotherapy in patients with acute myeloid leukemia (AML) without increasing toxicity and potentially lessening some of the adverse effects associated with chemotherapy, according to David Sallman, MD.

Unlike some traditional combination therapies in oncology, where 2 or more agents target different aspects of a cancer, uproleselan can amplify the effects of chemotherapy by allowing the treatment to attack cancer cells that would normally go unaffected, Sallman added.

“I would consider [uproleselan] more of an adjunct [treatment because] it is helping [the chemotherapy] target these cells that are not targetable, traditionally, by chemotherapy [alone] and allowing the chemotherapy to exert its normal function,” Sallman said. “Without uproleselan, this would likely not be possible.”

In an interview with OncLive^®, Sallman, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, provided perspective on the novel agent uproleselan, its efficacy in a phase 1/2 trial (NCT02306291), and its investigation in phase 3 trials in AML.

OncLive^®: Could you provide an overview of the novel E-selectin antagonist uproleselan, which is being investigated in AML?

Sallman: To give a little bit of context, in general for AML, remissions can be achieved with both intensive and non-intensive therapies in sometimes up to 70% or greater of patients. However, relapse is a major issue, with a vast majority of patients relapsing unless they are bridged to allogeneic stem cell transplant. [There is always the concern] of having some leftover amount of disease after frontline therapy, which is associated with poor outcomes, even in those groups of patients that are ultimately bridged to transplant. Improving the depth of remission and targeting leukemic stem cells that may be left behind is of paramount importance to further improve treatment outcomes.

Uproleselan is a novel and specific E-selectin inhibitor. As a brief background, [E-selectin] is a vascular-adhesion molecule that is expressed on the vascular endothelium that helps leukocytes stick to the vessel wall. The thought is it helps keep these leukemic stem cells protected almost in a little house. A lot of times, these cells will not be dividing. Intensive chemotherapy does not target the cells that are not dividing, because it requires active cell cycle for that to occur.

There are other potential bone-marrow microenvironment markers that may be targeted, but this is the one that is furthest along. There is other important work that shows that E-selectin may help support and nurture these leukemic stem cells.

Ultimately, the goal is [determining whether] E-selectin [can] be used in conjunction with intensive chemotherapy to target these specific leukemic stem cells that are a major driver of relapse. One question with that is: Are the cells that are minimal residual disease [MRD] positive or left behind leukemic stem cells? Those comparisons and novel translational analyses, particularly on the single-cell level, [have yet to be done]. Essentially, the goal [is determining whether we can] target leukemic stem cells and help eradicate them in conjunction with more of our standard-of-care therapies.

Please discuss the role of E-selectin in the tumor microenvironment and the rationale for targeting it in this patient population.

The long-term goal is [to] improve the cure rates and overall survival [OS] for patients with AML. For a high percentage of this group, which has been predominantly targeting either relapsed/refractory leukemia or frontline patients that are over the age of 60 years, transplant is also part of that. [We are] also thinking of the long-term improvement of outcomes and prevention of relapse after transplant.

The goal is to improve the depth of remission and the duration of survival in patients that may not be able to go to transplant, but particularly in the setting of transplant, to improve the depth of remission to allow for the best long-term survival in patients that ultimately go to transplant.

What is the unique mechanism of action of uproleselan?

[It is] a very specific inhibitor, so there should not be any increase in toxicity. It is specifically targeting E-selectin or CD62E and does not have any other significant off-target [effects]. It is very selective, and an interesting observation [from the phase 1/2 trial is that fewer instances of] mucositis, which is 1 of the most important toxicities of standard intensive chemotherapy, were seen [with the addition of uproleselan, and that may be a benefit. The hope is that we are not going to add any toxicity. If anything, we may have less toxicity [with the combination of uproleselan and chemotherapy].

How does this agent disrupt cell survival pathways?

By blocking E-selectin, uproleselan prevents this protective bone-marrow niche or microenvironment from protecting the cells from survival and eventually resistance to chemotherapy. By directly abrogating this E-selectin interaction of the bone-marrow microenvironment to the leukemic stem cell, it loses its protective house that should make it more susceptible to intensive chemotherapy.

Does uproleselan act synergistically with chemotherapy?

I do not find it as much of a synergistic combination. It is not [like] a lot of clinical trials where when you use 2 [agents] together there is more, for example, apoptosis, cell-cycle arrest, [and] cytol effects against the leukemic cell.

Could you provide an overview of the phase 1/2 trial investigating uproleselan in addition to chemotherapy in patients with newly diagnosed and relapsed/refractory AML?

The clinical trial of uproleselan first focused on patients with relapsed/refractory leukemia, and the chemotherapy backbone they used in this was MEC [mitoxantrone/etoposide/cytarabine]. Essentially, the investigators first did a phase 1 dose escalation, and the recommended phase 2 dose [RP2D] ultimately was found to be 10 mg/kg. They then did a phase 2 expansion of this combination with the RP2D of uproleselan in patients with relapsed/refractory AML. An important caveat is that most of these patients had failed just 1 line of therapy. Patients who fail more than 1 line of therapy are even less likely to have good outcomes and represent a distinct cohort when you are comparing them with other relapsed/refractory groups.

In a smaller cohort of 25 newly diagnosed patients over the age of 60 years, uproleselan [was combined] with standard 7+3 [chemotherapy] with idarubicin and cytarabine.

There are other salvage chemotherapy regimens such as FLAG [fludarabine/cytarabine/ granulocyte colony stimulating factor (G-CSF)], CLAG [cladribine/cytarabine/G-CSF], or CLAG-M [cladribine/cytarabine/G-CSF/mitoxantrone]. In retrospective studies, there has been overall no difference [between these regimens], but potentially, MEC has had slightly lower response rates. Additionally, in patients over the age of 60 years, cytarabine and daunorubicin [Vyxeos] is approved as frontline treatment and was superior to standard 7+3 intensive chemotherapy independent of age. Although the phase 1/2 trial focused on this similar group of patients, they were [required] to either have myelodysplastic-related changes, therapy-related history, or an antecedent myeloid neoplasm.

When we look at overall outcomes [with the addition of uproleselan to chemotherapy], the response rates are good. A composite complete remission [CR] was achieved in 41% of patients in the relapsed/refractory group, with a median OS of 8.8 months. In the frontline group, the composite CR rate was up to 72%, with a median OS of 12.6 months.

[It is worth noting the phase 1/2 trials were] single-arm studies. The response rates are good. The big challenge is figuring out whether [the response rates would be] any different [with] the absence of uproleselan. The problem in cross-trial comparisons is there are retrospective cohorts that have similar response rates and there are some that [have] worse [response rates]. The response rates appear to be at least as good and I would say on the favorable side of [treatment with chemotherapy alone.] Survival was not dramatically different in these cohorts of patients, particularly in the setting of additional salvage therapies that we have, such as targeted inhibitors and hypomethylating agent [HMA]/venetoclax [Venclexta]–based combinations. The safety profile [of uproleselan] looked good. The critical next steps will be phase 3 clinical trials.

Could you speak the dosing options for uproleselan and what has been learned from the phase 1 trial in that regard?

[Uproleselan] is a very selective inhibitor of E-selectin, and we do not expect a lot of increased toxicity [with the agent]. [It was] noteworthy that no dose-limiting toxicities were observed [in the phase 1 study]. Overall, likely from a combination of pharmacokinetic and pharmacodynamic data, the 10 mg/kg dose was utilized, [with] no significant increase, [and] if anything, a lower rate of mucositis, which can be a significant toxicity.

Clearly, [uproleselan] is safe. It does not add toxicity in combination with intensive chemotherapy. For example, [no] prolonged cytopenias were seen, which is often a major challenge when we are looking at novel combinations with intensive therapeutic options.

What is the safety profile for uproleselan and how does it affect the typical toxicities associated with chemotherapy when the agent is added to a chemotherapeutic backbone?

The good thing is uproleselan does not seem to add significant toxicities [to chemotherapy]. There can always be some infusional adverse [effects (AEs)], but for severe or life-threatening toxicities, which is really the focus when we are thinking about intensive chemotherapy, there is no increase [in toxicity with uproleselan]. Overall, the 60-day mortality rates were comparable. They are not dramatically lower, but are potentially on the low side in patients who are over the age of 60 years.

Could you speak to any ongoing or developing phase 3 trials that are investigating uproleselan?

We have learned that non-randomized studies, particularly in this group of patients, are somewhat irrelevant in thinking [about] the long-term benefit of these medications, so conducting randomized trials is important. The data in Blood [on the phase 1/2 trial] clearly support the randomized phase 3 trials.

There are 2 main phase 3 trials ongoing right now: [NCT03701308 and NCT03616470]. Both are placebo-controlled studies, and they are mirrored after [the phase 1/2 study]. One is being done in the first-line setting in patients over the age of 60 [years and is evaluating] 7+3 chemotherapy with or without uproleselan and the other is being done in the salvage setting. In this case, the investigator’s are allowing 2 options: MEC or FLAG-IDA [fludarabine/cytarabine/idarubicin/G-CSF]. FLAG-IDA and CLAG-M are more commonly utilized regimens in the first-line salvage setting.

Those trials are both ongoing with a long-term primary end point of OS. Patients who are over the age of 60 years cannot have FLT3 mutations. They also cannot have an antecedent myeloid neoplasm or therapy-related disease. This is partially in the context that cytarabine and daunorubicin has an approval. There will be a little bit of overlap [between patient populations in the 2 trials]. For example, [treatment for] AML with myelodysplastic-related changes without those antecedent histories could be improved [with the addition of uproleselan]. Again, there are reasonable comparator arms and a clear primary end point to see whether the addition of uproleselan does improve outcomes either in the frontline setting or in the relapsed/refractory setting for first-line salvage therapy.

Although these data are pending, how could uproleselanaffect the treatment landscape for AML?

If these trials are positive, they would support [uproleselan’s] approval either in a frontline or relapsed/refractory space. What is nice about uproleselan is that its toxicity profile is good.

[It is important to note] that the landscape of frontline AML is changing quite quickly. For elderly [patients with AML who are] not fit for intensive chemotherapy, so classically over the age of 75 years or younger with specific comorbidities, HMAs in combination with venetoclax are a standard of care. Although, already at some academic centers, places are already favoring an HMA plus venetoclax over intensive chemotherapy in this group of patients who are 60 years of age or older. The question is: Are we going to move away from intensive chemotherapy? Does this [regimen] make [intensive chemotherapy] potentially less relevant? If the combination of an HMA and venetoclax becomes a standard for all patients over the age of 60 years, you could say response rates are comparable and MRD negativity rates are at least as good [compared with intensive chemotherapy]. We do not have the long-term data or data after allogeneic stem cell transplant [ASCT], which is a big [gap] in those datasets, but clearly some have already started to transition to [using an HMA plus venetoclax in that population].

There are prospective clinical trials comparing standard chemotherapy regimens in this age group with azacitidine and venetoclax. There is a clinical trial, not registrational, looking at uproleselan with an HMA plus venetoclax. We will eventually have some safety and outcome data there. [Would uproleselan have the same relevance] if we had an approved agent and the standard of care shifted? That is a critical question in the changing paradigm for [identifying] the best treatment.

Hopefully there will be some translational data. Are there subsets of patients that may have the greatest benefit with uproleselan? Could this therapy be used in conjunction with novel cellular therapy, which is a major focus, particularly in the relapsed/refractory space? There are 2 key trials with the goal of getting this agent approved. How it will eventually be utilized may change over time based on the results, but [we are] eagerly awaiting the data readout of these studies.

Is there anything else you wanted to add?

[It will be intriguing to see] additional translational data. Hopefully there will be robust single-cell analyses looking at leukemic stem cells. Can we really see, particularly in the placebo-controlled trial, the eradication of those? That will speak a lot to the mechanism of action of [uproleselan]. [Our improved technologies will help us understand] what happens preclinically vs in clinical trial patients. Therefore, I hope those key analyses will be done, and hopefully we will also [identify whether] there are subsets that may have the greatest benefit of therapy and may help us understand which patients to utilize that approach in, assuming the [trials] are positive.