Tapan M. Kadia, MD, discusses what makes uproleselan unique from other agents under investigation in acute myeloid leukemia and sheds light on the many research efforts dedicated to further exploring its use in this disease.
The addition of the E-selectin antagonist uproleselan (GMI-1271) to chemotherapy has been shown to improve outcomes in patients with relapsed/refractory acute myeloid leukemia (AML), according to Tapan M. Kadia, MD, who added that based on these findings, the investigative agent is now under further exploration in several disease subsets and settings with varying unmet need.
“The idea is that [uproleselan] may reduce or subvert chemotherapy resistance. This has been shown in several preclinical studies where mice that had been treated with cytarabine and had leukemic blasts left over after [treatment] showed that they had tight binding to E-selectin within the tumor microenvironment,” Kadia explained. “When uproleselan, or an antibody blocking E-selectin, was added, those cells then became sensitive to the cytarabine, suggesting that the E-selectin binding was leading to chemotherapy resistance. This [supported the hypothesis that] blocking E-selectin within the microenvironment can be an important mechanism to provide benefit in patients with AML.”
Data from a phase 1/2 clinical trial (NCT02306291) showed that when uproleselan was administered at the recommended phase 2 dose of 10 mg/kg twice daily in combination with mitoxantrone, etoposide, and cytarabine (MEC), it produced a remission rate of 41% in those with relapsed/refractory disease (n = 47).1 In a cohort of patients with newly diagnosed disease who were at least 60 years of age (n = 25), the combination of uproleselan plus cytarabine and idarubicin (7+3) resulted in a remission rate of 72%.
Now, a phase 3 trial (NCT03616470) is examining MEC or fludarabine, cytarabine, and idarubicin (FAI) with or without uproleselan in patients with relapsed/refractory AML who are eligible for intensive chemotherapy in the salvage setting.2 Another phase 3 trial (NCT03701308) is exploring 7+3 chemotherapy with or without uproleselan in patients aged 60 years or older who are fit for intensive induction chemotherapy.3 Moreover, a phase 1/2 trial (NCT04848974) is evaluating cladribine and low-dose cytarabine in combination with uproleselan in difficult-to-treat patients with treated secondary AML.4
In an interview with OncLive®, Kadia, an associateprofessor in the Department of Leukemia, of the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed what makes uproleselan unique from other agents under investigation in AML and shed light on the many research efforts dedicated to further exploring its use in this disease.
Kadia: E-selectin is a relatively new target, but it is a protein that we have known about for many years. E-selectin is present on activated endothelial cells, [which are] the cells that make up a blood vessel. E-selectin is present, upregulated, and overexpressed in activated endothelial cells at the sites of inflammation and damage.
We [believe] E-selectin is meant to help attract or traffic leukocytes and white blood cells, including monocytes, neutrophils, and natural killer [NK] cells, to the sites of inflammation. Neutrophils, NK cells, and monocytes have E-selectin ligands, which are glycoproteins that are attracted to or attached to E-selectin. E-selectin on the endothelial cells helps to traffic these cells and adhere them to the endothelial cells.
More recently, E-selectin has become recognized as a potentially important marker in malignancy, because they are also expressed in endothelial cells associated with malignancy. For example, in solid tumors, there is a suggestion that it may have a role in metastasis or distant metastasis of solid tumors, such as colon cancer.
In leukemia and hematologic malignancies, the endothelial cells in bone marrow also overexpress E-selectin, particularly in advanced disease. They are expressed at higher levels in patients who have adverse-risk AML, patients who have been previously treated, and they allow the adherence of leukemic blasts of the malignant cells to the endothelial microenvironment within the bone marrow.
As [the endothelial cells do that], we believe that the E-selectin binding to these cells upregulates nuclear factor kappa B [NF-κB] within the tumor or the blast, and elicits a type of chemotherapy resistance, or prosurvival pathways, that allow them to survive chemotherapy or treatment. Blocking this [from happening] has been the rationale behind [the development of] uproleselan. Blocking this may help prevent the trafficking of the blast cells to the bone marrow and from adhering to the bone marrow microenvironment, therefore inhibiting activation of the cancer survival pathways, such as NF-κB.
Uproleselan is an antagonist of E-selectin that binds to E-selectin and prevents the interaction between E-selectin and E-selectin ligands, which are present on leukemia or AML blasts. It is an intravenous product that is given over 20 minutes twice daily.
[During] an initial study, [investigators] observed no significant toxicities [with uproleselan] as a single agent. The mechanism is that it blocks the interaction between the E-selectin and the E-selectin ligands on the blasts, therefore reducing the trafficking of these leukemic blasts to the bone marrow. It disrupts the adhesion-mediated drug resistance within the bone marrow microenvironment.
In that respect, it also inhibits the activation of potential cancer survival mechanisms, such as upregulation of NF-κB, and may reduce chemotherapy-based toxicity that may occur. By reducing [E-selectin adhesion] and adding chemotherapy, you are treating cells that are potentially more sensitive to [chemotherapy].
The [hypothesis] was that blocking E-selectin would thereby sensitize the resistant leukemic blasts to chemotherapy, particularly in the salvage setting. You want to start in patients with relapsed/refractory AML.
This was a phase 1 study that looked at the combination of the E-selectin antagonist, uproleselan, with either MEC chemotherapy in patients with relapsed/refractory AML, or in combination with 7+3 chemotherapy in a small cohort of newly diagnosed patients with AML who were aged 60 years and older. Once patients achieved remission, they could also get uproleselan with their consolidation, whether it be MEC consolidation or intermediate-dose cytarabine-based consolidation.
A total of 66 patients with relapsed/refractory AML were treated, with a median age of 59 years of age. Moreover, 17% of those patients had prior transplant, and one-third of the patients had 2 or more induction regimens; [as such, it was] a heavily pretreated population. Fifty percent of patients had adverse-risk [disease] by European LeukemiaNet risk [classification].
If you look at the adverse [effects (AEs)], and this is 1 of the first striking observations, there may have been potentially lower toxicity—particularly along the gastrointestinal tract starting with mucositis, nausea, and vomiting—than what you would expect with MEC chemotherapy based on historical experience. The most common complications were infections, which are common in patients [with leukemia] who are treated with intensive chemotherapy.
When you look at efficacy among the 66 patients who were treated, the complete response [CR]/CR with incomplete count recovery [CRi] rate was [41%], and the early mortality [rate] was fairly low, at 9% at 60 days, which is reasonable. Patients who had a longer CR1 duration had a higher response rate at 75% vs those who had refractory disease or a short CR1 duration, [with] response rates in the range of 23% and 36%.
[Additionally], 69% of patients had minimal residual disease [MRD] negativity, which is good for a relapsed/refractory cohort setting. The efficacy was there, as seen by the overall response rate [ORR] of 39%, which is in line with what you would expect with salvage chemotherapy in the relapsed/refractory setting. The median overall survival [OS] of the patients is [8.8] months, [which is] promising for a study looking at relapsed/refractory AML.
One of the interesting correlative studies looked at E-selectin ligand expression on the blast cells and survival. Looking at baseline AML, a prior study suggested that patients whose blasts had high expression of E-selectin ligand had a more adverse prognosis then those with low expression. Moreover, E-selectin ligand overexpression [is known to] correlate with relapsed/refractory disease and adverse prognosis disease. As such, high E-selectin ligand is associated with a poor prognosis.
[However, in this correlative study,] patients who had high E-selectin ligand expression and were treated with uproleselan had a more favorable outcome, with a median OS of 12.7 months compared with 5.2 months in those who had low [E-selectin ligand] expression. That suggests that in those patients who typically would have a more adverse prognosis with high E-selectin ligand expression, when you added uproleselan, which blocked that interaction, their prognosis improved. That was an early signal that suggested that targeting that receptor flips the adverse prognosis associated with E-selectin ligand expression.
[The phase 1/2] study also had an arm of newly diagnosed patients, who were treated with 7+3 chemotherapy plus [uproleselan]. These were older patients with newly diagnosed AML; [this cohort was comprised of] 25 patients who had a median age of 67 years. Half of patients had secondary AML, which is commonly seen in that population.
Here, the rates of grade 3 or 4 mucositis were 0%, with about 20% [of patients experiencing] grade 1/2 mucositis, so lower rates in mucositis than we may have expected with intensive chemotherapy. The CR/CRi rate was 72% [with this approach], with 52% [of patients] achieving a complete remission. The early mortality [rate] at 60 days was 12%, [which is] higher than you might expect in older patients, but still reasonable and promising. The MRD negativity [rate] was 56% among the patients who were evaluated for it. As such, this was a pretty good response rate that was in line or higher than what you would expect with intensive chemotherapy.
Based on the promising data from the phase 1 trial, looking at patients with relapsed/refractory AML treated with MEC plus uproleselan, as well as the small cohort of frontline patients treated with uproleselan and 7+3, the sponsor decided to proceed with a couple of phase 3 randomized trials to register uproleselan for patients in these particular settings.
The primary end point for both studies is OS, to evaluate the combination of anti-leukemic activity uproleselan with the respective chemotherapy. Secondary end points also include trying to further study and nail down the incidence of severe oral mucositis. Is it less than what you would expect with the control arm?
The first is a randomized phase 3 study [NCT03616470] for patients between the ages of 18 years and 75 years, with relapsed/refractory AML who are eligible for intensive chemotherapy in the salvage setting. They may have had 1 or fewer allogeneic stem cell transplants [ASCTs] prior to enrollment. Patients are randomized [1:1] to either MEC or FAI chemotherapy, plus or minus uproleselan. If patients achieved remission, they could receive consolidation with high-dose [cytarabine] or intermediate-dose [cytarabine], plus or minus uproleselan. The primary end point of the study is OS. The study is in the early stages [and we] hope to see data in the next couple of years.
The second is an National Cancer Institute study [NCT03701308] that is looking at patients aged 60 years or older who are fit for intensive chemotherapy [in the frontline setting]. Patients who have secondary AML [will be included], but those with FLT3-mutated AML [will not], since there is a standard of care for that [in the form of] FLT3 inhibitors.
Here, patients are randomized [1:1] to 7+3 chemotherapy with or without uproleselan, with consolidation with intermediate-dose cytarabine, with or without uproleselan. The primary end point [is] OS, and there will be an interim analysis looking at event-free survival [EFS]. If there is an inferior EFS at the interim [analysis], then the study would be closed at that point for futility. Otherwise, it would continue to look for OS benefit [with this approach]. Hopefully, we will see some data in the next year or 2 [to shed light on whether] this is a good strategy [for these pateints].
The treatment paradigm in AML has shifted significantly over the past few years with the incorporation of new molecules, such as venetoclax [Venclexta], [plus] IDH1, IDH2, and FLT3 inhibitors. Things are changing rapidly, even as uproleselan is being developed.
Now, instead of saying we have patients who are older and fit for chemotherapy, you must ask [questions about mutations]. Does a patient have a FLT3 mutation? If so, maybe they should be treated with a FLT3 inhibitor combined with chemotherapy. Does a patient have an IDH1 or IDH2 mutation? Recent data from the 2021 ASH Annual Meeting suggested that the combination of ivosidenib [Tibsovo] and azacitidine showed a significant survival benefit in patients who are IDH1 mutated compared with azacitidine alone. As such, there is another option for that specific subset of patients.
We have other medications or intensive chemotherapy for patients who have secondary AML. [For example,] CPX-351 showed a significant survival benefit compared with 7+3 chemotherapy. Where does uproleselan fit in secondary AML? Well, if you start with the relapsed/refractory setting, there is no 1 standard of care. As such, if uproleselan does show significant benefit compared with MEC alone in terms of survival, that is one place to go.
[If patients] have FLT3-, IDH1-, or IDH2-mutated, options such as gilteritinib [Xospata] and ivosidenib are available for those respective subtypes. However, in those patients who do not have those mutations, [uproleselan] could be an option.
A [phase 1/2] pilot study [NCT03214562] that is being done by [investigators at The University of MD Anderson Cancer Center] looked at [the combination of] FLAG [fludarabine, cytarabine, granulocyte colony–stimulating factor] plus idarubicin and venetoclax [in patients with relapsed/refractory AML] and showed very high rates of complete remission with MRD negativity. This is a very intensive study, that needs close follow-up and close safety evaluation, but certainly, [we are seeing] high response rates with most of the patients able to proceed to ASCT and good survival in the long term. How does uproleselan fit in that setting?
If [the addition of uproleselan] shows a benefit over MEC as a single agent, it is certainly an option. [Now, we must determine] which patients you would put on that particular study, if they have no targetable mutations or if they cannot tolerate intensive chemotherapy plus venetoclax, whether it be FLAG plus idarubicin/venetoclax, or a regimen we developed, [like CPX-351] plus venetoclax.
In the frontline setting, it gets even more difficult because frontline studies are looking at [combining] a hypomethylating agent [HMA] with venetoclax in older patients. This [approach] is currently approved for patients who are aged 75 and older, or those who are unfit for intensive chemotherapy. However, [this approach] may start to be applied to patients who are slightly younger than that or who are more fit than the most unfit patients. [Investigators] are examining HMA plus venetoclax in that older, fit population. New regimens, such as cladribine, low-dose cytarabine, plus venetoclax, have also demonstrated high response rates in that older, fit population.
A set of studies is evaluating [CTX-351 in secondary AML]. For patients with IDH1 mutations, we now have the option of HMA plus ivosidenib. For FLT3-mutated disease, we are still looking, but HMA/venetoclax has high response rates in that setting. Moreover, triplet combinations are also being investigated, where [agents such as] gilteritinib or quizartinib are being added to the backbone of HMA plus venetoclax.
In the frontline, so many different options [are available] for specific subtypes, so we must define where 7+3 plus uproleselan will fit in, if data are positive. This is still a question that will need to be answered.
We are conducting a trial in a specific subset of patients who do not have great options [available to them] right now: those with treated secondary AML. This is a population of patients who may have had myelodysplastic syndrome [MDS] or chronic myelomonocytic leukemia [CMML] prior to developing AML, which is very common in the population. These patients were treated with the standard of care, which is HMAs and 5-azacytidine or decitabine in the frontline for MDS or CMML.
Eventually, these patients may respond [to treatment], but they may then progress to AML. At the time of their progression, they are considered to have newly diagnosed AML, but they may have received months or years of HMAs. This [scenario] used to be [referred to as] HMA failure, but this is a specific subset of AML that arises from previously treated MDS or CMML. In these patients, the complete remission rates are in the range of 20% to 25% with standard agents, and early mortality is very high. These patients have a median OS in the range of 4 to 5 months at the time of diagnosis AML, so it is a difficult subset of patients [to treat] for whom there really is no therapy [available]. If you look at CPX-351 in that setting, which is treated secondary AML, outcomes are pretty much the same, with high rates of early mortality and poor OS.
We wanted to address this key subset of patients. One of the things that we learned from the preclinical studies with uproleselan is that E-selectin is upregulated and overexpressed in AML blasts that have been previously exposed to HMAs. AML or MDS blasts that have been treated with or exposed to HMAs upregulate E-selectin significantly. The rationale was if these patients who have failed or have been treated extensively with HMAs then develop AML, their blasts may have upregulated E-selectin, and they may be the ideal target for uproleselan in combination with chemotherapy.
We took that specific subset of patients, and we are studying the combination of uproleselan plus cladribine and low-dose cytarabine [as part of a phase 1/2 trial (NCT04848974)]. The cladribine and low-dose cytarabine regimen has been developed at MD Anderson and, for many years now, has been used in frontline AML and treated secondary AML. In that specific subset [of treated secondary AML], we have seen a response rate [ranging from] 35% to 40% in the frontline [setting].
Since it is not [additional treatment with a] HMA, this backbone in combination with uproleselan is being studied in patients with treated secondary AML, with the end point of safety, [as well as] secondary end points of remission rate and OS in this difficult population, where there is a [need] that needs to be critically addressed.