Commentary
Article
Ashkan Emadi, MD, PhD, discusses early efficacy signals with venetoclax plus pegcrisantaspase in relapsed/refractory AML.
Findings from a phase 1 study (NCT04666649) evaluating venetoclax (Venclexta) plus pegcrisantaspase (PegC), a glutamine-depleting amino acid modulator, demonstrated that the combination produced early signals of clinical activity and a manageable safety profile in patients with relapsed/refractory acute myeloid leukemia (AML), offering a potential avenue to utilize venetoclax in patients who have developed resistance, according to Ashkan Emadi, MD, PhD.1
Findings published in Blood showed that hyperbilirubinemia was identified as a regimen-limiting dose; any-grade hyperbilirubinemia occurred in 60% of patients (n = 25), and 20% had grade 3 or higher increased bilirubin levels. Based on safety findings, the recommended dose of the combination was established as 400 mg of venetoclax per day plus 750 IU/m2 of PegC once every 2 weeks.
The most common any-grade treatment-related adverse effects (AEs) comprised decreased antithrombin III levels (52%), elevated aminotransaminase levels (36%-48%), fatigue (28%), and hypofibrinogenemia (24%).
Efficacy data showed that evaluable patients (n = 18) experienced an overall complete remission (CR) rate of 33%; 2 patients experienced a CR, 2 achieved a CR with partial blood count recovery (CRh), and 2 had a CR with incomplete blood count recovery (CRi). Half of responders had undetectable minimal residual disease. One additional patient also experienced a partial response with VenPegC and survived 6 months on trial without receiving any other concurrent or subsequent therapy.
“This is a very novel mechanism that could overcome resistance to prior exposure [to] venetoclax,” Emadi said. “We hope that in the phase 2 study, by enrolling a higher number of patients, we [can] learn more about this combination, particularly in terms of the genetic background, the cytogenetic and mutational landscape of the AML, the rate of CR, the durability of CR, and [identify] patients [who] potentially could be candidates for allogeneic stem cell transplant.”
In an interview with OncLive®, Emadi discussed the scientific rationale for this combination and preclinical data that supported the phase 1 study; detailed the findings from the phase 1 trial; and explained the potential role for this regimen in the management of AML.
Emadi serves as the inaugural chair of the Department of Medical Oncology at the West Virginia University (WVU) School of Medicine, where he is also the Alexander Bland Osborn Endowed Chair and Distinguished Professor of Medical Oncology and serves as physician-in-chief for Medical Oncology and associate center director for Translational Research at the WVU Cancer Institute in Morgantown.
Emadi: We showed in the previous preclinical study that [the] combination of the BCL-2 inhibitor venetoclax and the glutamine depletor/amino acid modulator PegC, which is an asparaginase derived from Erwinia chrysanthemi, can be synergistic.2 One of the mechanisms that cells use after the BCL-2 inhibition is upregulating another anti-apoptotic protein: MCL-1. MCL-1 is a labile protein.
The combination ofPegC and BCL-2 [inhibition], as we have shown in the preclinical model and [the phase 1] study, decreases the level of MCL-1 indirectly. By doing so, it overcomes the resistance to venetoclax.
This combination decreases the level of MCL-1 [by interfering] with the mRNA translation. mRNA gets transcribed from the DNA and then gets translated into the protein. mRNA goes through the ribosome, and then the ribosomal machinery—or the initiation complex—gathers around the mRNA, and then [it] gets translated to the protein. This combination is inhibiting that cap binding of the mRNA to the ribosome, [halting] protein synthesis in AML cells compared [with] normal cells.
We published preclinical [data] in Leukemia [in 2021]. We used multiple available AML cell lines, as well as primary AML cells from patients with AML that I treated. We developed an in vivo animal model of the leukemia cells that were very resistant to conventional chemotherapy, hypomethylating [agents], and [venetoclax].
In multiple models, both in vitro and in vivo, we showed that [venetoclax plus PegC] could be effective in killing leukemia cells in vitro and significantly decreasing the growth of leukemia in the animal model, resulting in increased survival of those animals. The data that we published, in my opinion, were as good as it can get in the preclinical model.
However, my job is not to cure leukemia in mice. It is to help patients. We used this VenPegC regimen to design this novel investigator-initiated phase 1 study to treat the most resistant AML in heavily pretreated patients who have received multiple prior regimens for their AML.
This is what academia is about and should be. That is the true translation of the data that originates from well-designed, well-conducted preclinical [studies] that identify the mechanism of action and then bring those [treatments] to the clinical arena. This is, in my opinion, how we advance science in oncology.
The [phase 1] study had 2 sections. The first was a dose-escalation study, which is typical of a phase 1 [trial], [with] the goal of identifying the maximum tolerated dose and dose-limiting toxicities—or in this case, regimen-limiting toxicities—because we have 2 agents.
Our regimen-limiting toxicity was hyperbilirubinemia. Sixty percent of [patients] had elevated bilirubin levels; however, 2 patients [experienced] grade 3 hyperbilirubinemia [where bilirubin] did not resolve back to normal levels.
We identified a few of the other AEs that were mainly laboratory [AEs] and were expected. They were not clinically significant, such as decreases in antithrombin III levels or a decrease in fibrinogen levels, which aligns exactly with the mechanism of action of the PegC. We also saw that [36% to 48%] of patients had some mild elevation in liver enzymes.
Learning from this phase 1 study, we are planning to do a phase 2 study and launch it at West Virginia University Cancer Institute and a few other selected sites. WVU is going to be the coordinating site, and then there are going to be a few other sites that are going to have this study because the novelty of the combination and the promising results generated a lot of interest in the leukemia community.
The dose and route of administration of PegC will be modified to try to mitigate the elevation of bilirubin and liver enzymes [levels]. The development of venous and arterial thrombosis, as well as pancreatitis, are known AEs of the asparaginase products. In our study, we did not see any thromboembolic AEs or any pancreatitis; so in that sense, [this regimen] was well tolerated.
There are ways to try to mitigate, treat, or prevent elevation of the bilirubin [levels] and to replete the antithrombin III level. If a patient’s platelet [count] allows, [we can use] anti-coagulation.
In terms of tolerability, [this] was an acceptable [and] tolerable regimen, and for the phase 2 [trial], we will be using the combination with the fixed dose, and I hope that toxicity will not be a major issue.
This is one of the strongest points of this study. [In] this study, we allowed for prior venetoclax exposure. There were patients who already had venetoclax, and they were refractory to prior therapy. We allowed them on this study because these days, if you want to be very selective and not enroll patients with prior exposure to venetoclax, [a given clinical trial would] not [replicate the] real-world experience.
Interestingly, 33% [of patients] who had prior exposure to venetoclax [n = 12] achieved a CR/CRh/CRi. In a sense, this shows that [in patients who received] prior venetoclax, this combination—with the mechanism of interfering with the mRNA cap binding to the ribosome, resulting in the decrease of the MCL-1—could resensitize [patients] to venetoclax.
We also tried to correlate the overall response with different mutational backgrounds. We were astonished that [all] 4 patients [harboring] a RUNX1 mutation achieved a CR. In the discussion of the paper, we elaborated on this more. It has been reported that leukemia cells—and some of the hematologic malignancy cells of non-leukemia nature—with RUNX1 mutations are completely dependent on the ribosomal biogenesis, or the mRNA translation through the ribosome. In other words, this combination, by targeting the mRNA capping at the ribosome, hits the Achilles heel of these cells with RUNX1 mutations.
For the phase 2 study, although we plan to include both patients with RUNX1-mutated and RUNX1 wild-type [AML], we will have a separate analysis on patients who have RUNX1 mutations. We will try to stratify enrollment based on the absence or presence of the RUNX1 mutation.
I discussed the molecular mechanism [of the combination] in terms of the interference of mRNA cap binding. However, I would also like to discuss another novel correlative scientific study of this protocol. We observed that 88% of patients achieved nadir plasma asparaginase activity more than 0.1 IU/mL. That [threshold] is known both as a regulatory and clinically accepted benchmark [for the efficacy of asparaginases]. Albeit, most of those data are from acute lymphoblastic leukemia, and this study is the first one showing this [asparaginase activity] in AML.
The second, novel correlative finding is that we checked the plasma amino acids. The 3 that are germane to the mechanism of PegC are glutamine, glutamate, and asparagine. The [mean] baseline plasma asparagine was 32 µmol/L [range, 18-70], which was significantly decreased in all patients [during the study]. After the first dose of PegC, asparagine levels in all patients decreased to undetectable levels, and asparagine remained undetectable for the entire study.
Glutamine levels also significantly decreased compared [with] baseline. The [mean] baseline plasma glutamine before receiving PegC was 435 µmol/L. The [mean] plasma glutamate was 53 µmol/L. If the drug is effective, you expect the glutamine level to go down, and simultaneously, the glutamate level to go [up]. For the patients that had a nadir plasma asparaginase activity greater than 0.1 IU/mL, we observed a consistent decrease in the plasma glutamine after administration of the PegC. Mean reduction was 170 µmol/L with a corresponding rise in the plasma glutamate—the mean increase was 210 µmol/L. Based on these data, in addition to the mRNA cap binding, decrease in plasma glutamine level, decrease in plasma asparagine level, and increase in plasma glutamate level could be used as novel biomarkers that can potentially predict the response to this combination.
The mechanism of action of this combination, which was based on a very strong preclinical finding, is extremely novel. There is absolutely no other combination that targets leukemia cells from these aspects of modulating the plasma amino acid level with simultaneous BCL-2 inhibition, resulting in negative interference with the mRNA cap binding. This is not the usual cytotoxic approach, [and] this is not a regular or usual anti-metabolite combination approach.
After achievement of CR, younger and medically fit patients could proceed to transplant as a potential curative option. In patients who are older or have a comorbidity, hence not a candidate for transplant, this completely outpatient regimen could extend their survival with an acceptable quality of life.
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