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“[This was] a negative trial, which is a disappointment, but we learn a lot from these trials. This is a trial that is enriched for a number of correlative analyses being done through the CIMAC collaboration with a number of outstanding laboratory and translational colleagues. Most of these are still underway, [and] we hope that the data generated from this trial will inform the next generation of trials.”

Rory Shallis, MD, assistant professor of medicine (hematology), Yale School of Medicine, Yale Cancer Center, discusses findings from the phase 2 BLAST AML-2 trial (NCT0428478) evaluating the addition of pembrolizumab (Keytruda) to venetoclax (Venclexta) and azacitidine in patients with acute myeloid leukemia (AML). Findings were presented by Shallis and colleagues at the 

The investigator-initiated trial included 60 patients who were randomly assigned 1:1 to receive either venetoclax plus azacitidine alone (n = 31), or pembrolizumab plus venetoclax and (n = 29). In both arms, 29 patients received treatment. The primary end point was the rate of measurable residual disease (MRD)–negative complete remission (CR) or CR with incomplete hematologic recovery (CRi) within the first 6 treatment cycles.

Shallis indicated that no significant efficacy differences were seen between the two arms; the MRD-negative CR/CRi rate was 44.8% in both groups (

 = 1.000), and the CR rates were both 24.1% (

 = .999). Similarly, best composite response rates—comprised of CR plus CRi and morphologic leukemia-free survival) were 89.7% in both the control arm and the triplet arm (

 = .528). Median overall survival (OS) was numerically shorter in the triplet arm at 8.87 months compared with 17.94 months in the control arm, although Shallis notes that this difference was not statistically significant (

Safety data revealed that rates of treatment-related adverse effects (TRAEs) were comparable across arms, with any-grade TRAEs occurring in 89.7% of patients in the control arm vs 93.1% of patients in the triplet arm. However, the triplet arm had a higher incidence of serious AEs (274 events vs 192 events) and a higher proportion of patients who discontinued treatment due to TRAEs (6 vs 1). There were no new safety signals observed with pembrolizumab.

The study was discontinued early following a recommendation from the data safety monitoring board due to futility. Exploratory correlative analyses conducted through the CIMAC collaboration will aim to identify biomarkers of response and guide the design of future immunotherapy trials in AML.

Shallis concludes that although the addition of pembrolizumab to azacitidine and venetoclax did not improve outcomes, the findings underscore the importance of conducting randomized trials in AML. Ongoing translational studies are expected to inform the next generation of combination regimens in this challenging patient population.

Videos

Rory Shallis, MD, discusses the addition of pembrolizumab to azacitidine citidine and venetoclax in patients with acute myeloid leukemia.

Dr Shallis on Data for Pembrolizumab Plus Venetoclax/Azacitidine in AML

! I’m your host today, Caroline Seymour.

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, supported by Bristol Myers Squibb, we had the pleasure of speaking with Rory Shallis, MD, an assistant professor of medicine and hematology at Yale School of Medicine, part of Yale New Haven Health in Connecticut.

Shallis sat down with us to share some of the research that has been generated in myelodysplastic syndrome (MDS) over the past year or so, touching on the evolution of clinical trial end points and where the field is headed in terms of therapeutic classes. He also spoke to the investigation of the late-stage erythroid maturation agent luspatercept-aamt (Reblozyl) in this population in the phase 3 ELEMENT-MDS (NCT05949684) and MAXILUS (NCT06045689) trials.

In our exclusive interview, Shallis discussed the research basis for the ELEMENT-MDS trial in MDS, the potential of intervening with luspatercept before patients become red blood cell transfusion dependent, and aspects of the trial to be aware of for patient enrollment.

That’s all we have for today! Thank you for listening to this episode of 

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Podcasts

Dr Shallis discusses the ELEMENT-MDS trial in MDS and the potential of intervening with luspatercept before patients become RBC transfusion dependent.  

How Luspatercept Could Shake Up MDS Management—With Rory Shallis, MD

Dr Shallis on the Utility of Luspatercept in the ELEMENT-MDS Trial in MDS

Rory Shallis, MD, assistant professor, medicine (hematology), Yale School of Medicine, Yale New Haven Health, discusses the utility of luspatercept-aamt (Reblozyl) as evaluated in the phase 3 ELEMENT-MDS trial (NCT05949684) for patients with myelodysplastic syndrome (MDS).

the FDA approved treatment with luspatercept for adult patients with anemia who present with very low– to intermediate-risk MDS)

 and may require regular red blood cell (RBC) transfusions; these patients will not have had prior treatment with an erythropoiesis-stimulating agent (ESA). The initial excitement for luspatercept in this patient population emerged from the phase 3 MEDALIST trial (NCT02631070), Shallis begins. The trial showed impressive responses in a placebo-controlled setting and was followed by the phase 3 COMMANDS trial (NCT03682536), he reports.

COMMANDS enrolled RBC-dependent patients with MDS who had not previously received ESAs, Shallis continues, adding that patients were randomly assigned to receive either luspatercept or an ESA. The primary end point, which was achieved in the luspatercept arm, measured at least 12 weeks of transfusion independence across various patient subgroups, including those with low endogenous erythropoietin (EPO) levels or low transfusion burdens, he states. Those 2 patient characteristics sparked investigators’ interest in using luspatercept earlier in treatment, Shallis emphasizes.

The ELEMENT-MDS trial will assess whether luspatercept can be introduced before patients become transfusion dependent, a common situation for patients with low-risk MDS at diagnosis, he explains. This randomized trial focuses on reducing progression to transfusion dependence in ESA-naive, non–transfusion-dependent patients with low-risk MDS, Shallis imparts. Low risk is defined using the revised International Prognostic Scoring System (IPSS-R), and the trial excludes patients with low-risk MDS with deletion 5q.

Patients must have a baseline EPO level below 500 U/L to be eligible for enrollment. The trial stratifies patients by baseline EPO level, ring sideroblast status, and IPSS-R risk category, he expands. ELEMENT-MDS will include some patients with intermediate-risk MDS per IPSS-R, who represent approximately 20% of all low-risk MDS cases, Shallis notes. The primary end point will evaluate the proportion of patients who become transfusion dependent during any continuous 16-week period in weeks 1 to 96.

There is confidence that using luspatercept earlier could prevent patients from becoming transfusion dependent, theoretically delaying the accumulation of significant transfusion burdens, he says. This delay is important as it may improve post-transplant outcomes by reducing iron overload, a factor that negatively affects stem cell transplant success, Shallis concludes.

Rory Shallis, MD, discusses the utility of luspatercept in the context of the phase 3 ELEMENT-MDS trial for patients with myelodysplastic syndrome.

Rory Shallis, MD, assistant professor of Medicine, Hematology, Yale School of Medicine, discusses the investigation of uproleselan (GMI-1271) in acute myeloid leukemia (AML).

Uproleselan is a small molecule, E-selectin inhibitor that has been shown to disrupt the microenvironmental protection of leukemia cells, according to Shallis. The agent mobilizes those cells into circulation and improves responses observed with traditional chemotherapy options, Shallis says. Notably, the efficacy of the agent does not appear to be dependent on a specific set of genetic or molecular profiles, Shallis adds. Rather, efficacy with uproleselan appears to be disease biology agnostic, according to Shallis.

This agent has been evaluated in combination with multiagent chemotherapy as part of a phase 1/2 trial (NCT02306291). The combination elicited a remission rate of 41% in the salvage cohort, with a complete response rate of 35%, Shallis adds. The data indirectly mirrored historical expectations of other treatments for patients in this setting, but there were no clear differences in time to or quality of count recovery, Shallis explains. 

The addition of uproleselan to chemotherapy resulted in low rates of toxicity, with lower-than-expected rates of mucositis were observed, Shallis notes; this is attributed to the role that E-selectin expression has on inflammation. According to Shallis, this may be relevant for older patients with AML who have other comorbidities that may make the risk of mucositis more problematic, Shallis concludes.

Rory Shallis, MD, discusses the investigation of uproleselan in acute myeloid leukemia.

Rory Shallis, MD

Articles

Dr Shallis on Data for Pembrolizumab Plus Venetoclax/Azacitidine in AML

How Luspatercept Could Shake Up MDS Management—With Rory Shallis, MD

Dr Shallis on the Utility of Luspatercept in the ELEMENT-MDS Trial in MDS

Dr. Shallis on the Investigation of Uproleselan in AML