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Large Study Identifies Potential Therapeutic Targets for MDS Patients who Fail Initial Treatment


NEW YORK – Research from MD Anderson Cancer Center may help guide treatment decisions for patients with myelodysplastic syndromes who fail initial standard-of-care treatments and progress to acute myeloid leukemia.

The study, published earlier this month in Nature Medicine, was one of the largest to explore the biological properties of hematopoietic stem cells driving myelodysplastic syndromes, according to Simona Colla, senior author of the paper and associate professor in MD Anderson's department of leukemia. The heterogeneity of MDS has made it difficult to study and understand disease biology in smaller cohorts, she added.

Patients who progress from MDS to AML tend to have poor prognosis, and once they progress, live on average for four to six months.

The researchers analyzed more than 400 samples from MDS patients taken at different stages of disease. They found that the standard-of-care treatment for MDS, hypomethylating agents (HMAs), could kill mature cells but did not eliminate stem cells in some patients, which can drive relapse. They also improved understanding of how to treat patients in two stem cell subgroups after they progress on HMAs.

In the study, researchers compared bone marrow samples from MDS patients and healthy donors. The comparison revealed two MDS subgroups with variable progenitor cell patterns within the myeloid hematopoietic progenitor cell compartment. These progenitor cells are precursors to certain types of blood cells.

More than half of the MDS samples had an increased frequency of common myeloid progenitors, which the researchers dubbed the CMP group. The other group, comprising the rest of the MDS samples, had a greater frequency of granulocytic-monocytic progenitors, which the researchers called the GMP group.

The researchers used several sequencing methods to analyze patient stem cell profiles and genetic expression including flow cytometry, immunohistochemistry, single-cell RNA sequencing, and the mass cytometry platform CyTOF, or cytometry by time of flight. They found through molecular profiling that the two subgroups relied on different genetic pathways to maintain stem cell survival after HMA treatments.

"One was based on BCL2 activation and the other one was based on NFKB pathway activation," Colla said. "This is very important, because it suggests that to overcome progression, you need to treat patients in a different way."

In a retrospective analysis on 21 MDS patients who progressed after HMAs, Colla's group further explored whether the different profiles could predict response to an approved AML treatment, AbbVie and Genentech's BCL2 inhibitor Venclexta (venetoclax). They found that Venclexta could overcome progression in patients with the CMP profile. These patients experienced a significant decrease in stem cells after Venclexta treatment. However, patients with the GMP profile did not see the same benefit.

The CMP group had a shorter time to complete remission on Venclexta, 1.2 months, compared to 6.5 months for the GMP group. CMP patients also had a longer duration of relapse-free survival, 16.3 months versus 5.2 months for GMP patients.

The researchers also explored the effects of Venclexta with or without 5-azacytidine in xenografts and mouse models that had the CMP pattern. They treated the models with Venclexta and found it reduced the numbers of CD45-positive T cells, suggesting it was able to deplete the blast population and kill the stem cells that could allow MDS to survive after treatment.

"This suggested that, based on the stem cell architecture, we can predict which patients will respond to venetoclax-based therapy," which is the only option for MDS patients after they relapse on hypomethylating agents, Colla said.

In further xenograft and mouse model experiments, the researchers explored the activity of the investigational molecule BMS-345541, an NFKB pathway inhibitor obtained from Selleck Chemicals. They isolated the stem and progenitor cells from MDS patients in the GMP group and treated them with BMS-345541. In the models, the drug reduced signaling activation in blastic cells and reduced the tumor burden in bone marrow samples.

While MDS patients with the CMP profile may already have a treatment that benefits them, Colla noted that there is no approved treatment targeting the NFKB pathway that drives the GMP profile. She and her team are exploring methods of targeting NFKB in the lab. They are attempting to inhibit NFKB by targeting downstream effectors of pathway activation, such as MCL1 and BCL2A1. If the proof-of-concept study targeting NFKB is successful, the researchers hope to enroll patients in a clinical trial next summer, Colla said.

The 21-patient retrospective analysis also showed that GMP patients who progressed on Venclexta had an increase of certain CD34-positive T cells, suggesting that Venclexta was not able to stop the disease from proliferating in those cells, Colla added.

Several pharma companies are developing drugs that can treat MDS and stall its progression to AML, including Gilead Sciences and Aprea Therapeutics. However, the development programs at both firms have experienced difficulties.

In 2020, Aprea's Phase III study of eprenetapopt plus the chemotherapy azacitidine in patients with TP53-mutant MDS failed to increase the rate of complete remission compared to azacitidine alone. However, Aprea continued analyzing data from eprenetapopt studies and last year reported positive data from a Phase II study of eprenetapopt and azacitidine in patients with TP53-mutated AML or MDS following allogeneic stem cell transplantation and a Phase I study of eprenetapopt plus Venclexta and azacitidine in TP53-mutant AML.

Earlier this year, the US Food and Drug Administration put a partial clinical hold on several Gilead trials exploring its anti-CD47 agent magrolimab with azacitidine in AML and MDS, due to an "apparent imbalance" of unexpected serious adverse reactions between study arms. Among the trials on partial hold is a Phase III trial of magrolimab and chemo in high-risk MDS and a Phase Ib study with several MDS patient cohorts stratified by risk level and previous treatments.

The researchers are hoping to expand these limited treatment options for MDS and AML with their findings. While they explore targeting NFKB in the lab, the group has already begun a Phase I trial exploring the CMP pattern as a biomarker of response for MDS patients treated with Venclexta and chemotherapy.

Colla also emphasized that even larger studies are needed in MDS to better understand the disease and its progression.

"The most important thing is the number of patient samples in this paper because it is really a full depiction of the disease at the biological level and at different stages," Colla said, recalling that when she started studying MDS, there were few published studies based on large cohorts.

"They would analyze something like a 10-patient sample, but it was not possible to understand the biology underlying the disease that is so heterogeneous in a small population," she noted. "Everything that we're doing in the study here is with the intention to try to figure out how to improve the lives of patients with MDS."