Exploring Potential Novel Therapeutic Interventions for Patients With Early-Stage Myelodysplastic Syndromes

Therapies targeting the biological mechanisms of pre-leukemic MDS may improve patient outcomes, according to data presented at the Society of Hematologic Oncology (SOHO) 2023 Annual Meeting in Houston, Texas by Juan Jose Rodriguez-Sevilla, PhD, The University of Texas, MD Anderson Cancer Center, Houston, Texas.

Myelodysplastic syndromes (MDS) arise from a small population of disease-initiating hematopoietic stem cells (HSCs) which contribute to disease progression, according to Simona Colla, PhD, The University of Texas, MD Anderson Cancer Center, Houston, Texas. Colla and researchers suggest that therapeutic strategies targeting the biological mechanisms underlying the pre-leukemic stage of MDS, namely, clonal cytopenia of undetermined significance (CCUS), can improve outcomes for patients. 

“Our results provide an in-depth analysis of hematopoeietic stem and progenitor cells (HSPCs) and [bone marrow] (BM) cells from CCUS samples at the single-cell level and identify, for the first time, therapeutic interventions to arrest MDS in its early stage, before the disease can have a dismal outcome,” wrote Dr Colla. 

Transcript:

Hello, everybody. My name is Juan Jose Rodriguez-Sevilla, I'm a postdoctoral fellow here at the Leukemia Department of MD Anderson Cancer Center, Houston, Texas. 

I presented yesterday at SOHO 2023 symposium an update on the biology of MDS. One of the focuses of our lab, the Simona Colla Lab, is understanding MDS biology, but also seeing new ways of preventing MDS development by targeting its pre-leukemic phase, which is called clonal cytopenia of undetermined significance (CCUS), where a minority of [hematopoietic stem cells] (HSCs) are altered, are mutated. And maybe we can improve the course of the disease by targeting this pre-leukemic stage.

What we essentially did, since we recognized CCUS as an aging-related disorder, we compared a subset of healthy donors, young healthy donors, elderly healthy donors, and CCUS patients through single-cell RNA sequencing. What we found is that, compared to young healthy donors, elderly healthy donors have an increased HSC frequency.

Contrary to the longstanding observation that they are mostly mildly primed, we found that they have these increased HSC frequency plus an aberration of [] signatures, but a reduced number of early and late myeloid and lymphoid compartment. We confirmed that by flow cytometry. What we saw is that, as we age, some of the hematopoietic stem compartment, helps regulates genes involved in the [] pathway, as well as cellular response to interferon gamma. Then since we already have figured out what was happening through physiological aging, then we compare these elderly healthy donors to CCUS patients. CCUS patients have mutations in the DNMT3A and TET2, which happened to be the most frequent mutations in CCUS patients. 

What we found is that in those CCUS, [hematopoietic stem and progenitor cells] (HSPCs] in the stem cell compartment, we saw a myeloid-prime from that compartment with myeloid skewing, and reduced number in the stem cell number in the stem cell compartment... We conducted a trial from 2020 to 2023 led by Dr. Garcia Manero here at MD Anderson Cancer Center. We used canakinumab, a monoclonal antibody, which inhibits the binding from interleukin-1β to its receptor interleukin 1, receptor 1, to see if this drug could overcome this HSC aberrancy differentiation, this myeloid priming, and also reduce the pro-inflammatory cytokine and the pro-inflammatory environment that had these patients.

We were able to enroll 25 patients for a follow-up around 18 months. Although the result, the clinical activity of canakinumab, in these patients was limited, we found 2 specific patients, overall 4, but 2 specific ones that were able to show hematological improvement and transfusion-independence lasting for more than a year. When we checked for those 2 specific patients, we saw that they were the only 2 patients in the whole cohort that had single driving mutations, either by DNMT3A or TET2, which again happened to be the most frequent mutations in CCUS patients. 

We ran single-cell RNA sequencing in the Lin-negative, 34-positive HSPC compartment, as well as in the bone marrow mononuclear cells. We saw that after canakinumab treatment, at the time of response, we saw an increased differentiation of these HSC to the erythroid compartment as well as a down regulation of the [] signaling pathway. Moreover, in the bone marrow mononuclear cells and single-cell RNA sequencing analysis, we found a specific subset of T cells, which are called the CD8 positive [] T cells, which are related to many inflammatory conditions, that were actually reduced after canakinumab. Using our public repository of ligands, receptors, we were able to infer that this specific subpopulation of T cells were talking to the monocytic compartment, inducing more pro-inflammatory differentiation and a higher migration, which was also pretty much vanished after canakinumab at the time of response. 

However, when we check for patients that never show a response to canakinumab, we didn't see first a change in the bone marrow cell classes. We didn't see an expansion or a better differentiation to the erythroid compartment. There were no changes in the bone marrow either at the Lin–CD34+ HSPC compartment or at the bone marrow mononuclear cell analysis. We still saw some on-target engagement due to the observation of interleukin-1β and its receptor expression in that specific compartment. We saw it at the HSPC level at the monocytic level. However, seeing that even these patients were, not only DNMT3A and/or TET2 mutations were, however, they had additional mutations.

This suggests that in interleukin-1β—it is consistent with previous findings from the lab—it drives the pathogenesis of clonal hematopoiesis, but it does not play a role and it doesn't drive the progression from CCUS to MDS. Another important thing that we saw throughout the clinical trial and through the single cell and the multiomics analysis that we did is that not only the genes regarding [ ] were down-regulated at the time of response, but also genes regarding cardiovascular diseases were also down-regulated, which is consistent with previous findings in the CANTOS trial, where canakinumab was able to reduce cardiovascular recurring events in a specific subset of patients with prior myocardial infarction.

Overall, we were able to demonstrate that the most frequent CCUS mutations, DNMT3A and TET2, rewire the HSCs aging phenotype, and that this also was associated with a pro-inflammatory environment. Targeting interleukin-1β with canakinumab was able to rescue anemia in only the low-risk MDS patients that harbored DNMT3A and TET2 mutations, as a single-driver mutation. We also saw changes related to genes related to cardiovascular disease, which again is consistent with previous findings and published data regarding the CANTOS trial. 

We think that further clinical trials are needed regarding this specific subset of patients, the CCUS patients, which we don't really know which one of them should we be treating. It's still an exciting area, but we don't really know much about them. We know that they're a high risk of progression compared to [] patients. Further clinical trials using, for instance, drugs like canakinumab, may tell us if this preliminary data can be confirmed, if canakinumab can rescue anemia in these patients, can change the microenvironment to a less pro-inflammatory milieu, and also review genes related to cardiovascular disease, which, in this subset of patients, the low-risk MDS are actually at high risk of them. 

We're currently opening a new clinical trial here at MD Anderson using canakinumab for CCUS patients, trying to confirm our data. Thank you all for listening. 

Source:

Colla S, Rodriguez-Sevilla, JJ. Update on the Biology of MDS. Presented at 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX. Abstract MDS-234