For a case of high-risk myelodysplastic syndrome [MDS], what are the newer medications that are on the table that might be very, very attractive? I would like to categorize this into 3 domains. The first domain is immune checkpoint inhibitors. Among them, we are paying significant attention to TIM-3 in combination with azacitidine. As you might remember, the combination has been associated with an overall response rate of 59% vs a single-agent HMA [hypomethylating agent] with a rate of about 42%. So the duration of response and the 1-year disease-free survival was 59% for the TIM3 inhibitor vs 32% for a single-agent HMA. So this is something that we should keep in mind for the case of 

[-mutated] MDS, even though the medication was paused recently by the FDA [United States Food and Drug Administration], we have a reactivation of enhanced 2 and 3. This will be for the medication magrolimab, which is a monoclonal antibody against CD47. CD47 is ubiquitously expressed in hematopoietic progenitors, and it's a molecule that might induce inhibition of prophagocytic activity by using the monoclonal antibody profile phagocytic activity increase stated, and it's preferentially observed among a subgroup of patients with 

-MDS. So we're paying significant attention to immune checkpoint inhibitors. And then I would like to move to the second domain which is the combination of azacitidine plus venetoclax, we have shown impressive responses, achieving almost 78% for high-risk MDS with excellent and durable remissions. The third domain would be the specific attention we should keep concerning those patients with high-risk MDS that are overexpressing RARA. As I mentioned before, almost 59% of these patients might upregulate RARA via super-enhancers. They've created an excellent biologic rationale for combination with HMA, and we will be paying attention to these 3 domains.

There will be a necessity—an urgent necessity, a biologic necessity—to understand biomarkers that respond to certain novel medications and biomarkers of durable response in high-risk MDS. So in regard to responses, I mentioned before that with the ability of immunophenotypic classification of MDS—whether or not we are going to be able to classify high-risk MDS in common myeloid progenitor-like disease or granulosa monocytic like-disease—we will be able to segregate a suitable patient that might be over expressing RARA. If that is the situation, then preferentially, we will derive or we will treat our patient with a combination of azacitidine and the RARAinhibitor. This is in the case that, potentially, we have a beneficial signal for the combination. So monocytic-like progenitors, AML [acute myeloid leukemia] have been associated with poorer responses to azacitidine and venetoclax, which I suspect will be the same situation for those patients with high-risk MDS. So phenotypic classification as a biomarker is emerging, and I'm expecting widespread use of this technology to better categorize the type of responses that we can have, to novel combinations of therapy. In regard to genomics, having P53 as an MDS-like disease should brand potentially, the possibility that immune checkpoint activation might be happening; therefore potentially using magrolimab in this setting might be beneficial.

Videos

Dr Gustavo Rivero comments on novel treatment combinations and potential new biomarkers in patients with MDS.

Future Perspectives in Higher-Risk MDS

The study SELECT-MDS-1 represents a significant advance in the way that we perceive the therapy of high-risk myelodysplastic syndrome [MDS]. We can lay out some ideas that might help us understand the rationale of combinational HMAs [hypomethylating agents] plus, the RARA [retinoic acid receptor alpha] inhibitor. I mentioned there is a subgroup of acute myeloid leukemia [AML] and patients with MDS who might overexpress RARA. It's conventionally believed that those patients that are overexpressing RARA might be less sensitive to venetoclax, which is a BCL-2 inhibitor. In the case of MDS it's expected [or] very likely in those patients who are exhibiting high expression of RARA to develop less sensitivity to hypomethylating agents. The combination will come from a set of recent developments, like trying to categorize MDS into 2 subgroups.

So the rationale for combinational HMA plus the RARA inhibitor will regain momentum and relevance if the classification of MDS can go beyond RIPSS-R [Revised International Prognostic Scoring System] only. I mentioned before that MDS could be categorized immunophenotypically as a CMP [common myeloid progenitor]-like disease and a GMP like-disease. CMP is a common myeloid progenitor MDS, and GMP is a granulocyte-monocytic progenitor-like disease. Granulocytic-monocytic progenitor disease is associated to likely have a high grade of RARA expression. This is a monocytic disease that has been historically associated with poor responses to HMAs like venetoclax, so I am predicting that it's likely that monocytic-like disease, MDS disease, might be responsive to this kind of normal combination.

The primary objective would be the overall response rate. And as I mentioned before, we will be able to determine the complete remission rate, the rate of partial remissions and hematologic improvement: erythroid, neutrophil, and platelet. I feel that with the development and the way that it has been strategized, the responses are appropriate.

How do I think azacitidine plus the RARA inhibitor might change the landscape of high-risk MDS? It will be extremely important to keep in mind that subgroup of patients with high-risk MDS, monocytic-like immunophenotypically, might exhibit a high grade of RARA overexpression. This condition might be associated with poor outcomes through a standard therapy of HMA—azacitidine or decitabine. So adding a RARA inhibitor that can stabilize the levels of RARA and induce further differentiation might improve significantly and very likely to respond beyond single-agent azacitidine and decitabine. Side effect-wise, remember for single-agent azacitidine cytopenia has been remarkable from cycle 1 to cycle 4. However, after cycle 4 the degree of cytopenia-transfusion dependency is minimized entirely as MDS-like cells are deleted. For the RARA inhibitor, the number of side effects has not been meaningful. I think grade 1/2 anemia has been described at initial therapy; however, these are not entirely magnified, synergized by the use of azacitidine or decitabine.

So for the side effects of the RARAinhibitor, I briefly mentioned that grade1 or 2 anemia has been described in almost 20% of the patients; however, in combination with azacitidine, it hasn't surpassed that level. A second adverse event is QT prolongation, grade 1 or 2, which has been mostly observed as a single agent. However, in combination with azacitidine, it also hasn’t passed that level.

A whole proportion of patients who are receiving hypomethylating agents in combination with their RARA antagonist experienced differentiation syndrome, which is characterized by a rapid increase in cytokines and is associated with hypoxemia, shortness of breath, swelling, and weight gain. There was some of this, and it is an additional adverse event that we should keep in mind.

Gustavo Rivero, MD, comments on the ongoing SELECT-MDS-1 trial and as well as reviewing the adverse events of the potential combination of tamibarotene with azacitidine in patients with higher-risk MDS.

SELECT-MDS-1: Review of Study Design and Objectives

: Historically, the 3 main high-risk myelodysplastic syndrome [MDS] have been concentrated on the use of hypomethylating agents. The 2 FDA [United States Food and Drug Administration]-approved agents are azacitidine and decitabine. These 2 agents’ composite overall response is about 45%, with almost 15% of the cases representing complete remission. The rest is an erythroid response of platelets and myeloid responses. So the 2 agents are equal in efficacy, but as I mentioned before, a substantial group of patients might exhibit primary refractoriness, and almost every single patient responding to the medication will develop secondary refractoriness.

The recent designation of tamibarotene as an orphan medication by the FDA represents an advance in the potential management of high-risk MDS. I just want to comment regarding the mechanism of action. I mentioned before that most of the data is being extrapolated from acute myelogenous leukemia. Specifically, a recent publication in 

 has revealed that pediatric acute myeloid leukemia [AML] may express in the same way adult AML expressesRARA [retinoic acid receptor, alpha] 

 super-enhancer. I explained that a super-enhancer is a new gene for which leukemia might develop an addiction, and these genes are no more than transcriptional deregulation in acute myelogenous leukemia. So, tamibarotene is a RARA agonist that creates a balance between the ligand, which is retinoic acid, and RARA overexpression by itself. By restoring RARA, acute differentiation might occur in cells that are specifically leukemic, but in the case of MDS, it is expected to leave about the same clinical benefit.

Dr Gustavo Rivero reviews the treatment options for patients with newly diagnosed higher-risk MDS and discusses tamibarotene’s recent orphan drug designation. 

A Potential Role for Tamibarotene in the Treatment of Higher-Risk MDS

 [gene expression] mean in the context of myelodysplastic syndrome [MDS]? I want to emphasize that most of the work has initially been done on acute myelogenous leukemia [AML], and this is an extrapolation of information about such a horrible disease. 

 is normally overexpressed in hematologic malignancy, via activation of super-enhancers. I want to explain what a super-enhancer is. It’s a new form of gene expression in our genome that isn’t expressed in normal conditions. Super-enhancers for 

 have been observed in almost 59% of acute myelogenous leukemia, which I think in the setting of high-risk MDS may be extremely relevant because it might be about the same proportion as in AML. So this overexpression of 

 is counter-regulated by retinoic acid ligands, and there is a significant imbalance between the ligand and the expression of 

We are seeing with significant enthusiasm the development of tamibarotene, which is a RARA agonist that restores the imbalance between the ligand and 

Dr Gustavo Rivero talks about the significance of the RARA gene in patients with higher-risk MDS. 

RARA Gene Expression in Higher-Risk MDS

: I am Gustavo Rivero. I am an associate professor in hematology-oncology at Baylor College of Medicine [Houston, Texas]. I concentrate my efforts on treating acute myelogenous leukemia and myelodysplastic syndrome [MDS].

I want to emphasize that myelodysplastic syndrome is a very unique entity. It's mainly classified as an apoptotic-like disease and being more resistant to apoptosis. It is a spectrum of disorders that we normally can distinguish by classifying the entity via the Revised International Prognostic Scoring System. There are some items that we should keep in mind for the risk stratification, which include the depth of anemia, thrombocytopenia, neutropenia, the number of blasts, and specifically the cytogenetic abnormalities that the patient might have at disease initiation. So the risk stratification allows a subcategorization for these entities into a low-risk biology and a high-risk biology. Points are assigned in an increasing mode; the higher the score, the more likely the patient will have high-risk disease vs with a low score, the patient will be categorized as having a low-risk disease. This is normally what we do in clinical practice every day.

Biomarker testing is becoming extremely relevant for acute myelogenous leukemia and myelodysplastic syndrome. There is an increasing necessity for detecting what type of drugs might be implemented in subcategories of patients with MDS. Specifically, we have retained a very agnostic therapy, which is an intravenous hypomethylating agent. Hypomethylating agents are azacitidine and decitabine, which are medications that have been associated with an overall response rate of 45%. However, there is a group of patients who won’t respond to the intervention, and these subgroups of patients are categorized as primary refractory. Almost every patient responding to the medication will develop secondary failure.

So biomarker testing is especially important because it will select the patients who might respond to normal interventions. Among them, we have recent evidence that subcategorization for MDS is grouped into monocytic-like and myeloid-like. These MDS groups might reveal a path for incorporation of novel therapies like RARA inhibition, and even a subgroup of patients in the high-risk setting who might respond better to BCL2 inhibition.

An overview of myelodysplastic syndrome (MDS) and the role of biomarker testing in patients with the disorder.

Overview of Myelodysplastic Syndrome and the Importance of Biomarker Testing

Gustavo Rivero, MD, associate professor, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, discusses evolving therapies for patients with acute myeloid leukemia (AML) with monocytic differentiation.

The current standard of care for patients with AML who are ineligible for intensive chemotherapy is the combination of a hypomethylating agent (HMA) and venetoclax (Venclexta), Rivero says. However, patients with monocytic differentiation often display inferior responses to this regimen, Rivero explains.

Recent evidence suggests that AML with monocytic differentiation can have lower BCL-2 expression and higher MCL-1 expression, potentially explaining their resistance to HMAs and venetoclax and serving as prognostic markers.

Sponsored in part by Servier Pharmaceuticals. Content independently developed by OncLive.

Gustavo Rivero, MD, discusses evolving therapies for patients with acute myeloid leukemia with monocytic differentiation.

Gustavo Rivero, MD

Articles

Future Perspectives in Higher-Risk MDS

SELECT-MDS-1: Review of Study Design and Objectives

A Potential Role for Tamibarotene in the Treatment of Higher-Risk MDS

RARA Gene Expression in Higher-Risk MDS

Overview of Myelodysplastic Syndrome and the Importance of Biomarker Testing

Dr. Rivero on Monocytic Differentiation in AML