Practical Strategies for Improving Outcomes in MDS: New HMAs, Combination and Novel Treatments

Dr. Aziz Nazha
Aziz Nazha, MD
Assistant Professor, Lerner College of Medicine
Associate Staff, Taussig Cancer Institute
Cleveland Clinic
Cleveland, Ohio

Risk stratification is critical when managing patients with MDS because guideline consensus treatment algorithms are distinguished by lower-risk disease and higher-risk disease. In an interview with Managing MDS, Dr. Aziz Nazha explains next steps after risk stratifying your patient and the goal of therapy based on this assessment. He will also review novel formulations of hypomethylating agents (HMAs) in development and their potential use in MDS. Lastly, Dr. Nazha will cover key genetic mutations and the potential future investigations.

Dr. Nazha, could you please provide a brief review of the current therapy landscape in myelodysplastic syndrome (MDS), including the limitations of current approved therapies?

The first step in patient management is to risk stratify patients into either lower-risk disease, with lower-risk of progression to acute myeloid leukemia (AML) or to higher-risk disease, with greater chance of progression and of leukemia transformation. The way we make that determination is by using the International Prognostic Scoring System, IPSS, or more recently, the IPSS-R, the revised version of the scoring system. Stratification is critical because guideline consensus treatment algorithms are distinguished by these two categories, and the FDA-approved drugs are different in the lower- and higher-risk setting.1 For higher-risk disease, the treatment is more aggressive, and the goal of therapy is different than for lower-risk disease. We tend to offer allogeneic stem cell transplantation (ASCT) to patients who qualify for the procedure because the benefit from the transplant outweighs the risks for patients in the higher-risk category. So, we recommend transplant as a curative option for patients with higher-risk disease. Otherwise, patients with higher-risk disease who are not candidates for transplant would receive hypomethylating agents (HMAs) until disease progression or development of intolerance to HMA therapy.2 Two agents, azacitidine and decitabine, are FDA-approved for use in higher-risk disease. The goal of this therapy is to prolong survival and improve quality of life of the patient. Overall, the response rate to this therapy is about 30% to 40% and if the patient responds, the response duration is about on average 18 months.2-4 For example, azacitidine has been associated with a median survival of 24 months, compared with chemotherapy, low-dose cytarabine, or best supportive care.2,3 A similar survival rate has not been seen with decitabine; however, many clinicians consider the treatments comparable.2 Because the effects of HMAs are limited, the majority of the patients, or almost all of them, will either not respond or will lose their response subsequently, termed hypomethylating agent failure. Their outcome is very poor with a median overall survival less than six months because there are no FDA-approved drugs that can improve the outcomes of this patient population.2,5-7

The goal of therapy with lower-risk disease is not mainly focused on survival, but to improve patient quality of life (QOL). These patients may have anemia, thrombocytopenia, or neutropenia, and some of those patients will have multiple cytopenias (anemia, thrombocytopenia, and neutropenia), and then the goal is to try to improve those cell lines overall. If the problem is anemia, therapy centers on erythropoietin-stimulating agents (ESAs) if a patient’s erythropoietin (EPO) level is <500 U/L).2 Other agents we could use in that space include HMAs, typically after ESA failure, or if the patient has multiple cytopenias. Data have demonstrated that shorter courses of HMAs may be effective, with decitabine providing a 32% transfusion independence rate and 70% overall response rate (ORR) vs azacitidine (16% transfusion independence rate/49% ORR).2,8 If the patient has a genetic abnormality called del(5q) which is typically present in about 5% to 10% of MDS patients, lenalidomide is FDA-approved in that setting, and the erythroid response rate to this agent is approximately 65% to 70% transfusion independence with 30% to 40% cytogenetic remission.2,9,10 There has also been a phase 3 trial using lenalidomide in non-del(5q), and the response rate to lenalidomide was 27% in that setting.11 If a patient with lower-risk MDS has a ring sideroblast SF3B1 mutation, the recombinant fusion protein luspatercept may be considered although this agent is not yet FDA-approved in this setting. This agent reduces SMAD2 and SMAD3, and the MEDALIST trial demonstrated that luspatercept provided transfusion independence of >8 weeks for 28% of patients treated vs 13% who received placebo, along with also achieving greater prolonged transfusion independence (28% vs 8% for weeks 1 through 24, and 33% vs 12% for weeks 1 through 48, respectively).12

How is failure to respond to HMAs defined and what are the most common therapeutic resistance mechanisms?

Most HMAs are administered through about 4 to 6 cycles of therapy. I tend to go for 6 cycles because we have shown that if you continue beyond 4 cycles to 6 cycles, about 85% of the patients will achieve their best response.2,3,13 Primary response failure to respond to HMAs occurs when there is no response after at least 4 to 6 HMA cycles, when the MDS progresses to one of the higher-risk states, or transforms to AML without having responded to therapy.13,14 Secondary failure of response to HMAs is defined as the loss of response or similar disease transformation in those who had an initial therapeutic response. Although some clinical parameters and genetic mutations have weak correlations with favorable HMA response, the molecular mechanisms underlying HMA resistance are poorly understood.13,15,16 I personally don’t think we really fully understand the mechanisms of resistance at this point in time.

Let’s move on to discussing the novel formulations of HMAs in development, such as oral azacitidine, guadecitabine or ASTX727, and their potential use in MDS.

Development of agents for resistance MDS is an area of continuous clinical investigation. Oral azacitidine is undergoing investigation because the usual formulation requires 7 days of intravenous (IV) or subcutaneous (SC) infusion creating substantial patient burden. Data presented at the 2019 America Society of Hematology (ASH) meeting included a study that showed that treatment with CC-486, an oral azacitidine formulation, improved overall survival (OS) and relapse-free survival (RFS) when used as maintenance therapy in patients with AML.17 Multiple clinical trials are ongoing studying this oral formulation in patients with MDS.18 Guadecitabine is essentially a “super drug,” similar to decitabine but with a mechanism to internalize the drug inside the cells. Early phase 1/2 data in patients with intermediate- to high-risk MDS showed an ORR of 55% in patients who were treatment-naïve and 43% in patients with relapsed disease.19 There is also interest in ASTX727 which is a compound that contains decitabine and cedazuridine, a cytidine deaminase inhibitor that inhibits decitabine degradation in the liver, allowing oral administration of this combination. Phase 1 data, in which 47% of patients studied had relapsed disease, showed an ORR of 32%.13,20 Phase 2 data confirmed that the fixed-dose combination of these two agents emulates IV decitabine, with a similar safety profile.13,21 Phase 3 studies are now undergoing investigation for ASTX727.13,18

How is BCL2 being investigated as a target and what are the key results surrounding BCL2 inhibitors, namely venetoclax?

There is always interest in venetoclax. Data in patients with relapsed/refractory (R/R) MDS and AML treated with venetoclax in combination with either azacitidine or decitabine in the majority of patients found an ORR of 21% with a median OS of 3 months.13,22 An ongoing phase 1 clinical trial studying the combination of venetoclax and azacitidine in higher-risk patients with MDS is ongoing.13,18

Let’s move on to the immune checkpoint inhibitors. What about these agents, such as pembrolizumab and ipilimumab, and the data surrounding them?

There are two camps surrounding thoughts on these agents; some people are enthusiastic and some people don’t see any value in MDS, and I tend to be in the “no value” camp for their use in either MDS or AML. Looking at early data, ipilimumab monotherapy proved to be safe in patients with MDS and HMA failure, but demonstrated limited efficacy.23 Preliminary data on the combination of pembrolizumab with azacitidine in a phase 2 trial showed that the combination was well-tolerated, and in seven patients, one achieved complete response (CR), one demonstrated hematological improvement, but five had disease progression.13,24 As single agents, these drugs don’t work at all in MDS. When you combine them with azacitidine, you get some response, and the question remains if that would be the response you would get from azacitidine alone. I would argue that it is, but with more toxicity, and again, it's worth it to mention that this is a very controversial topic.

What are the key genetic mutations that we are looking at undergoing current and potentially future investigations?

TP53 is a tumor suppressor gene that is beneficial in itself; however, TP53 mutations have been associated with several adverse features in terms of prognosis, including lower median platelet count, and high median, bone marrow blast percentage, both of which are unfavorable disease risk factors. In addition, these mutations are linked to lower survival.25 APR-246 is a prodrug spontaneously converted to methylene quinuclidinone that binds to cysteines in mutant p53, resulting in protein reconfirmation that reactivates TP53 pro-apoptotic and cell cycle arrest functions. As a single agent it doesn’t have that much activity, but when combined with azacitidine data in patients with TP53-mutated MDS and AML has shown an ORR of approximately 75% in the evaluable population per protocol, with a 63% response rate in the intent-to-treat (ITT) population.26 The FDA granted a breakthrough designation to this drug combination for the treatment of TP53-mutated MDS in January 2020. APR-246 received the FDA’s fast-track and orphan drug designation in April 2019, and phase 3 investigation is ongoing.27

Mutations in isocitrate dehydrogenase 1 or 2 (IDH1 and IDH2) promote aberrant leukemogenesis. IDH1 and IDH2 inhibitors (eg, ivosidenib and enasidenib) are FDA-approved in AML, but we have been using them off-label in MDS.13 Mutated IDH1 or IDH2 is present in about 4% to 12% of patients with MDS, so it’s a small patient population.13,28 That said, enasidenib is currently undergoing investigation in combination with azacitidine in patients with IDH2-mutant MDS.18

Another area of interest is targeting CD47, a macrophage immune checkpoint. A first-in-class anti-CD47 agent, Hu5F9-G4 is in early development for treatment of MDS and AML, with early results as monotherapy or with azacitidine demonstrating a CR/CRi of 60% in patients with MDS.29 It’s something to consider, but to be honest, it’s a little bit too early to draw conclusions here.

Imetelstat is a telomerase inhibitor and data presented at ASH in 2018 showed that the agent provided an 8-week transfusion independence rate of 42% in heavily transfusion-dependent patients with lower-risk R/R MDS.30 Clofarabine is a second-generation nucleoside analog with a potential role in HMA failure, but treatment was associated with high rates of adverse events (AEs) that required significant supportive care, and investigation was halted.13 CPX-351 is a liposomal formulation of cytarabine daunorubicin recently approved for use in patients with secondary AML and newly-diagnosed therapy-related AML and is undergoing investigation in patients with MDS after HMA failure.13,18 One final note, our group has an ongoing clinical trial that actually uses vitamin C with azacitidine to target TET2 mutations in high-risk MDS, and we have enrolled about 11 patients. The investigation is still in the early phases, but it may show the value of vitamin C in TET2-mutated MDS.18

One final question. What do you consider the most critical treatment factors if you’re going to use a new drug on a patient with resistant MDS or place them in a clinical trial?

As we talked about all the responses and duration of response, what you can see really, is that one of the disappointing areas of leukemia is MDS. So you have three FDA-approved drugs, azacitidine and decitabine approved in 2004 and 2005, and then lenalidomide approved only in del(5q) and that is all that is available You have nothing else that is FDA-approved, and as we mentioned when the patient fails azacitidine, their outcome is very poor, so this is a very big area of investigation. Even upfront, we’re trying to study drug combinations with azacitidine, and we have not been successful. The short answer to this is that I think all patients with MDS should be in a clinical trial whether the protocol is azacitidine combined with something or HMA combined with something or after treatment failure. We know that after they fail HMAs, patients do not have much in the way of options except supportive care, low-dose cytarabine, or clinical trial, so all of those patients should be in a clinical trial with novel therapy. There simply is no cure at this point in time. In addition, one must look at these compounds in the early phases with a grain of salt because you have huge patient selection bias in clinical trials, and often a smaller number of patients which can present challenges to actually interpreting those results. For patients and the community oncologists whose patients experience HMA failure, clinicians should definitely consider a clinical trial, as this remains a huge area of unmet need.


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