Myelodysplastic Syndrome (MDS) is a term used to encompass of family of malignant diseases where immature blood cells in the bone marrow fail to become healthy blood cells. The result of this defect is that individuals with MDS can fail to make mature blood cells (i.e. have ineffective hematopoiesis associated with reduce numbers of certain blood cells), and have a predisposition to develop acute myeloid leukemia (AML). MDS is distinguished from AML based on the number of immature blood cells detected; patients who have less than 20% blasts (e.g. immature blood cells) in the bone marrow do not have AML but may have MDS.

In the US, 20,000 new cases are reported every year in the US, making MDS one of the most common blood cancers. The prevalence of MDS has been poorly assessed, but is estimated to be between 60,000 – 170,000 patients in the US. Advanced age is the predominate risk factor, with a median age of diagnosis of 71-76 years. A scoring system was developed to further refine which patients fall into the following risk categories: very low, low, intermediate, high and very high; the range of median survival times for these categories are 8 months to 8 years. Approximately 25-30% of MDS patients have high-risk disease. The disease can progress to high-risk MDS and secondary AML in approximately 30% of cases. Although deaths can result from AML, mortality in MDS patients can be due to bleeding or infection without AML.

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Current Treatments for MDS

Myelodysplastic syndrome (MDS) has seen very little progress in clinical development with only three therapies approved for patients. Two new exciting agents are currently being developed in frontline MDS that have the potential to change the landscape dramatically. LLS funded Forty Seven and another company, Aprea, are currently exploring their agents in combination with azacitidine, the current standard of care for MDS, in registration enabling trials. There is still much work to be done but LLS is leading the charge for ongoing and future work to change the MDS treatment landscape.

Currently, there are limited treatments for MDS. The only known curative therapy is a hematopoietic stem cell transplant (HSCT) from an allogeneic matched donor, which is used in younger patients (who can tolerate this therapy) who have more advanced disease. HSCT is not entirely effective and mortality after transplantation is high due to relapsed disease or transplant-related complications. Treatment-related mortality from HSCT occurs in approximately 30% of patients. FDA approved therapies are azacitidine and decitabine for intermediate to high-risk MDS and lenalidomide for patients with transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion the 5q chromosome.

Promising New Therapies and Future Directions.

Novel therapies from both Forty Seven and Aprea are very promising clinical updates were presented at recent scientific meetings, including the annual American Society of Hematology (ASH) meeting in December 2019 and the American Society for Clinical Oncology (ASCO) in May 2020. News from both companies are below:

• Forty Seven announced in July 2019 additional funding commitments from The Leukemia & Lymphoma Society (LLS), aimed at accelerating the development of 5F9 (anti-CD47 antibody) for the treatment of MDS. Forty Seven presented updated initial data from its Phase 1b clinical study of 5F9 in patients with MDS at a recent international scientific meeting in May 2020, showing an overall response rate (ORR) of 91% and a complete response (CR) rate of 42% among patients treated with 5F9 in combination with azacitidine. Forty Seven plans to initiate a randomized, registration-enabling trial in higher-risk MDS patients in the second quarter of 2020.
• Aprea Therapeutics announced that the FDA has granted Fast Track and Breakthrough designations to APR-246 for the treatment of patients with MDS having a TP53 mutation. Mutations in p53 are found in up to 20% of MDS and AML patients and are associated with poor overall prognosis. Aprea has commenced a Phase 3 clinical study in p53 mutated MDS and completed enrollment in two Phase 1b/2 clinical trial in p53 mutated high-risk MDS, one in the US and another in Europe with APR-246 and azacitidine. The ORR were between 74-88%, with ~60% patients achieving a CR.

In the past 15 years, LLS has invested heavily into research examining the molecular basis of MDS and a great deal of progress has been made. In particular, MDS is derived from precursor blood cells that may contain mutations in many genes. The genes that are frequently mutated in MDS are also found in patients with secondary AML, and some are seen in de novo AML. It is generally believed that secondary AML arises from MDS following the acquisition of additional mutations. In addition, some of the mutations in MDS are also detected in healthy patients with no disease detectable; the phenomena is called clonal hematopoiesis of undetermined potential (CHIP), and may be a precursor state for some patients who develop MDS as well as other blood cancers.

Mutational analysis of MDS is important for many reasons. First, certain mutations place patients in categories for low or high risk of progression or treatment outcomes and therefore have prognostic value. Second, certain mutations may have therapies that specifically target the mutations and therefore, such drugs may eliminate, or control the growth of, the cell with the mutation. In particular, an oral small molecule inhibitor of IDH2 has demonstrated efficacy in AML and was recently approved by the FDA for patients with AML that have IDH2 mutations. This mutation also occurs in MDS (although it is found in less than 5% of patients). It is also conceivable that that mutational profile may be segregated to different types of MDS, which suggest that personalized therapies for subtypes of MDS will be needed. Third, mutational profiles help identify patients that may preferentially respond to regulators of epigenetic changes, such drugs as azacitidine or decitabine, which are approved therapies for MDS. Alternatively, mutations in one pathway may indicate sensitivity to drugs that regulate collateral pathways that control the disease. Unfortunately, many of the mutated genes found in MDS patients do not have drugs that specifically target the genes leading to selective cell killing. Therefore, these mutations are, in part, a focal point of drug discovery and development programs funded by LLS.

The ultimate goal of LLS is to develop curative therapies for all types of MDS. To get to this endpoint, a considerable amount of research and development will be needed. It is our firm belief that understanding the causative basis for MDS through intensive research will lead to new therapies that can control MDS. Our beliefs that precision medicine and immunotherapies will lead to cures are reinforced by such success that have been used to treat many hematological malignancies, including acute lymphoblastic leukemia, certain types of AML, chronic lymphocytic leukemia, as well as other hematological diseases.

LLS currently has several active grants that have a major focus on MDS in addition to many other grants also focused on AML. Beyond this, since a greater understanding of all blood cancers are likely to be relevant to MDS, LLS brings to forefront its entire 210 active grant portfolio, which represents more than a $100 M commitment (over approximately 3-5 years) to blood cancer research.

Here are some of the key areas of research funded by LLS that are being addressed by our awardees focused on MDS as well as areas that could be explored in the near future with additional funding:

1. Understand how mutations in epigenetic regulators lead to MDS. This will help define how to use emerging molecules that target epigenetic regulators in MDS. (Tak Mak, University Health Network & Stephen Nimer, University of Miami)
2. Dissect and understand how defects in the RNA splicing machinery lead to MDS. Since splicing is controlled by a multi-protein system, mutations within individual proteins need to be identified and proven to lead to MDS/AML. Develop therapeutics to target specific mutated proteins in the splicing machinery and test those in the clinic. The problem is complex since it is possible that two or more mutations occurring simultaneously lead to disease. (Robert Bradley Ph.D. at the Fred Hutch Cancer Center & Yan Liu Ph.D. at Indiana University)
3. Understand the molecular events that control normal blood cell production. We already know many of the master controlling elements (e.g. many transcription factors) that regulate blood cell development, but their interaction and sequencing are areas that need further exploration. By understanding how the normal hematopoietic system works, a deeper understanding of the disease state can emerge. Furthermore, since MDS is a disease that is associated with aging, we need to understand how the molecular basis of hematopoietic system ages over time. (Maria Figueroa M.D., University of Miami)
4. Develop superior methods to activate the immune system that will selectively kill MDS cells. Such adoptive immunotherapies include the use of so-called natural killer cells, which can be harvested and given to patients with MDS or AML. Other therapies can activate the immune system by removing signals that turn off the immune system (provided by the tumor cells or in the stroma). Further research into understanding how/if the aging immune system leads to CHIP, MDS, or AML will be needed to help explore the use of immune activators for the treatment of these diseases. (Amer Zeidan, MBBS, MHS at Yale University)
5. Identify and develop novel inhibitors of leukemic stem cells that cause MDS. It is believed that eliminating the stem cell that causes the disease will be required to cure patients. Current therapies often do not eliminate these cells, which may be why the disease returns after therapy.
6. Understand the regulation and targeting of inflammatory circuits in MDS. Defining the causes of chronic inflammation in the bone marrow of MDS patients could reveal new targets that can be exploited to treat patients and restore proper blood cell development and immune cell function. Thus, by exploring how to precisely block key regulators of inflammation in MDS by developing new drugs or repurposing existing drugs that will restore proper blood development in MDS patients would be impactful.

The image was originally published in ASH Image Bank. Girish Venkataraman, MD, MBBS and James Godfrey, M.D.: MDS-RS-MLD-Aspirates. ASH Image Bank. 2018;62008. © the American Society of Hematology.