The Future of Targeted Therapy in MDS

Dr. Shannon R. McCurdy
Shannon R. McCurdy, MD
Assistant Professor
Department of Hematology Oncology
Hospital of The University of Pennsylvania
Philadelphia, Pennsylvania

Managing MDS recently interviewed Shannon R. McCurdy, MD, a renowned oncologist at Penn Medicine, to learn more about the future of targeted therapy in MDS. In this interview, Dr. McCurdy discusses molecular markers that may be used to identify optimal treatments in MDS and evaluates the efficacy and safety of currently available targeted therapies. She also reviews the possible role of emerging targeted therapies and how they may enhance the management of MDS patients.

Can you provide an overview of the role of targeted therapies in MDS and at what point clinicians should consider using these treatments?

The primary therapies for treating myelodysplastic syndromes (MDS) currently recommended by guidelines from the National Comprehensive Cancer Network and approved by the FDA include erythropoiesis stimulating agents, azacitidine and decitabine, which are hypomethylating agents (HMAs), and lenalidomide, an immunomodulatory agent.1 Treatment with HMAs are standard of care for patients with higher-risk MDS.2 However, data show that HMA use induces responses in less than half of MDS cases, and the majority of these patients will relapse or develop progressive disease despite treatment. Ongoing clinical trials are now combining azacitidine or decitabine with investigational or existing therapies in hopes of achieving more synergistic activity and better patient outcomes.2

Lenalidomide, the only currently FDA-approved targeted therapy, is indicated for the treatment of patients with transfusion-dependent anemia due to low or intermediate-1 risk MDS. It is also approved for treating MDS with isolated del(5q), a distinct subtype of MDS.3 In studies leading to its approval, 83% of del(5q) patients responded to lenalidomide, usually by 1 to 2 months after initiating therapy, and two-thirds became transfusion independent for almost 1 year. Patients who achieved cytogenetic responses had a survival advantage, demonstrating a 10-year overall survival (OS) of 87%. However, response rates are much lower for MDS patients without del(5q) and for those with del(5q) and a TP53 mutation.4

With an immense need for more effective MDS treatments, clinical trials are exploring drugs that target TP53, splice factor mutations, IDH1, and IDH2 as single agents and in combination with HMAs. In addition, venetoclax, a BCL-2 inhibitor, combined with an HMA has shown promise in AML and is now being studied in MDS.5 In general, targeted therapies in the context of clinical trials should be considered in patients who failed to respond to HMAs or progressed during treatment. Targeted therapy should also be considered in MDS patients who relapse after undergoing an allogeneic blood or marrow stem cell transplant.1 Clinicians should also consider up-front clinical trial in patients with a TP53 mutation given the poor prognosis and response to standard therapies of this sub-type of MDS.

What is the role of molecular testing in MDS and why is collecting and interpreting data on molecular markers so important?

Molecular analyses at the time of diagnosis are essential to prognosis and prediction of response in MDS and for enrollment in particular clinical trials investigating targeted therapy. For example, research has shown that MDS patients with TP53 mutations are less likely to respond to lenalidomide and are at increased risk of transforming to acute myeloid leukemia (AML). Those with DNMT3A, FLT3, and RAS mutations, among others, are also at higher risk for transforming to AML. A repeat molecular analysis is warranted when patients exhibit clinical changes, such as progressive cytopenias, or if they develop new symptoms like fever, weight loss, night sweats, or any other signs of progression.6

Table: Incidence of Common Mutated Genes in MDS1,7

Mutated Gene Incidence in MDS Patients
TET2 >20%
SF3B1 >20%
ASXL1 >20%
SRSF2 >10%
DNMT3A >10%
RUNX1 >10%
TP53 >10%
U2AF1 >5%
ZRSR2 >5%
STAG2 >5%
TP53 >5%
EZH2 >5%
CBL >5%
NRAS >5%

Research shows that the most commonly mutated genes in MDS are TET2, SF3B1, and ASXL1, occurring in more than 20% of patients, but many other abnormalities also have important prognostic implications (Table). TP53, EZH2, ETV6, RUNX1, and ASXL1, among others, have all been associated with a poor prognosis.7,8 The presence of a TP53, ETV6, ASXL1, EZH2, or RUNX1 effectively raises the International Prognostic Scoring System (IPSS) risk by one risk group. As a group, splice factor mutations (SF3B1, SRSF2, ZRSR2, and U2AF1) are seen in approximately 50% of MDS cases.9 Other than SF3B1, which is associated with a good prognosis, splice factor mutations have been associated with low response rates to HMAs.10 An increasing number of mutations has also been linked to lower response rates to therapy. Although there are currently no FDA-approved therapies for MDS that target any of these point mutations, many clinical trials are investigating novel targeted therapies.

Which emerging targeted therapies being investigated in clinical trials appear to be especially promising as treatment options for MDS?

Many exciting targeted therapies are currently being assessed in clinical trials for the treatment of MDS and may soon play a significant role in how patients are managed. For example, research has shown that the isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) pathways appear to be important targets in MDS. IDH1/2 mutations are seen in 5% of MDS cases and are more prevalent in patients with higher blast counts and higher platelet counts.11,12 Ivosidenib, an IDH1 inhibitor approved by the FDA for AML, is now being investigated more closely as treatment for MDS. In a recent preliminary efficacy analysis, investigators observed a 91% overall response rate (ORR) for previously untreated MDS patients who received ivosidenib.13 Enasidenib, an IDH2 inhibitor, has also been approved as treatment for AML and is being evaluated in MDS. In a study of 16 MDS patients, enasidenib was associated with a 50% response rate in patients who had received a previous HMA.14

Rigosertib is another investigational targeted therapy that inhibits the KI3 kinase pathway. Studies previously found that rigosertib was not superior to best supportive care as treatment for high-risk MDS, but research also revealed that those who failed treatment with primary HMAs had a trend towards longer OS.15 A recent phase 2 trial found that combining oral rigosertib and standard-dose azacitidine elicited a response in the majority of HMA-treatment-naïve MDS patients. The combination also induced responses in a significant number of patients who failed prior HMA therapy. Based on these results, a phase 3 study of rigosertib plus azacitidine is underway in patients with MDS.16

BCL-2 overexpression is also common in MDS and can be targeted with venetoclax, an agent already approved for use in chronic lymphocytic leukemia or small lymphocytic lymphoma. It is now being investigated in combination with HMAs for the treatment of MDS. Early clinical trials have shown that venetoclax in combination with an HMA or low-dose cytarabine may be effective for relapsed/refractory MDS.17

In addition to these agents, researchers are actively exploring other novel therapies that are targeting TP53, one of the most challenging mutations in MDS because of its association with a poor prognosis, poor response to therapies, and short duration of response. In a recent trial, researchers found that all patients with TP53 mutant MDS receiving APR-246 plus azacitidine achieved responses. This combination was also associated with deep molecular remissions and was well tolerated.18

What factors should clinicians keep in mind when enrolling older patients with MDS in a clinical trial evaluating a targeted therapy?

Clinical trials assessing targeted therapies in combination with HMAs appear to be particularly promising for patients older than 75 years and/or those with poor performance status in whom standard high-intensity chemotherapy and allogeneic transplantation are associated with significant treatment-related mortality. Of note, preliminary data from trials of venetoclax plus an HMA or low-dose cytarabine are promising in the older high-risk MDS patient population or MDS that has progressed to AML. These combinations have a low associated treatment-related mortality but have been linked to significant treatment-related cytopenias.19

What is the likely trajectory of the impact of targeted therapies on the management MDS?

Over the past several years, next-generation sequencing has greatly expanded our knowledge of genetic markers in MDS, leading to the discovery of more than 45 genetic mutations.20 The future of MDS treatment lies in targeted therapy because the majority of novel drugs in development are focused on targeting commonly mutated genes. While high-risk MDS patients have the most to gain from novel therapies because of the life-threatening nature of their disease, it is important to recognize that even low-risk MDS patients may benefit from targeted therapies. For example, luspatercept is being studied in an ongoing phase 3 clinical trial for refractory anemia patients not responding to ESAs.21

A downside of targeted therapies is that they typically have efficacy for only one genetic mutation, which often represents a small proportion of MDS patients. However, recent estimates suggest that 45% to 60% of MDS patients have a splice factor mutation. Therefore, a drug developed to target this category of mutations could have widespread clinical utility.22 A wave of targeted therapies will likely be approved for MDS over the next few years, much like what was seen with FLT3 and IDH inhibitors that were approved for AML in 2017 and 2018. Similar to the impact of these drugs on AML, the treatment of MDS will be more targeted and effective, but it will also become more nuanced and complicated.


  1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Myelodysplastic Syndromes. Version 1.2019. October 18, 2018. Available at: Accessed November 20, 2018.
  2. Ball B, Zeidan A, Gore SD, Prebet T. Hypomethylating agent combination strategies in myelodysplastic syndromes: Hopes and shortcomings. Leuk Lymphoma. 2017;58:1022-1036. Available at: Accessed November 20, 2018.
  3. Allen T, Razavi GE. Targeted therapy in myelodysplastic syndrome. EC Cancer. 2016;2.1:34-44. Available at: Accessed November 20, 2018.
  4. Duong VH, Komrokji RS, List AF. Efficacy and safety of lenalidomide in patients with myelodysplastic syndrome with chromosome 5q deletion. Ther Adv Hematol. 2012;3:105-116. Available at: Accessed November 20, 2018.
  5. DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 2018;93:401-407. Available at: Accessed November 20, 2018.
  6. Nybakken GE, Bagg A. The genetic basis and expanding role of molecular analysis in the diagnosis, prognosis, and therapeutic design for myelodysplastic syndromes. J Mol Diagn. 2014;16:145-158. Available at: Accessed November 20, 2018.
  7. Bejar R, Stevenson K, Adbel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364:2496-2506. Available at: Accessed November 20, 2018.
  8. Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122:3616-3627; quiz 3699. Available at: Accessed November 20, 2018.
  9. Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal hematopoiesis to secondary leukemia. Nat Rev Cancer. 2017;17:5-19. Available at: Accessed November 20, 2018.
  10. Kuendgen A, Müller-Thomas C, Lauseker M, et al. Efficacy of azacitidine is independent of molecular and clinical characteristics - an analysis of 128 patients with myelodysplastic syndromes or acute myeloid leukemia and a review of the literature. Oncotarget. 2018;9:27882-27894. Available at: Accessed November 20, 2018.
  11. Gill H, Leung AYH, Kwong YL. Molecular and cellular mechanisms of myelodysplastic syndrome: implications on targeted therapy. Int J Mol Sci. 2016;17:440. Available at: Accessed November 20, 2018.
  12. DiNardo CD, Jabbour E, Ravandi F, et al. IDH1 and IDH2 mutations in myelodysplastic syndromes and role in disease progression. Leukemia. 2016;30:980-984. Available at: Accessed November 20, 2018.
  13. DiNardo CD, de Botton S, Stein EM, et al. Ivosidenib (AG-120) in mutant IDH1 AML and advanced hematologic malignancies: results of a phase 1 dose escalation and expansion study. Blood. 2017;130:725. Available at: Accessed November 20, 2018.
  14. Stein EM, Fathi AT, DiNardo CD, et al. Enasidenib (AG-221), a potent oral inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzyme, induces hematologic responses in patients with myelodysplastic syndromes (MDS). Blood. 2016;128:343. Available at: Accessed November 20, 2018.
  15. Garcia-Manero G, Fenaux P, Al-Kali A, et al. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17:496-508. Available at: Accessed November 20, 2018.
  16. Navada SC, Garcia-Manero G, Hearn KP, et al. Combination of oral rigosertib and injectable azacitidine in patients with myelodysplastic syndromes (MDS): results from a phase II study. Blood. 2016;128:3167. Available at: Accessed November 20, 2018.
  17. DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 2018;93:401-407. Available at: Accessed November 20, 2018.
  18. Sallman DA, DeZern A, Sweet K, et al. Abstract CT068: phase Ib/II combination study of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Cancer Res. 2018;78(suppl 13):CT068. Available at: Accessed November 20, 2018.
  19. Kubasch AS, Platzbecker U. Beyond the edge of hypomethylating agents: novel combination strategies for older adults with advanced MDS and AML. Cancers (Basel). 2018;10:158. Available at: Accessed November 20, 2018.
  20. Xu Y, Yan L, Hou G, et al. Application of next generation sequencing for prognostic stratification in myelodysplastic syndromes. Blood. 2016;128:5559. Available at: Accessed November 20, 2018.
  21. A phase 3, double-blind, randomized study to compare the efficacy and safety of luspatercept (ACE-536) versus placebo for the treatment of anemia due to the IPSS-R very low, low, or intermediate risk myelodysplastic syndromes in subjects with ring sideroblasts who require red blood cell transfusions. NLM Identifier: NCT02631070. September 18, 2018. Available at: Accessed November 20, 2018.
  22. Armstrong RN, Steeples V, Singh S, et al. Splicing factor mutations in the myelodysplastic syndromes: target genes and therapeutic approaches. Adv Biol Regul. 2018;67:13-29. Available at: Accessed November 20, 2018.