Current State of Myelodysplastic Syndromes: Standard Treatment Practices and Therapeutic Advances

Abstract: Patients with myelodysplastic syndromes (MDS) collectively have a high symptom burden and are also at risk of death from complications of cytopenias and acute myeloid leukemia. The goals of therapy for patients with MDS are to reduce disease-associated symptoms and the risk of disease progression and death, thereby improving both quality and quantity of life. Treatment is based on the type of MDS, MDS risk group, and other factors, as well as patient age and overall health. Often more than one type of treatment is used. This article discusses the novel MDS therapies in development, with a focus on those that seem most likely to reach regulatory approval.

Treatment options for patients with myelodysplastic syndromes (MDS) remain fairly limited. Per National Comprehensive Cancer Center Network guidelines, current therapies include lenalidomide, growth factors, hypomethylating agents (HMA), and allogeneic hematopoietic cell transplant (allo-HCT).¹ Despite years of therapeutic stagnation, several promising agents have recently emerged as front runners for potential approval, hopefully breaking the 10-year drought in approvals for this disease. These include luspatercept, rigosertib, splicing inhibitors, IDH inhibitors, and small molecules targeting apoptosis. Despite the historical failure of combination strategies in MDS, recent data with novel combinations and “enhanced” DNA methyltransferase inhibitors such as guadecitabine show promise. A cautious optimism is emerging about the future of novel MDS therapies. Here we summarize some recent advances in the management of patients with MDS.

Current State of MDS and Standard Treatment Practices

MDS refers to a heterogenous group of myeloid disorders characterized by somatically mutated hematopoietic stem cells, the presence of variable peripheral cytopenias, and a broad risk of progression to acute myeloid leukemia (AML).² MDS is most prevalent in older adults, with the median age at diagnosis ranging between age 70 and 75 years.¹ The incidence of MDS in the United States increases exponentially from age 40 where the rate is 0.2 per 100,000 people, to age 85 where there are 45 cases of MDS per 100,000 people.² Currently there are approximately 10,000 to 15,000 new cases of MDS diagnosed annually in the United States. The exact number of new cases is unknown; however, the incidence is believed to be increasing.³ With the aging demographic of the US population, the incidence of MDS and AML are likely to increase. 

Despite an improved understanding of disease biology in MDS, novel therapeutics have been limited. No new drugs for MDS have been approved in the last 10 years. Growth factors, immunosuppressive therapy, and lenalidomide are the standard of care for lower risk MDS, while hypomethylating agents, ie, azacitidine and decitabine, as well as allo-HCT remain the standard of care for higher risk patients.² For those who fail to respond to the standard of care, outcomes are dismal.⁴ There is a guarded optimism owing to data from promising early phase trials as well as a phase 3 trial in low-risk disease in the management of MDS. There remains a pressing need to enroll patients in therapeutic MDS clinical trials to alter the current stagnation in approved therapies. Stringent inclusion criteria of clinical trials pose a challenge to MDS clinical trials accrual, as typical MDS patients are older in age and often have comorbidities. Figure 1 depicts a snapshot of current treatment pathway for MDS management. 

In this article, we will discuss the novel MDS therapies in development, with a focus on those that seem most likely to reach regulatory approval.

Novel Therapies in the Pipeline

Lower Risk MDS

Luspatercept (ACE-536) is a modified activin receptor IIB-IgG Fc fusion protein that targets transforming growth factor beta (TGF-B) signaling via Smad2/3 and growth and differentiation factor 11 (GDF-11) enhances late-stage red blood cell (RBC) maturation.⁵ ACE-536 was investigated in patients with lower risk MDS; this agent was developed for transfusion-dependent, anemic patients who do not meet criteria for erythropoiesis stimulating agents (ESA) therapy or who have failed to respond to such treatment (Figure 1).⁶ In practice, this agent has shown the most promise for patients with ringed sideroblasts (RS), particularly those harboring mutant SF3B1. In a phase 2 trial, PACE-MDS, examining the safety and efficacy of luspatercept, 63% of the 51 patients treated with higher-dose luspatercept achieved hematological improvement-erythroid (HI-E), and 38% of 42 patients eligible for RBC transfusion independence (RBC-TI) achieved RBC-TI.⁶ The PACE-MDS study also revealed a significant response among patients with RS levels of at least 15% and SF3B1 mutations; 69% and 77% achieved HI-E, respectively.⁶ Recently, a randomized, double-blinded, phase 3 trial (MEDALIST) enrolled participants with lower risk MDS with RS with the primary endpoint of RBC-TI for at least 8 weeks.⁷ A total of 229 patients received luspatercept 1 mg/kg subcutaneously every 21 days or placebo in a 2:1 randomized fashion. Of the 153 patients who received luspatercept, 58 participants (38%) met the primary endpoint of RBC-TI compared with 10 participants (13%) in the placebo group with a mean hemoglobin of >1.5 g/dL for 8 weeks (P <.0001).⁷ Most common treatment-related adverse events (AEs) included fatigue, dizziness, asthenia, and diarrhea.⁷ Luspatercept is currently under Food and Drug Administration (FDA) review for approval in lower risk MDS with RS.

Imetelstat is a telomerase inhibitor currently being studied for lower risk MDS patients who are transfusion-dependent and have failed with ESA. In a prior study, myelofibrosis patients on imetelstat had achieved complete responses in the setting of U2AF1 or SF3B1 mutations.⁸ The IMerge study, a phase 2/3 clinical trial, focused on lower risk MDS patients who were transfusion-dependent as well as refractory to ESA and naïve to lenalidomide and/or HMA.⁹ The rates of 8- and 24-week TI were 37% and 26%, respectively.⁹ The 24-week TI responses were accompanied by a rise in hemoglobin of at least 3 g/dL, and the HI-E rate was 71%.⁹ The side effects were mostly related to cytopenias. The phase 3 part of the study is soon to begin patient enrollment.⁹ 

Iron chelation therapy is a key component of managing lower risk MDS patients with transfusion requirement. The randomized, double-blind, phase 2 TELESTO trial evaluated the safety and efficacy of deferasirox vs placebo in 225 adults diagnosed with low/intermediate-1 MDS who had iron overload.¹⁰ The primary endpoint was an event defined as a composite of liver function abnormalities, cardiac abnormalities, transformation to AML, or death. Participants were required to have a significant transfusion history, an elevated serum ferritin, and be free from cardiac, liver, and renal abnormalities. Patients in the deferasirox group experienced significantly longer median event-free survival  compared with the placebo group; 1440 days vs 1091 days (P=.01).¹⁰ However, the median overall survival (OS) was not significantly different between the two groups. The rate of all severe AEs was comparable in both groups.¹⁰ Despite lack of survival advantage, specific subsets of MDS patients with high transfusion burden might benefit from iron chelation.

Improved HMA 

Improved HMA had not been available to take orally due to rapid clearance by cytidine deaminase in the gastrointestinal tract and liver.¹¹ 

ASTX727 is a combination of oral decitabine (DAC) with an oral cytidine deaminase inhibitor (E7727). In a phase 1 study,  ASTX727 achieved the pharmacokinetic objective of matching intravenous (IV) decitabine under the curve (AUC) levels with a similar safety profile.¹¹ A phase 2 trial showed that an oral fixed dose of ASTX727 (100 mg cedazuridine and 35 mg DAC) successfully followed the AUC of IV decitabine with 5-day treatment.¹² The pharmacokinetic equivalence of ASTX727 to decitabine is currently being confirmed in a phase 3 study.

Guadecitabine (SGI-110) is a dinucleotide of decitabine and deoxyguanosine that is resistant to degradation by cytidine deaminase compared with other DNA HMA, resulting in a longer in-vivo half-life.¹³ This drug is being investigated in patients with prior failure with HMA. In a phase 2 study focusing on patients with higher risk MDS and AML with 20% to 30% blasts, all of whom had previously failed azacitidine, the overall response rate (ORR) was 14.3% with an OS rate of 7.1 months.¹⁴ There was a response rate of 26% and 9% in patients with primary HMA failure and relapsed disease, respectively. None of the 11 patients with TP53 mutation responded to treatment. The tolerance was similar to that of standard HMA, though 18 of the 55 patients who received SGI-110 had a dose reduction.¹⁴ In a recent phase 2 study, 94 patients with previously untreated intermediate-2 or high-risk MDS were treated with SGI-110. ¹⁵ The ORR was 61% with a complete response rate of 22%.¹⁵ There is an ongoing phase 3, randomized, open-label study comparing guadecitabine vs treatment choice (TC) for patients with MDS and chronic myelomonocytic leukemia (CMML) after failure of azacitidine, DAC, or both agents (NCT02907359).¹⁶ TC includes low-dose cytarabine, standard 7+3 intensive chemotherapy with cytarabine and an anthracycline, and supportive care. 

Combination Strategies

Combining histone deacetylase inhibitors with HMA therapy thus far has not yielded significant improvements in MDS treatments. A phase 2 study revealed that the combination of azacitidine with pracinostat did not improve survival when compared with azacitidine plus a placebo. In the experimental group, pracinostat was discontinued in 20% of patients due to AEs.¹⁷

The combination of hedgehog inhibitors and azacitidine is currently being studied in both AML and MDS. Smoothened (SMO) gene, when silenced in the hedgehog pathway (HhP), has been identified as a sensitizer to azacitidine in some patient samples.¹⁸ The inhibition of SMO with erismodegib when combined with azacitidine showed a degree of synergy in AML and MDS patient samples.¹⁸ A phase 1/1b trial of azacitidine with erismodegib or DAC is currently underway to further investigate HhP inhibition in those with myeloid malignancies (NCT02129101).¹⁸ The combination of glasdegib, a hedgehog inhibitor with cytarabine and daunorubicin (7+3 schedule) in patients with high-risk MDS or untreated AML is being investigated. In a recent phase 2 study (NCT01546038) with 69 patients, 46.4% achieved an investigator-reported complete remission with a median OS of 14.9% months and a 12-month survival probability of 66.6%.¹⁹ Among the patients older than 55 years, 40% achieved a complete remission. The study also revealed no significant associations between mutational status and clinical response.¹⁹ 

Therapies in the Setting of Failure of HMA

For patients with high-grade MDS, DNA methyltransferase inhibitors such as azacitidine and DAC are standard therapies, unless they undergo an allo-HCT. Unfortunately, some patients show no response to DNA methyltransferase inhibitors, while many relapse after achieving an initial response. 

Rigosertib (ON01910.Na) is a benzyl styryl sulfone that has been shown to act as a RAS-mimetic and interacts with RAS-binding proteins of RAF family proteins, thereby blocking RAS signaling.²⁰ In a phase 3 study of patients with MDS progressing while on HMA, rigosertib failed to show a significant survival benefit compared with best supportive care (BSC).²⁰ However, a post-hoc analysis revealed that patients with very high-risk disease according to International Prognostic Scoring System (IPSS-R) revealed a significantly longer survival in the rigosertib group compared with the BSC group. There was no difference in OS between the rigosertib and BSC groups for patients with a low-risk IPSS-R score.²¹

Splicin inhibitors. Splicing factor mutations often occur early in MDS. Mutations commonly seen in MDS, AML and CML include those of SF3B1, SRSF2 and U2AF1. The mutations result in dysregulated mRNA splicing, which leads to myelodysplasia. There is an ongoing phase 1 study evaluating the splicing factor modulator, H2B-8800, which targets SF3B1. H2B-8800 modulates splicing and induces antitumor activity in xenograft leukemia models.²²

Other targeted agents. Isocitrate dehydrogenase 2 (IDH2) mutations are present in approximately 5% of patients with MDS.²³ IDH2 mutations are associated with DNA and histone hypermethylation, altered gene expression, and blocked differentiation of hematopoietic progenitor cells.²³ The oral agent enasidenib (AG-221) is an allosteric inhibitor of mutant IDH2 protein and was granted FDA approval in 2017 for patients with relapsed or refractory AML with an IDH2 mutation.²⁴ In a phase 1 study of patients with IDH2-mutant MDS, more than half of the patients had a hematologic response with an ORR of 53% (8 participants out of 15); 1 patient was not evaluable for response.²³ Importantly, this agent induced responses in half of the patients who had previously failed HMA therapy.²³ Only 2 patients experienced disease progression during treatment.²³

Immunotherapy. It has been reported that hypomethylating therapies may increase the expression of programmed death 1 (PD-1), programmed death ligand 1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) in MDS CD34⁺ cells.²⁵ A phase 2 study was conducted to examine nivolumab and ipilimumab, which target PD-1 and CTLA-4, respectively, in monotherapy or in combination with azacitidine for patients with MDS.²⁵ There was a tolerable safety profile and clinical activity for the untreated MDS group receiving the combination of nivolumab and azacitidine. Single-agent ipilimumab was capable of inducing responses in previously treated MDS patients, though single-agent nivolumab showed no clinical response.²⁵ In a phase 1b study, pembrolizumab, a humanized monoclonal antibody against PD-1, demonstrated in 27 of the participants, and the OS rate was 49% at 24 weeks across the entire cohort, including 29% for those with a high IPSS.²⁶ There were no treatment-related deaths.²⁶ More studies are being conducted to further investigate the use of these immunotherapy agents in patients with MDS, some of which will be used in combination with HMA.

BCL2 inhibition. Deregulation of proapoptotic and antiapoptotic BCL-2 family proteins have been identified in bone arrows of MDS patients. There have been reports of BCL-2 overexpression in higher risk MDS, thus causing antiapoptotic resistance. A phase 2 study has shown that BCL-2 blockade by venetoclax (ABT-199) alone in high-risk AML patients have had encouraging results.²⁷ A phase 1 study of venetoclax in combination with cytarabine for treatment-naïve patients with AML, aged 65 and older and not fit for intensive chemotherapy, had an objective response of 75% (15 of 20 patients).²⁸ Of the patients who achieved an objective response, 14 of 20 achieved either a complete remission or a complete remission with incomplete marrow recovery. The study also included patients who were previously treated for MDS.²⁸ A correlative analysis of the venetoclax plus HMA and venetoclax plus low-dose cytarabine studies revealed that patients who responded to these regimens had a higher percent of blasts with BCL-2.²⁹ Patients with mutations of NPM1, IDH1/2, and genetic alterations of chromatin-RNA splicing were also noted to have a better response to the venetoclax-based regimens.²⁹ There is an ongoing phase 1 clinical trial evaluating venetoclax alone and in combination with azacitidine in higher-risk MDS patients who failed HMA (NCT02966782)³⁰ and in treatment-naïve patients (NCT02942290).³¹

Chimeric antigen receptor T-cell therapy. Previous studies have demonstrated that there is high expression of CD123 in high-risk MDS cells compared with low-risk MDS and normal cells. In a phase 1 study, chimeric antigen receptor (CAR) vector containing CD123-specific single-chain variable fragment was expressed on healthy donor and patient-derived T lymphocytes utilizing lentiviral vector delivery to target high-risk MDS cells. Patient bone marrow was used to study the in vitro antitumor function while NSG-S mice were used for in vivo analysis. For the in vitro study, anti-CD123 CAR T-cells eliminated MDS cell line and primary bone marrow derived MDS cells. The anti-CD123 CAR T-cells also generated approximately 50% to 70% transduction efficiency in patients with high-risk MDS. There was a noted increase in cytokine release and degranulation by anti-CD123 CAR T-cells, unlike with the control anti-CD19 CAR T-cells. When evaluated in vivo, there were significant decreases in CD34⁺/CD38^-/CD123⁺ MDS cells and MDS BULK (hCD45⁺/EGFRt^-) while mice with the mock CAR T-cells did not reduce tumor burden.³² Numerous oncologic drugs were tested to identify the ones to increase the expression of CD123, and therefore increase the efficacy of anti-CD123 CAR T-cell therapy. The drugs found to increase CD123 expression were trifluridine, sunitinib, mitoxantrone, dasatinib, imatinib, regorafenib, dabrafenib and DEAB.³² The concept of anti-CD123 CAR T-cell activity against high-risk MDS cells will continue to be studied in combination with drugs which increase CD123 expression.³² 

Conclusion

Current treatments for MDS remain limited. New therapies are in advanced clinical testing in lower risk, higher risk MDS as well as HMA failure settings. There is an increased need for patients to be enrolled in clinical trials to change this therapeutic stagnation. Supportive care with transfusions, growth factors, and iron chelation is equally imperative in improving the quality of life of MDS patients. Several promising agents under investigation usher increased optimism among hematologists managing patients with MDS.

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