a select group of oncologists who specialize in the treatment of hematologic malignancies participated in a virtual workshop to discuss the emerging treatment landscape in myelodysplastic syndromes (MDS). In an expert discussion led by Dan DeAngelo, MD, PhD, perspectives and insights on novel agents in MDS were exchanged. Experts aimed to describe and discuss pertinent issues they face as physicians when treating patients with MDS, discuss the limitations of currently available therapeutic agents, review novel treatment approaches and new treatment strategies for patients with MDS, and gain insight into how the potential approval of newer therapies may impact the treatment landscape in MDS.

Approximately 10,000 people in the United States are diagnosed with MDS per year, although the number of cases of MDS is thought to be higher because of underreporting. MDS is uncommon in people aged younger than 50 years; in individuals aged older than 70 years, the incidence is at least 20 cases per 100,000. Of all patients with MDS, about one-third will go onto develop acute myeloid leukemia (AML).

In the current treatment landscape for MDS, transplantation remains the standard curative modality. Selecting candidates for transplantation is based on risk stratification; high-risk patients may receive transplants at the time of their diagnosis while those with lower-risk disease may delay transplant. Nevertheless, survival outcomes are limited, even in low-risk cases.3 Among high-risk MDS cases, life expectancy is 3.2 years for immediate transplant compared with 6.5 years for low-risk cases.

 Beyond transplantation, therapeutic options in the current landscape are lacking. The hypomethylating agent (HMA) azacitidine is the only agent that has shown improvement in overall survival (OS) among patients with higher-risk MDS. Findings from the AZA- 001 trial showed that patients who received azacitidine had a median survival of 24.4 months compared with 15.0 months for patients who received conventional care regimens, a 9.4-month median survival benefit. Two-year survival rates were 50.8% for patients receiving azacitidine and 26.2% for patients who received conventional care regimens.

With no other agents yielding OS results comparable to those of azacitidine, stakeholders agreed that the lack of compelling data and approved options in the treatment landscape of MDS represents a great unmet need. Because life expectancy is often less than 2 years, the stakeholders agreed that new therapeutic strategies that yield increased response rates and depth of response, as well as better durability and tolerability, are needed.

Another unmet need, according to stakeholders, pertains to the limited use of HMAs as monotherapies, as patients could potentially benefit from combination approaches using other HMAs. In other hematologic malignancies and diseases, different combinations of therapies are routine, whereas MDS is among the few diseases that continues to rely on monotherapy. As the treatment landscape moves forward, new combinations with more durable response or higher rates of response may be able to challenge the timing of the transplant. Additionally, stakeholders noted that patients should not be prematurely discontinued from therapy.

Rigosertib inhibits cellular signaling as a Ras mimetic by targeting the Ras-binding domain, thus blocking multiple cancer targets in the downstream pathways, such as PI3K/ AKT and Raf/PLK.

At the 24th European Hematology Association Congress in 2019, investigators shared findings from a trial showing that sequential exposure with rigosertib followed by azacitidine achieved maximum synergy with clinically achievable concentrations. In the trial, 55 patients were treated with rigosertib at a dose greater than 840 milligrams per day; 29 were HMA-naïve, and 26 had received previous HMA therapy. Findings showed that 34% of patients in the HMA-naïve group achieved complete remission (CR), with a median duration of response of 12.2 months and a median duration of treatment of 7.8 months. Among patients who failed HMA therapy, 4% experienced complete remissions and 4% experienced partial remission (PR) with a median duration of response of 10.8 months and a median duration of treatment of 4.9 months.

 The stakeholders noted that the 12-month response duration rate in the combination treatment was low; however, the treatment-naïve patients had CR and PR rates similar to those achieved with azacitidine. Thus, the utility of rigosertib may depend on the results of a randomized HMA failure trial in very high-risk patients. If the results of this study are positive, rigosertib may play an important role in MDS care, with potential for combinations in the future. The data were disappointing and stakeholders 

questioned the role of rigosertib in MDS care, pending the readouts of additional trials.

Pevonedistat is a first-in-class small molecule NAE inhibitor. Ubiquitination and degradation of select NAE-active regulatory proteins are important for cancer cell growth; therefore, inhibition of these proteins can induce apoptosis and cell death. Findings from a phase 2 trial (NCT02610777) evaluating pevonedistat in combination with azacitidine versus azacitidine alone were presented at the American Society of Clinical Oncology 2020 Virtual Scientific Program. The primary end point was OS; the secondary end points were event- free survival (EFS), defined as time to death or transformation to AML in higher-risk MDS/chronic myelomonocytic leukemia (CMML), and overall response rate (ORR). Notably, the study was powered on EFS as the original primary end point, with OS originally being a secondary end point, but this was changed based on regulatory feedback after enrollment. Patients had either higher-risk MDS (nearly half of patients), higher-risk CMML, or oligoblastic or low-cast-count AML, and they had not received previous HMA therapy. They were randomized into the pevonedistat/azacitidine arm (n = 60) or the azacitidine-alone arm (n = 60).

Findings showed that the safety profile of pevonedistat/ azacitidine was comparable with that of azacitidine alone. The median number of azacitidine treatment cycles was 13.0 in the combination group and 8.5 in the azacitidine group. Median OS was 21.8 months in the combination group and 19.0 months in the azacitidine group (HR, 0.802; 95% CI, 0.512-1.256; 

 = .334). Median EFS was 21.0 months in the combination arm and 16.6 months in azacitidine arm (HR, 0.665; 95% CI, 0.423-1.047; 

 = .076). Among patients with higher-risk MDS, median EFS was 20.2 and 14.8 months in the pevonedistat/azacitidine and azacitidine-alone groups, respectively (HR, 0.539; 95% CI, 0.292-0.995; 

 = .045). Thus, although the clinical difference in EFS between the regimens was not statistically significant among the overall population, those with higher-risk MDS did have a statistically significant benefit from the pevonedistat/azacitidine combination. In the overall response-evaluable population, ORR was 70.9% in patients receiving the pevonedistat combination regimen and 60.4% in the azacitidine-alone group. Additionally, 40.0% of patients in the pevonedistat combination group had a CR, compared with 30.2% of patients in the azacitidine-alone group.

Assessing the value of the phase 2 trial results, stakeholders noted that pevonedistat was well tolerated and that the lower response rates among those in the smaller CMML patient population was an important contributor to the EFS findings that failed to reach statistical significance in the overall intent-to-treat population. Patients with higher-risk MDS appeared to respond best to pevone

distat, which, coupled with pevonedistat’s unique mechanism of action, warrant further study for this agent. To avoid dilution of the data, stakeholders suggested that future studies evaluate a more focused patient population of patients with higher-risk MDS.

Magrolimab is an anti-CD47 antibody, leading to phagocytosis of cancer cells. It contains a antiphagocytic signal that enables macrophage immune evasion. The 5F9005 study evaluated magrolimab either alone or in combination with azacitidine in patients with AML and MDS.

 Patients received a dose ramp-up from 1 mg/kg to 30 mg/kg by week 2, then 30 mg/kg maintenance dosing. The primary end points were safety of magrolimab alone or with azacitidine, and the efficacy of magrolimab plus azacitidine in untreated AML/ MDS. Secondary end points were the pharmacokinetics, pharmacodynamics, and immunogenicity of 5F9 and addi- tional measures of efficacy (DOR, PFS, OS). Patients were eligible for the study if they had untreated AML or untreated high-risk MDS.

Magrolimab plus azacitidine induced a 92% ORR (50% CR) in MDS, which compares favorably with azacitidine monotherapy. The median time to response was 1.9 months among the entire patient population, which is more rapid than the time with azacitidine alone. Even in patients who did not have a transplant, some of the responses were durable and appeared to have relatively long duration of response. The median duration of response and survival has not been reached, which compares favorably with current therapies.

 The faculty concluded that magrolimab looks to be more active in the up-front setting and questioned why it is inactive in the relapsed setting. It is possible that macrophages get exhausted or there is some immune phenomenon in which they’re not responsive. A major challenge identified is the question of whether blood banks would be able to handle the complexity of the typing and screening. This issue is further complicated amid the coronavirus disease 2019 pandemic.

APR-246 is a methylated derivative and structural analogue that reactivates p53 and induces apoptosis. A study of the frontline combination therapy with APR-246 included patients with treatment-naïve, high-risk MDS, as well as oligoblastic AML.

 APR-246 plus azacitidine was studied in patients with TP53-mutant myeloid neoplasms. The phase 1b part of the study treated patients with APR-246 4500 mg/day on days 1 to 4 plus azacitidine (75 mg/m

) on a classic 7-day schedule. The primary end point was CR rate and secondary end points were ORR, duration of response, and OS in the phase 2 portion of the study.

The most common adverse effects (AEs) related to APR-246 were mostly gastrointestinal (nausea/vomiting) and neurologic, which were transient and reversible in all cases. Three patients (5%) discontinued because of secondary AEs. The hematologic toxicities appeared to be similar to what is seen with a single agent. The ORR for patients who received the APR-246 regimen was 87% among evaluable patients. Additionally, approximately half of the evaluable patients had a CR. Time to remission was about 3 months for this combination. Of the patients included in the study, 66 

 mutations were sequenced in 45 evaluable patients; 53 (80%) were missense and 62 (94%) were in the DNA-binding domain. All patients had at least 1 TP53 mutation in the DNA-binding domain.

 The faculty agreed that although these data will not lead to an imminent approval, APR-246 could allow physicians to transplant patients more frequently than with other therapies, given the lack of significant myelosuppression-related toxicities. Inducing patients with a doublet, giving them a transplant, and then continuing with posttransplant maintenance therapy will be very important. The high efficacy data ultimately warrant further consideration in clinical trials.

ASTX-727, a combination of oral decitabine and cedazuridine, was evaluated in a phase 3 study (ASCERTAIN, NCT03306264) in which patients with MDS/CMML received either oral decitabine alone or oral ASTX-727 in combination with intravenous decitabine. Among the 101 evaluable patients who were treated with ASTX-727, 64.4% of patients experienced some response, with 11.9% achieving CR, 45.5% experiencing marrow CR, and 11.9% of patients achieving marrow CR with some hematologic improvement.

 A major advantage of this therapy is that it would allow for an all-oral regimen, which could prove to be valuable in the community. Generally, in the first 2 cycles of treatment, the patient needs transfusion support if there is no remission. If the patient goes into remission, however, this agent could be a game-changer and result in quality-of-life improvements. Cost and the financial impact to the patient may also be a concern with ASTX-727 if it is approved.

BCL-2 overexpression allows cancer cells to evade apoptosis. Venetoclax, which has been approved for other indications, frees proapoptotic proteins that initiate programmed cell death. A phase 1b study included 57 eligible patients with untreated, de novo, intermediate-2 risk or high-risk MDS, with 60% of patients being high risk. Findings showed that almost 40% of patients had a CR and another 40% had a CR/ marrow. The time to response was about 2 months, and 70% of patients maintained response at 12 months.

 Stakeholders agree that venetoclax may be an important therapy in MDS, particularly in combination with other agents such as azacitidine. A trial evaluating this combination is in development now. AEs included myelosuppression and gastrointestinal- predominant toxicity, but generally venetoclax was very well managed.

Significant unmet needs and barriers to effective treatment remain in the MDS therapeutic landscape. Despite a historic lack of approvals in MDS, compelling data for several potential treatment options in the pipeline offer the promise of improved outcomes. If the agents discussed in this article earn FDA approval, the new challenge for clinicians will be selecting an optimal treatment regimen.

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Aster JC, Stone RM. Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS). UpToDate. Updated May 28, 2020. Accessed August 12, 2020. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-myelodysplastic-syndromes-mds#:~:text=CLIN- ICAL%20PRESENTATION%20Clinical%20manifestations%20of,complete%- 20blood%20count%20(CBC)

Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. 

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Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al; International Vidaza High- Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. 

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Navada SC, Garcia-Manero G, Atallah E, et al. Phase II study of oral rigosertib combined with azacitidine in patients with higher-risk myelodysplastic syndromes (MDS). Presented at: 24th European Hematology Association Congress; June 13-16, 2019; Amsterdam, the Netherlands. Abstract S839. https://library.ehaweb.org/eha/2019/24th/267422/mi- chael.e.petrone.phase.ii.study.of.oral.rigosertib.combined.with.azacitidine. html?f=listing%3D3%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D1

Ades L, Watts JM, Radinoff A, et al. Phase II study of pevonedistat (P) + azacitidine (A) versus A in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (LB AML) (NCT02610777). 

Sallman DA, Asch AA, Al Malki MM, et al. The first-in-class anti-CD47 antibody magrolimab (5F9) in combination with azacitidine is effective in MDS and AML patients: ongoing phase 1b results. 

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Cluzeau T, Sebert M, Rahmé R, et al. APR-246 combined with azacitidine (AZA) in TP53 mutated myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). a phase 2 study by the Groupe Francophone Des Myélodysplasies (GFM). Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract S181. https://library. ehaweb.org/eha/2020/eha25th/295001/thomas.cluzeau.apr-246. combined.with.azacitidine.in.tp53.mutated.html?f=menu%3D6%2Abrowse- by%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D1766%2Aot_ id%3D23227%2Afeatured%3D16775

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Articles

Oncologists who specialize in the treatment of hematologic malignancies participated in a virtual workshop to discuss the emerging treatment landscape in myelodysplastic syndromes.

Emerging Approaches for Myelodysplastic Syndromes

Mikkael A. Sekeres, MD, vice-chair for Clinical Research and director of the Leukemia Program at Cleveland Clinic Taussig Cancer Institute, discusses staging patients with myelodysplastic syndromes (MDS).

When considering available treatments for patients with MDS, the first thing to examine is whether they have lower- or higher-risk disease, says Sekeres. This is done through the use of the International Prognostics Scoring System (IPSS), particularly the revised version, which is generally the default staging system for MDS. This process used to be fairly straight forward: A patient’s risk assessment was based on their blood counts, blast percentage in their bone marrow, and their cytogenetics, explains Sekeres. Patients who have a lot of cytopenias also have a relatively high blast percentage of above 5%, but this can be up to 19%, Sekeres notes. Those who have poor-risk cytogenetics, particularly those who have complex cytogenetics, fall into higher-risk categories. 

Now, molecular typing has thrown a wrench into the system, according to Sekeres. Patients who might be classified as having lower-risk MDS using the IPSS or its revised version could have poor-risk molecular profiles that might include, for example, p53.

With higher-risk MDS, no matter how it is defined, the standard of care is usually a hypomethylating agent (HMA), which can be either azacitidine or decitabine, says Sekeres. More recently, an oral version of decitabine has been approved and appears to have activity that is equivalent to azacitidine or decitabine. However, no head-to-head comparisons have been made among the available HMAs, concludes Sekeres.

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Mikkael A. Sekeres, MD, discusses staging patients with myelodysplastic syndromes.

Dr. Sekeres on Staging Low- Versus High-Risk MDS

The combination of pevonedistat and azacitidine has shown encouraging clinical activity in patients with myelodysplastic syndromes (MDS) and low-blast acute myeloid leukemia (AML), according to Jamile M. Shammo, MD, who added that if the benefit is upheld in longer-term follow-up, the regimen could potentially alter the up-front management of this patient population.

 showed that the combination led to a trend toward improved event-free survival (EFS) and a numerical improvement in overall survival compared with azacitidine alone in patients with high-risk MDS, chronic myelomonocytic leukemia (CMML), and low-blast AML.

Specifically, the median EFS was 21.0 months with the pevonedistat combination versus 16.6 months with azacitidine alone in the intent-to-treat population; this translated to a 34% reduction in the risk of death or transformation to AML. Moreover, the median OS was 21.8 months with the combination versus 19.0 months with azacitidine alone.

, Shammo, a professor of medicine and pathology in the Department of Internal Medicine at Rush University Medical Center, discussed the current treatment landscape of high-risk MDS recent data with the investigational small molecule inhibitor of the NEDD8-activating enzyme pevonedistat, and ongoing research efforts in the space.

: How do you currently approach the treatment of your patients with high-risk MDS?

: For patients with high-risk MDS, the main question is not 

 to treat; for the most part, most patients require immediate treatment with a hypomethylating agent, or, if they are eligible for a clinical trial, then that would be ideal. There are very few patients who have high-risk MDS who do not require immediate treatment; however, I have had some of those patients. I don’t think that there’s any problem with monitoring those patients, as long as you are careful.

When you have to start treatment, usually with either azacitidine or decitabine, you should try to assess response rates at certain points in time; the literature is clear on that. You should also be cognizant on when a patient has progressed [on treatment]. There's some lack of familiarity in terms of criteria for disease progression, but once they do progress, we know there is no second-line treatment [option available].

Oftentimes, MDS may turn into leukemia, but not always. If [disease] progresses to leukemia but [the patient is] not [eligible for] transplant, then perhaps they could receive a combination of venetoclax (Venclexta) with another hypomethylating agent that was not already used up front or they can be considered for a clinical trial.

A subset of patients is simply too sick to receive anything chemotherapy-related and so they may end up with [no options other than] simple transfusions or hospice. In a nutshell, that is how we approach the treatment of these patients every day in practice.

Could you expand on the unmet needs in this space?

We don't know which of the 2 hypomethylating agents [to start with]; we have little guidance on them. Additionally, we don't know what the second-line treatment [should be] or whether [up-front] combination therapies are better. We also don’t know how molecular analyses fit into the formula of treating these patients.

Pevonedistat plus azacitidine is a combination that has recently emerged in the space. Could you speak to the data from the phase 2 study presented during the 2020 ASCO Virtual Scientific Program?

Results showed an improvement in EFS in patients with high-risk MDS who received the combination therapy compared with azacitidine alone. If you look at the low-blast AML population, [the median OS was 23.6 months]; this wasn't nearly as impressive as what was seen in the MDS population. Interestingly, the [EFS in the] CMML population was actually a bit worse with the combination [compared with azacitidine alone].

The numbers are really small and it's hard to think about the statistical power for each of those groups. To me, it's a positive signal for the combination, particularly in the [patients with] intermediate- and high-risk MDS. That's why we need to get more data and longer follow-up to see whether this actually duplicates the data that we saw in the phase 2 study. If that's the case, we should see a huge difference or change in the up-front management of patients with MDS [in the future].

How do you eventually see pevonedistat fitting into the treatment landscape of high-risk MDS?

We must first wait for phase 3 study data. The agent is not yet available. However, if the phase 3 data pan out, and prove to be similar to the phase 2 data, [pevonedistat/azacitidine] may be a promising combination for patients with MDS in the frontline.

It would be helpful if we could identify a particular subset of patients who may benefit from this combination because many other combinations are being studied right now, including those with venetoclax in the frontline setting. For all those trials, it would be helpful to determine which patients may benefit from this the most. We're conducting next-generation sequencing so we can identify the best responders [for these combinations].

Beyond pevonedistat, what are some of the other exciting research efforts that are being made in this space?

 mutation–directed agents that seem to have an impressive up-front response rate with the combination. However, again, we need more comparisons, larger trials, longer follow-ups, comparing the combination with azacitidine alone to see what would happen. Some data with magrolimab in combination with azacitidine were also reported, which looks to be very interesting.

My excitement is tempered by the lack of positivity when you assess those agents side-by-side with standard of care. We have to tame our excitement a bit, but many interesting combinations are out there for frontline treatment. It’s also important to not forget about rigosertib, which is an agent that has been studied in the frontline management of immediate- and high-risk MDS that showed a significant overall response rate.

The complete and partial responses with rigosertib were similar to those seen with azacitidine, but it’s an oral agent. Again, if we’re able to improve response rates and extend the duration, that would be ideal. A trial with rigosertib has recently completed accrual. We still have to wait and see what they find in the relapsed setting.

. 2020;38(suppl 15; abstr 7506). doi:10.1200/JCO/2020.38.15_suppl.7506

Jamile M. Shammo, MD, discusses the current treatment landscape of high-risk MDS recent data with the investigational small molecule inhibitor of the NEDD8-activating enzyme pevonedistat, and ongoing research efforts in the space.

Shammo Previews the Potential of Pevonedistat Combo in High-Risk MDS

Daniel J. DeAngelo, MD, PhD, institute physician, chief, Division of Leukemia, Dana-Farber Cancer Institute, professor of medicine, Harvard Medical School, discusses the utility of the investigational agent pevonedistat in myelodysplastic syndrome (MDS).

Pevonedistat is a novel inhibitor of the NEDD8-activating enzyme that has been under evaluation for some time, says DeAngelo.

The agent may offer an alternative treatment to proteasome inhibitors with a similar dosing schedule, explains DeAngelo.

Notably, pevonedistat given as monotherapy is associated with limited toxicity, which lends itself to combination therapies, DeAngelo says. The toxicities that are associated with the agent are similar to those observed with hypomethylating agents (HMAs). 

Additionally, the agent appears to augment the activity of HMAs without increasing toxicity, concludes DeAngelo.

Daniel J. DeAngelo, MD, PhD, discusses the utility of the investigational agent pevonedistat in myelodysplastic syndrome.



Dr. DeAngelo on the Utility of Pevonedistat in MDS

Rami Komrokji, MD, professor, Medicine and Oncologic Sciences, College of Medicine, University of South Florida, senior member, Malignant Hematology and Experimental Therapeutics Program, and head of the Leukemia and MDS Section, Moffitt Cancer Center, discusses the current treatment landscape in myelodysplastic syndrome (MDS).

Hypomethylating agents (HMAs) such as azacitidine and decitabine have been the frontline standard of care for patients with MDS for over a decade, says Komrokji. While these agents improve survival and delay leukemic transformation, they are only active in about half of patients with MDS for around 1 year.

Allogeneic stem cell transplantation (allo-SCT), the only curative option for patients with MDS, is typically reserved for patients with higher-risk disease, explains Komrokji. Many patients with MDS are ineligible for allo-SCT due to disease risk, age, or comorbidities.

Patients with high-risk disease, including those with 

 mutations, tend to have poor survival despite treatment with HMAs or intensive chemotherapy, Komrokji says.

Future research efforts should focus on improving response rates and the durability of response with HMAs, as well as developing novel agents for patients who progress on HMAs, concludes Komrokji.

Rami Komrokji, MD, discusses the current treatment landscape in myelodysplastic syndrome.



Exploring Therapeutic Strategies in Myelodysplastic Syndromes | Supplements and Featured Publications

Emerging Approaches for Myelodysplastic Syndromes

Dr. Sekeres on Staging Low- Versus High-Risk MDS

Shammo Previews the Potential of Pevonedistat Combo in High-Risk MDS

Dr. DeAngelo on the Utility of Pevonedistat in MDS

Dr. Komrokji on the Current Treatment Landscape in MDS