Novel Combinations Could Spark Shift in Treatment Paradigm for Higher-Risk MDS

Rami Komrokji, MD

Several clinical trials are exploring combination therapies that include agents such as venetoclax (Venclexta), magrolimab, sabatolimab (MBG453), and others, with the goal of improving upon the efficacy achieved with hypomethylating agents in patients with higher-risk myelodysplastic syndromes (MDS), according to Rami Komrokji, MD.

“There are even some ambitious clinical trials trying to start looking at triplets, [such as] an azacitidine [Vidaza], venetoclax, and magrolimab combination. Not only are we seeing doublets, but there are earlier studies looking at triplets,” Komrokji said in an interview following an OncLive^® State of Science Summit^™, which he chaired. “Hopefully, those trials will translate to change of the current standard of care [SOC] or the backbone of having hypomethylating agents as the treatment.”

Komrokji expanded on the disease factors and treatment options for lower-risk and higher-risk MDS, and highlighted other key updates made in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and myelofibrosis. He is the vice chair of the Department of Hematology and head of the Leukemia and MDS Section at Moffitt Cancer Center.

OncLive^®: How have changes in disease classification affected research and treatment in MDS?

Komrokji: We provided an overview on changes in MDS, namely starting with the newer pathological classifications. There are 2 new classifications from the World Health Organization and the International Consensus Classification. [There are some differences with the newer classifications], but they also recognize some of the [increased] understanding of the disease, as we now know more of the molecular aspects of the disease. Now, we have classification based on the biology of the disease and molecular entities. 

There is also a debate in the field about the cutoff between what we call acute myeloid leukemia [AML] and MDS, and that will be very important down the road for clinical trial design. Part of the discussion was that we also have a new risk-stratification model that’s molecular. That is the most comprehensive [way] to integrate all the clinical variables and the molecular variables [of MDS], and that refined the classical revised International Prognostic Scoring System that we [previously] used.

We also gave an overview on what is available for the treatment [of patients with] lower-risk MDS. We looked at the natural history for those patients, the need for treatments, and what is on the horizon. Some studies are starting to look at pre-MDS conditions and [investigators are] trying to look at earlier intervention. Some newer promising agents [are also under exploration] in the lower-risk MDS, such as the drug called imetelstat that finished a phase 2 trial [NCT02598661].

In higher-risk MDS, there is a focus on ongoing research, with 3 contender drugs added to the hypomethylating agents, that have [served as] the backbone for treatment, to see whether we are going to be able to [shift] the SOC. We discussed venetoclax, which is approved for AML and is being studied heavily in MDS; [we also talked about] a drug called magrolimab, which is [under investigation in combination with azacitidine in the phase 3 ENHANCE trial (NCT04313881)]. Sabatolimab has also been tested, [and investigators continue to explore the role of allogeneic stem cell transplant (ASCT)].

What factors are considered when classifying a patient with lower- or higher-risk MDS?

As we move forward, [risk classification will be based on] a combination of clinical and molecular factors. Historically, all the risk models have included the patient's blood counts, the percentage of myeloblasts or leukemia cells, and chromosome makeup or cytogenetics. The new models incorporate data from next-generation sequencing, where we can look at single-gene somatic mutations. We’ve learned that certain mutations [can affect outcomes]. For example, P53 is a very bad prognostic one, and SF3B1 is a very favorable [mutation].

The newest models incorporate all those. The idea is [to assess] the risk of MDS transforming to leukemia and [provide] an estimate of the survival, which at the end, allows us to put patients into 2 main categories: higher risk or lower risk. With lower risk, our goal is to alleviate the cytopenia [burden]. With higher risk, it means that the disease has enough risk to start considering ASCT.

[Disease classification] is now a state-of-the-art combination of [considering] clinical variables and some molecular features. I always say we must [also consider] patient-related factors. Something that not all the models capture is the comorbidities of the patients, their other medical conditions, as well as [ECOG] performance status. We must keep [all of that] in mind when thinking of the whole picture. Something I follow in practice is the kinetics of the disease. We see some patients who have their disease stay stable for a while; in others, we see a progressive decline in blood counts.

The models don't incorporate [all of this]. However, putting all those things [together]—the patient-related factors, the disease-related factors, the clinical and molecular risk models, and the disease kinetics—we get an idea about the risk of the disease and can tailor treatment accordingly.

How do you approach treatment for a patient with lower-risk MDS in your practice?

The first step is deciding whether patients need treatment. If a patient has mild cytopenias and they are not symptomatic, we do not yet have evidence that early intervention is helpful. In select cases, observation is reasonable. Most patients are either symptomatic or have profound cytopenias that need treatment. The next question becomes, What are we treating? The majority of patients will be anemic, and over time, more than half of them will become transfusion dependent. Most of the time, the indication to treat is the anemia. Rarely, we will treat for neutropenia or thrombocytopenia [if they are] isolated, but their presence could dictate our choices of treatment for the anemia.

For anemia in general, if patients are symptomatic, their hemoglobin is below 9 g/dL, or they are heading to transfusion dependency. Erythropoiesis-stimulating agents [ESAs] are still an appropriate step. If patients are heavily transfusion dependent or their endogenous erythropoietin level is high, one could even skip the ESA step. The next question we ask is whether they have deletion 5q; those patients’ treatment of choice is lenalidomide [Revlimid]. If patients have ring sideroblasts or a SF3B1 mutation, their treatment of choice is luspatercept-aamt [Reblozyl]. This is a new drug that was approved after a decade of not having new drugs for MDS; it’s a fusion protein that works on later stages of erythropoiesis that leads to responses [of more than] 40% in that category.

In patients who do not [have deletion 5q, ring sideroblasts, or a SF3B1 mutation], if they are young, sometimes we consider immunosuppressive therapy. If they are just anemic, sometimes even lenalidomide could be tested.

Finally, if patients have gone through all those options, or they have concomitant thrombocytopenia or neutropenia, we consider hypomethylating agents. We now have an option of some of the oral hypomethylating agents coming into play. We have oral azacitidine [Onureg] that is already approved, and there are trials going on with oral azacitidine. We are looking at abbreviated courses of hypomethylating agents in lower-risk MDS.

If patients have isolated thrombocytopenia and they need treatment, sometimes we think of [thrombopoietin receptor agonists] or hypomethylating agents. If patients have isolated neutropenia, there are not many good options. There are some emerging data on IDH inhibitors, and maybe that could be an approach, but that's still [under investigation]. However, patients don’t often need treatment for isolated neutropenia if they are lower risk.

Could you elaborate on combinations that are under investigation to improve upon the SOC in higher-risk MDS?

Higher-risk MDS is, in a way, a life-threatening disease that’s going to progress to AML. We are always first considering whether those patients are candidates for ASCT. Most of the studies or models have looked at the maximum gain of survival, and if somebody is categorized as higher risk, the [way to achieve the] maximum gain of survival [would be] to proceed to ASCT as soon as possible. The decision to transplant should be individualized for patient goals and disease risk. There is really no age cutoff, per se, for ASCT. It depends on patient performance [status], comorbidities, and the patient preference. However, the benefit [for ASCT] outweighs the risk in higher-risk MDS.

Short of transplant, the SOC has been hypomethylating agents. With those, we expect somewhere around 50% overall response [rates], 20% complete response (CR) [rates], and a median overall survival (OS) of around a year and a half. That has been our SOC, and [ongoing] trials are trying to improve on that SOC. There is no doubt that hypomethylating agents help our patients, but the bar is not acceptable, and we need to [raise it].

Several trials are [ongoing]. Venetoclax, a drug approved for AML, has become the standard in combination with hypomethylating agents for patients who cannot go to chemotherapy; it has been studied in MDS, and phase 1/2 trials have shown promising activity, with it almost doubling the response and remission rates. There is the large phase 3 VERONA trial [NCT04401748] and OS data will read out in a year or 2.

[In the real world, clinicians] are borrowing a little bit from AML because the line is fine [between AML and MDS]. We know with venetoclax that the dosing in MDS is different. Patients need to be observed with bone marrow [testing] needing to be repeated earlier. However, cumulative data from phase 1 and phase 2, and the real-world evidence suggests that the combination is promising, particularly in patients going to ASCT or who have uncertain mutations. 

The other drug is called magrolimab. This is a drug that targets the immune system in a way; it blocks a receptor called CD47, which is known as the ‘don’t-eat-me signal,’ so it prevents the macrophages from engulfing the cells, and this allows the immune system or the macrophages engulfing the immune cells [to attack the cancer cells]. In a phase 1 trial [NCT03248479], promising activity has been reported [with magrolimab plus azacitidine], with a doubling of responses and higher CRs.

Interestingly, the combination seems to be agonistic of mutations. There are certain things like P53 mutations that are notorious in being resistant to hypomethylating agents. Although patients respond, they relapse quickly. Even the addition of venetoclax to azacitidine did not overcome P53 mutations in [those with] AML. Magrolimab activity seems similar, [irrespective of] P53 mutations. That’s promising, and that led to the ongoing [ENHANCE] study which is probably finishing accrual soon. Patients are randomized to azacitidine with or without magrolimab; CR and OS benefit [is being evaluated].

There is another drug called sabatolimab; this is a TIM-3 inhibitor, so it engages the immune system and attacks leukemia cells. That [agent] has also shown some promising activity in terms of durability of response, and it’s being tested in the randomized phase 2 STIMULUS MDS-US trial [NCT04878432]. If that [trial is] positive, then [the agent] will move into phase 3.

IDH1/2 inhibitors that are being tested in AML are also being evaluated in MDS in different settings, including up front in combination with azacitidine. [Data with] those [agents have] been positive in AML, so they have been looked at in MDS; they have also been looked at after hypomethylating agent failure if patients harbored somatic mutations. There are early studies of immune therapy with CAR T-cell therapy in MDS and AML. At Moffitt Cancer Center, we have a few that are being [conducted].

Javier Pinilla-Ibarz MD, PhD, of Moffitt Cancer Center, spoke about the use of BTK inhibitors in CLL. How could noncovalent BTK inhibitors affect the treatment paradigm beyond the 3 FDA-approved covalent BTK inhibitors?

Compared with years ago, the landscape has shifted completely from traditional chemotherapy; the newer BTK inhibitors offered more efficacy and less toxicity for those patients. It seems that is where things are moving forward. Dr Pinilla-Ibarzalso discussed the sequencing of those therapies and all the potential combinations. There is no doubt the newer BTK inhibitors offer better efficacy and more safety than the classical ones. The field is rapidly evolving, [to the point] that some of those patients may not need continuous treatment. Sometimes they could have shorter courses of treatment.

Bijal Shah, MD, MS, of Moffitt Cancer Center, explored updates in MCL. How have treatments evolved beyond chemotherapy in this space?

Similar to the theme in CLL, the field has been moving from traditional chemotherapy and stem cell transplant to more targeted therapies. He discussed a lot of the newer BTK inhibitors in MCL. There is now the introduction of CAR T-cell therapies in MCL. Again, the field is moving to more targeted molecular therapy or biological agents, rather than the classical chemotherapy.

Julio C. Chavez, MD, of Moffitt Cancer Center, discussed progress made in DLBCL treatment. How can CD19 serve as a target for novel agents, even beyond CAR T-cell therapy?

One of the major advances we’ve made in the past few years is the treatment for [those with] lymphomas with the approval of CAR T-cell therapies and immune therapy. We’ve historically had treatments like rituximab [Rituxan], which target CD20; those are the naked monoclonal antibodies. Then we have the option of antibody-drug conjugates [ADCs], and we also now have the option of CAR T-cell therapy. Those [approaches] are definitely replacing traditional salvage chemotherapy in the relapse setting.

There is now a debate on whether patients should receive ASCT in relapse vs CAR T-cell therapy. That [area] will continue to evolve, and some of those drugs will find their way to up-front treatment. With some targets like CD19, you could think of different ways [to target it]; you have antibodies, ADCs, bispecific T-cell engagers, and CAR T-cell therapy. Down the road, we probably will start talking about what we call off-the-shelf therapies, like allogeneic CAR T-cell therapies—that will also be exciting.

There is no doubt that there is a huge improvement [in the treatment of DLBCL]. Nowadays, we do offer [CD19-directed] CAR T-cell therapy as part of SOC in settings where, in the past, patient outcomes were dismal. Now, we are talking about 30% or 40% of patients achieving long-term, durable responses with those approaches.

Andrew Kuykendall, MD, of Moffitt Cancer Center, explored the changing treatment landscape in myelofibrosis. How could novel combinations of established agents affect outcomes for these patients?

The field of myelofibrosis has witnessed some new approvals with a few more down the road. Similar to MDS, we have been understanding more about the biology of the disease and risk assessment. The way we are thinking of those patients now is with proliferative myelofibrosis or cytopenic myelofibrosis. Sometimes the challenge is when patients are cytopenic and still have splenomegaly and proliferative features. For more than a decade, we had ruxolitinib [Jakafi] as the SOC for patients with splenomegaly constitutional symptoms. This drug really changed the landscape and improved patient outcomes; however, it has a lot of limitations that, particularly in the cytopenic patients, [affect its efficacy]. [The agent is] also [known to] work for a while and stop working. 

Now, we have fedratinib [Inrebic], another JAK2 inhibitor that is approved, that probably has a lot of similarities to ruxolitinib in that it is probably better positioned for patients with proliferative disease, maybe as a second-line [treatment]. We recently got approval of pacritinib [Vonjo], a third JAK2 inhibitor, that also has less JAK1 activity compared with ruxolitinib and targets other inflammatory pathways. Pacritinib appears to be the most gentle in terms of cytopenia. For patients with platelets less than 50 × 10⁹/L, studies that showed patients did not need dose reductions [of pacritinib, which] allows you to deliver a meaningful dose to lead to the spleen [volume] reduction and symptom improvement. Pacritinib, by the National Comprehensive Cancer Network guidelines, is the first-line choice for patients with thrombocytopenia, and it’s listed as a second-line choice regardless of platelet count.

There is another JAK2 inhibitor that hopefully will get approved very soon called momelotinib. [In the phase 3 MOMENTUM trial (NCT04173494) that agent] also had positive [data] in the second-line setting compared with danazol. [Momelotinib also] showed superiority in terms of spleen response and anemia response. The appeal of momelotinib will be the anemia response, and it’s going to be positioned in the second line for patients who are anemic. We now probably have 3 new JAK2 inhibitors that are positioned in a different way.

The other area where the field is moving is with combinations; [we are] introducing other drugs in addition to ruxolitinib, either in hope of improving responses up front, overcoming some of those cytopenia issues, or overcoming the suboptimal responses we see with ruxolitinib. There is pelabresib [CPI-0610], which is a BET inhibitor. There is navitoclax that targets different BCL family members. Both [agents] had shown promising activity in phase 1/2 trials, and both are moving up front into randomization [to evaluate ruxolitinib with or without those agents].

Frederick L. Locke, MD, of Moffitt Cancer Center, discussed the evolution of CAR T-cell therapies in hematologic malignancies. How could cellular therapies make inroads in earlier lines of treatment and reach more patients?

Dr Locke provided a very comprehensive overview, highlighting some differences among the current available or approved CAR T-cell products. He [also] touched base on the role of when to introduce those agents. We asked him about myeloid diseases, and obviously those [studies] are very early on, but there are some ongoing [efforts being made] there, and that will [represent a] huge advancement.

In the lymphoid world, [these therapies] are being explored beyond the original DLBCL; we have MCL and other types of lymphomas. We have CAR T-cell therapies approved for multiple myeloma, as well. The focus down the road with those CAR T-cell therapies will be to enhance efficacy and reduce toxicity. There are probably going to be discussions about off-the-shelf products. There is the issue of generalizing those treatments because, so far, they are [administered] at really selective referral centers. The issue is how to make this [modality] readily available for all patients who [could derive] benefit.

Is there any ongoing research being done at Moffitt Cancer Center that you would like to highlight?

We stay very heavily involved in myeloid diseases, whether it’s in AML, MDS, or other [myeloproliferative] diseases. We are part of many of those efforts that we discussed, as well as [ones that are focused on] bringing earlier drugs in development. We do have 2 or 3 [trials evaluating] CAR T-cell therapy for myeloid diseases that are promising, and in the lymphoid program, CAR T-cell therapy is part of many clinical trials, highlighting many of the topics that the presenters spoke about. It is an active program with several clinical trials. We discussed most of them, [as] most are [efforts that are] ongoing here, at Moffitt.