Although JAK inhibitors have been a standard of care for patients with myelofibrosis, the exploration of other targeted therapies such as BET inhibitors could lead to new agents and combinations to address symptoms for these patients, according to Andrew T. Kuykendall, MD, who added that disease modification remains a goal in the development of novel treatment approaches.

In the phase 2 MANIFEST trial (NCT02158858), 68% (95% CI, 57%-78%) of patients with JAK inhibitor–naïve myelofibrosis (n = 84) experienced a reduction in spleen volume of at least 35% (SVR35) at week 24 when treated with the combination of the BET inhibitor pelabresib (CPI-0610) and ruxolitinib (Jakafi). Additionally, 20% of patients with myelofibrosis who had previously experienced a suboptimal response to ruxolitinib (n = 81) experienced SVR35 at week 24.¹

Pelabresib plus ruxolitinib is being compared with ruxolitinib plus placebo in the phase 3 MANIFEST-2 trial (NCT04603495) in patients with JAK inhibitor–naïve myelofibrosis, and topline findings are anticipated by the end of 2023.²

“We need to do more [for patients with myelofibrosis] than what we’re currently doing. We see the limitations with single-agent JAK inhibition when we start to look at long-term data. It’s very effective and can change the lives of patients, but it seems to have a shelf life.” Kuykendall explained.

In an interview with OncLive^®, Kuykendall expanded on the rationale for exploring BET inhibition in the treatment of patients with myelofibrosis, detailed the implications of data from MANIFEST, and discussed other potential targets for novel therapies for myelofibrosis. Kuykendall is assistant member of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

OncLive: What makes BET inhibition a potentially valuable approach in myelofibrosis?

Kuykendall: BET inhibition has been looked at for a long time in many different circumstances, and it is an intriguing pathway specifically within the hematology space. One of the things that BET inhibition does is target the NF-κB inflammatory pathway and signaling pathway.

Recently, the focus in myelofibrosis and myeloproliferative neoplasms [MPNs] has been on the JAK-STAT pathway, which is the hallmark of the disease. All these driver mutations lead to JAK-STAT upregulation. However, this is an inflammatory disease, and it’s not just driven by 1 pathway. This isn’t a one-lane road that goes from one place to another. There are a lot of different pathways that are activated, and if you shut down that [road], [the disease is] going to find other roads around it, especially with the molecularly complex diseases and myelofibrosis, as opposed to essential thrombocythemia and polycythemia vera.

Patients come off JAK inhibitors, often by 3 years. They develop cytopenias and have symptoms that aren’t necessarily responsive to the JAK inhibitors, and they continue to have fatigue. With JAK inhibitors, we’re not seeing complete responses or partial responses. We are seeing very good but symptomatic improvement. The idea is that we may need to target multiple pathways of inflammation to be able to suppress the advantage this malignant clone has. We have great basic science that shows that the combination of BET inhibition and JAK inhibition is synergistic, or at least additive, from the clinical side of things to suppress this clone.

What has been the impact of the MANIFEST trial?

In the MANIFEST trial, we saw that when you treat with a BET inhibitor, it gives this additional level of benefit in terms of spleen volume control, symptom control, and maybe even anemia control. NF-κB may be more important in the cytopenia pathways.

There are emerging data when we look at some of the translational studies being done on the MANIFEST study that [suggest] maybe we are having some impact at the level of the bone marrow microenvironment, and maybe we are seeing some changes with these malignant megakaryocytes that seem to be the driving force behind this disease.

We need long-term data, and we need changes over time. The idea is that we’re bringing something additional to the table that not only can improve symptomatic responses, but maybe can lead to disease modification. We are suppressing enough of those inflammatory pathways that promote continued progression of these diseases, and we may be tipping the scales back in our favor.

Are there any targets beyond BET that have garnered further attention?

There are other targets that are certainly intriguing. The most intriguing one right now, other than BET, is the BCL-2/BCL-XL pathway. BCL-2 inhibitors with venetoclax [Venclexta] have gained a lot of traction in many different diseases, recently getting into the myeloid space with myelodysplastic syndromes and acute myeloid leukemia. However, maybe BCL-2 itself isn’t the key target in MPNs. It seems like BCL-XL might be more of the key target, [and that] is where navitoclax [(ABT-263) is directed]. [Navitoclax] is an older drug that wasn’t as effective or had some toxicity concerns in other diseases, and it is now being re-leveraged in [myelofibrosis] with good impact.

In the phase 2 [REFINE] study [NCT03222609], we saw that adding navitoclax to ruxolitinib was able to recapture spleen responses [with 27% of patients achieving a SVR35 at week 24 (n = 9/34)], which is not a small number.3 This [combination] has some mechanistic rationale and some clinical data to support it. [Navitoclax] is probably the most exciting targeted agent, besides what’s going on with BET inhibition.

We are looking at how to best target the NF-κB pathway. There are a lot of NF-κB inhibitors out there, and there is some interest right now in selinexor [Xpovio] as an XPO1 inhibitor. Selinexor certainly has gotten great responses in early phase studies. [Although] this [has been] in a small number of patients, it is exciting.

There are other targets and other pathways that we’re trying to figure out how to leverage. Myelofibrosis is an inflammatory disease, and that inflammation leads to continued disease progression and evolution of the disease. If we can figure out the most optimal way—which is probably not a one-size-fits-all situation—to stop that inflammation and suppress disease progression, there is potential for combination strategies.

What are your thoughts on combining agents up-front vs sequencing them?

Regarding the idea of combination strategies up-front vs add-ons, this is something that we’re not too sure about. If you can make the case that combination does not allow the disease to progress, then let’s leverage these [combinations] early on. However, you have to build that rationale.

On the contrary, if we’re just giving an extra level of symptomatic benefit and that’s what we’re shooting for, then start with a ruxolitinib- or JAK inhibitor–based therapy. If that works well and the patient feels well, continue with just that. If that doesn’t work effectively, if it is suboptimal, or you think [a patient] could do better, then add the other agent on and see what you can capture.

The idea for combination therapy is a push for disease modification. We hem and haw about what that actually means, but if we do think the disease is driven by multiple pathways of inflammation, then we need to hit it hard early with a combination strategy. However, to have that translate into clinical practice, you need good data to support that [disease modification is occurring].

Although many of these agents are still in early development, could targeted approaches potentially displace the role of stem cell transplant down the road?

It’s tough because none of these [agents] look like they’re curative at this point. If we can get meaningful, more durable, longer responses, then [targeted agents] could potentially replace transplant for a subset of patients. Right now, a lot of patients are diagnosed [at] older [ages], and with our limited treatment options, we’re considering transplant in a lot [of patients]. The equation is different if we can get sustained responses.

[For example, if you have] a 74-year-old patient with high-risk disease who you do not think is going to do well with the single-agent ruxolitinib approach and who is motivated for transplant, that changes the equation for that patient. Maybe with a combination or the potential to add something later on as ruxolitinib or the JAK inhibitor stops having as marked of an effect, that patient may decide to change course and pursue a different option and get good quality-of-life.

We know that transplant, while potentially curative, is not 100% [effective]. Even in patients who do get cured, it doesn’t mean that they have no toxicity from the transplant process. Often, patients come out on the other side a different person. While [targeted agents] won’t replace transplant, they could certainly obviate the need for transplant in a subset of patients.

What has exploration of different targeted approaches meant for the treatment landscape in myelofibrosis?

There are a lot of different agents at play, and there’s a ton of optimism. The overarching message is that we’re taking what we’re learning from the basic scientists and the translational scientists, and we’re putting that into rationally designed treatment options, we’re bringing that to patients, and we’re hopefully going to get new drug approvals.

We need to continue to understand that this is not going to be a one-size-fits-all approach. Navitoclax, pelabresib, selinexor, and any of these additional agents that go into late-stage development are not going to be great for every single [patient with] myelofibrosis. Right now, they’re being tested broadly in myelofibrosis. However, we need to work in the academic side to try to figure out which patients these [agents] benefit. Instead of giving [a treatment] broadly and getting a 30% response rate, let’s enrich the population with who’s likely to benefit, figure out how to get the right population, and get a 70% response rate.

There are toxicities to these additional agents. Especially when you treat with 2 agents over 1, you’re going to have multiple toxicities. Understanding who’s unlikely to benefit vs who’s likely to benefit can make a huge difference for patients clinically.

We do have to have some humility in this as well. We always reference the COMFORT studies [of ruxolitinib] and the JAKARTA studies of fedratinib [Inrebic] as far as our response rates and symptoms. However, I don’t believe that’s going to be how it plays out in phase 3 trials. We’re better now at patient selection, and patients who go on trials are typically more favorable than they were when we didn’t have any agents. We were putting anyone onto the COMFORT studies. [With improved patient selection], the response rates for the [control] arm [in future phase 3 trials] may be higher than we think, and that may present a challenge for getting some of these new agents approved because it is a higher bar to reach if you have to show significant improvement over a higher response [in the control arm].

These are exciting times. We’re going to get readouts of some of these big trials over the course of the next [couple] years. Hopefully, we have some new agents to leverage, but once we get the approvals, that is when we must do the real work and try to figure out how best to use these in practice.

References

1. Mascarenhas J, Kremyanskaya M, Patriarca A, et al. BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis – JAK inhibitor-naïve or with suboptimal response to ruxolitinib – preliminary data from the MANIFEST study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S198.
2. MorphoSys completes enrollment of phase 3 MANIFEST-2 study of pelabresib in myelofibrosis with topline results expected by end of 2023. News release. MorphoSys AG. April 4, 2023. Accessed May 23, 2023. https://www.morphosys.com/en/news/
3. Harrison CN, Garcia JS, Somervaille TCP, et al. Addition of navitoclax to ongoing ruxolitinib therapy for patients with myelofibrosis with progression or suboptimal response: phase II safety and efficacy. J Clin Oncol. 2022;40(15):1671-1680. doi:10.1200/JCO.21.02188

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While younger matched donors and older matched sibling donors provide similar outcomes, matched sibling donors are the optimal donor type for patients with cancer in need of a stem cell transplant, according to Salman Fazal, MD.

According to previous research, 3 to 5-year survival rates and outcomes between these donors are similar. However, a study published in Blood revealed that the average 3-year overall survival for patients with a matched sibling donor was 46% while it was 43% for unrelated donors. Having a matched sibling donor also lowered the risk of acute graft-versus-host-disease (GVHD).

“[A]t this point in time, even if we have a matched sibling, probably even above the age of 50, we would prefer using that matched sibling over a younger matched unrelated donor,” Fazal, director of the cell transplantation program in the division of hematology & cellular therapy at the Allegheny Health Network, told Targeted Oncology^TM.

In the interview, Fazal discussed the differences between older matched sibling donors vs younger unrelated donors in stem cell transplants and donor preferences at his institution for patients with cancer.

Targeted Oncology: What is the difference between younger, matched, unrelated donors and donor matched sibling donors? According to research, which achieves the better results?

Fazal: For each patient, we sometimes do not have the option of choosing between matched sibling [donor] vs an unrelated donor. So, if we have a match on an unrelated donor, we take that match from the unrelated donor for allogeneic stem cell transplant. However, in a situation where we have the options between an older matched sibling vs a younger matched unrelated donor the clinical study that was published in Blood, roughly about 8 to 10 years ago, looked at this comparison.

[They] found that using a matched sibling has resulted in a better outcome in terms of lowering the risk of acute and chronic graft versus host disease, and other complications related to transplant. So, at this point in time, even if we have a matched sibling, probably even above the age of 50, we would prefer using that matched sibling over a younger matched unrelated donor.

Can you discuss what kind of disease-free survival we’re seeing with young matched unrelated donors?

It is very relevant in terms of disease-free survival. It depends upon the type of disease the patient has, whether we’re dealing with acute leukemia or myelodysplastic syndrome, and we’re also dependent upon their status of the disease moving into the transplantation. In general, for different types of acute leukemia, depending upon the intensity of the conditioning, the disease-free survival rates vary between 50% to 70%, depending upon the status of the disease and the intensity of the conditioning chemotherapy. We do try to improve the disease-free survival with maintenance therapies which are used in conjunction with reducing the immunosuppression following the stem cell transplant to improve the disease-free survival.

Can you talk about acute and chronic GVHD occurring and younger match unrelated donor transplant?

Over the last few years, there has been a lot of interest in terms of using different modalities to lower the risk of acute and chronic graft-versus-host disease. I always feel that we would be performing more allogeneic stem cell transplantation for different diseases if there was no significant risk of acute or chronic graft-versus-host disease. In general, the matched donors prefer per cell transplantation, there have been different modalities or methods have been used to lower the risk of acute and chronic graft-versus-host disease. Historically, we have used strategies, which include calcineurin inhibitors and methotrexate to lower the risk of graft-versus-host disease.

More recently, there was a study which compared tacrolimus and methotrexate with post-transplant cyclophosphamide to further lower the risk of graft-versus-host disease. We found that using post-transplant cyclophosphamide, even in matched related donors, led to lowering the risk of acute and chronic graft-versus-host disease. However, that study did not have the comparator arm with antithymocyte globulin, which is 1 of the other modalities that has been used to lower the risk of acute and chronic graft-versus-host disease. But as we all know, post-transplant cyclophosphamide came into the scene with the haploidentical transplantation, and now it is making its way in other types of transplantation, including measuring later donor transplantation. It has shown that it is an effective strategy in terms of both acute and chronic efforts. However, we do still see significant risk of both acute and chronic, although I believe that chronic graft-versus-host disease remains a challenge in terms of allogeneic stem cell transplantation.

What is the donor preference in your institution and what studies support that choice?

It all depends upon each individual patient, which options we have at our institution, and we do always consider matched siblings and over a matched unrelated donor. However, unfortunately, because of health conditions and other exceptions, matches are not sometimes available in those circumstances. We do prefer using a match on a later donor for transplantation. However, in situations where we do not have a match and later donor, then we are posed with the question whether we choose a mismatched, unrelated donor vs a haploidentical transplantation?

Currently, that trial is ongoing in terms of trying to figure out which is a better strategy in that type of situation. Is a mismatched unrelated donor transplantation a better option than a haploidentical transplantation? At this time, at our institution, because of the reliability of haploidentical transplantation and immediate availability of the donor, we do usually prefer to proceed with the haploidentical transplantation.

I think clinical trials have to show that if using a haploidentical transplantation is associated with better outcomes as compared with mismatched unrelated donors, I think the use of post-transplant cyclophosphamide in haploidentical transplantation has now made its way of using post-transplant cyclophosphamide following mismatched unrelated donor transplantation as well. I think in that context, the outcomes probably could be similar between the 2 strategies. However, because of the reliability of availability of the donor with the haploidentical transplant and with the unrelated donor, we always are concerned about the possibility of a situation where an unrelated donor is unavailable. In that situation, the patient may be left with delay in transplantation. We like to proceed with haploidentical transplantation because of its reliability of availability. I think that is also stems from the time when we were doing transplantation during the COVID pandemic because during the COVID pandemic, it was much more practical to use a haploidentical transplant donor where we don’t have to cryopreserve the cells and use the the or the fresh stem cells from the haploidentical donor.

Can you discuss haploidentical donors and their overall survival and relapse-free survival data?

In general, with haploidentical transplantation, there is overall improvement in the outcomes. However, we still prefer to do unrelated donor vs haploidentical transplantation. There are certain institutions across the country that do prefer haploidentical transplant over unrelated donors. However, now, at least at our institution, we prefer to do match unrelated donor transplantation. In terms of the outcomes of the haploidentical transplantation, it is dependent on different diseases. In terms of acute leukemia, depending upon the intensity of conditioning, chemotherapy, and the status of the disease, the outcomes vary. Again, in terms of acute leukemia, as I mentioned earlier, the disease-free survival rates vary between 50% to 70%. Outcomes with chronic graft-versus-host disease vary somewhere between 30% to 50%. Up to 50% can develop graft-versus-host disease, however, the majority of these graft-versus-host diseases are mild to moderate.

How would you advise other doctors on deciding on which donor to select in deciding when to do a transplant?

In terms of the other dissenters, I would prefer that we continue to use the match unrelated donor. However, I think, for mismatch vs the haploidentical transplant, we certainly have to look at the data. I do like the idea that the haploidentical has the bigger liability. So, I think in those situations, taking a haploidentical donor is preferable over a mismatched unrelated donor.

In terms of the difference for transplantation, we hope that the transplant physician is involved with the care of the patient from the beginning. There are situations in acute leukemia, where the choice of initial therapy impacts the post-transplant outcome. There are situations even with the availability of immunotherapy where use of certain agents can increase the risk of graft-versus-host disease and such complications after transplantation. I think incorporating the transplant physician in terms of choice of initial therapy, and then getting them to the transplant physician in a timely fashion is important.

Data that was presented in terms of comparing post-transplant cyclophosphamide vs tacrolimus and methotrexate confirmed that post-transplant cyclophosphamide does improve the outcomes following the transplantation. I think using these during this phase 2 clinical trials are a way to improve patient outcomes following the transplantation.

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