Combination Therapies and New Research Drive Progress in Myelofibrosis


In an interview with Targeted Oncology, Raajit K. Rampal, MD, PhD, provided an update on developments, unmet needs, and future directions for the treatment of patients with myelofibrosis.

Raajit K. Rampal, MD, PhD

Raajit K. Rampal, MD, PhD

2023 brought a wave of positive developments for patients with myeloproliferative neoplasms (MPNs), particularly myelofibrosis. According to Raajit K. Rampal, MD, PhD, one study of particular interest was the phase 3 MANIFEST-2 trial (NCT04603495) of ruxolitinib (Jakafi) with pelabresib (CPI-0610).

This study, in addition to the TRANSFORM-1 trial (NCT04472598), showed significant improvement in spleen size and potential benefits in symptom reduction with combination therapies compared with single-agent treatments, suggesting that these combinations could become valuable options for treating patients with myelofibrosis upfront.1,2

Other studies, including early data of TP-3654 and selinexor (Xpovio), show potential for further advancements in myelofibrosis treatment.

“There is a lot to be excited about for the first time in a very long time. There are all of these other small molecule inhibitors in clinical trials [and] I think we will learn a lot from that,” said Rampal, hematologic oncologist at Memorial Sloan Kettering Cancer Center, in an interview with Targeted OncologyTM.

In the interview, Rampal provided an update on developments, unmet needs, and future directions for the treatment of patients with MPNs, especially myelofibrosis.

Targeted Oncology: What were some of the key takeaways from the 2023 American Society of Hematology (ASH) Annual Meeting?

Rampal: This [was] a big year in terms of developments for MPNs at ASH. We had 2 phase 3 trials read out, which is extremely uncommon in our field, 2 combination agents, both I think that could show some promising results, as well. There were a number of other newer drugs that are non-JAK inhibitors that were also showcased, and also some developments in mastocytosis as well.

There is a lot to be excited about for the first time in a very long time. There are all of these other small molecule inhibitors in clinical trials [and] I think we will learn a lot from that. Now, we have the first antibodies, we have calreticulin antibodies from a couple of different companies that are in clinical trials that have just started, and I think those could potentially make a major impact, so we will learn a lot about those shortly.

3D rendering of red blood cells flowing: © Kodjovi -

3D rendering of red blood cells flowing: © Kodjovi -

Can you provide an overview of the MANIFEST-2 study?

I presented the phase 3 data for the MANIFEST-2 trial, which was a phase 3 trial that was comparing ruxolitinib and pelabresib, which is a BET inhibitor, vs ruxolitinib and placebo. This was a trial of untreated patients with myelofibrosis who had symptoms and an enlarged spleen. It was a double-blind, placebo-controlled trial, the primary end point being the spleen volume reduction by 35%, as well as the key secondary end points of total symptom score reduction and the proportion of patients who achieved a 50% reduction in their total symptom score.

What were the main findings presented at the meeting?

The top-line data from this study demonstrated that as compared with ruxolitinib monotherapy, there was a clear superiority of the combination therapy in terms of reducing the spleen size, which was almost a 2-fold magnitude increase in the proportion of patients whose spleen was reduced in size. I think the significance of that is that, at least historically, it has shown that there is a survival benefit that correlates with spleen volume reduction. That was not what was directly assessed with this trial, but I think that is part of what makes it important.

With regards to symptom reduction, there was a numerical benefit in terms of the combination vs single-agent ruxolitinib, although it did not quite reach statistical significance. I think beyond those end points were some other compelling and important data, including reductions in inflammatory cytokines that we are seeing with a combination [that are] not seen quite so much with ruxolitinib alone, better hemoglobin parameters for the combination, more patients had anemia with ruxolitinib alone, and better preservation with the combination therapies. [For] bone marrow fibrosis, a greater proportion of patients appeared to have an improvement in their bone marrow fibrosis with combination than what we have seen with ruxolitinib alone. I think those are kind of the key positive takeaways.

Importantly, there were not any new adverse event signals from the combination therapy. The 1 thing that if we think about hematologic and non-hematologic toxicity, there was a little bit more thrombocytopenia seen with combination therapy, and in non hematologic toxicities, that was observed with combination therapy than with ruxolitinib. But again, largely there [were] no new safety signals from the combination therapy over what we have seen with ruxolitinib.

What should a community oncologist know about these data?

This data is 1 of the first 2 studies to report on combinations of a JAK and non-JAK inhibitor therapy. I think what we are seeing is that these drugs seem to be better for reducing spleen size and they do not seem to add toxicity from a symptom standpoint, which is important with combination therapy. I think that if these are approved, [they] will be useful drugs to think about utilizing upfront for [patients with myelofibrosis].

Are there any other ongoing trials or research in this space that particularly excite you?

There are certainly a couple of things to think about, and we have to see more mature data. I would put that in the category of things we want to follow-up on for the MANIFEST-2 study, but also for the TRANSFORM-1 study, and we want to see longer term data on what we see occurring, what benefits do we see, are there any late toxicities that we observed there?

There are also newer drugs looking promising and showing some early signs of efficacy. One is TP-3654, which is a PIM-1 kinase inhibitor, which was presented as an oral abstract at ASH as well. This was a drug that was being used as a monotherapy. I think the intriguing thing from that data is there seems to be pretty profound symptom responses and spleen responses as well. Other drugs like selinexor had data presented at ASH. The follow-up is a phase 3 trial that is currently ongoing with that drug plus ruxolitinib vs ruxolitinib alone. Hopefully, in 2 years or so we will get a readout of that trial as well.

For this trial specifically, what are the next steps?

At this point, the trial has completed accrual, and I think it is important. The data readout was week 24. There are patients who are in various stages of their being in the study. We will get more data and a more mature data read out over the next 3 to 6 months, so I think more to come on this study at some of the upcoming congresses

What unmet needs still exist in the myelofibrosis space?

I think an unmet need is that we do not have a curative therapy, we do not have a true therapy that is able to put patients into sustained remission, aside from stem cell transplant. That remains the biggest unmet need. I think all of these therapies, hopefully, will get us closer to that, but that is the unmet need.

How might pelabresib impact the field of myelofibrosis down the line?

If practice is based on the data that we have from the phase 3 trial, it may allow us to treat patients earlier in their course of disease with the combination and achieve a more of a deep response. It remains to be seen how durable that response will be, and only time will tell us the answer, but it may make us a step closer towards initiating therapy that is able to keep the disease under better and hopefully longer control.

What advice do you have for community oncologists treating patients with myeloproliferative neoplasms in their practice?

It is hard to stay up to date on all of the developments. I think it is always, particularly for patients with [myelofibrosis], important for physicians to consider referral to stem cell transplant specialists, even in the initial stages of the disease, just for planning purposes. I think it is important to think about having an overall strategy for a patient. That long-term may be a stem cell transplant. In the short term, it may be a JAK inhibitor, but I think it is important to gather all of that information early on in a patient's course.

1. Pelabresib in combination with ruxolitinib for janus kinase inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Blood. 2023;142(1):628. doi:10.1182/blood-2023-179141
2. Mascarenhas J, Kremyanskaya M, Patriarca A, et al. MANIFEST: Pelabresib in combination with ruxolitinib for janus kinase inhibitor treatment-naïve myelofibrosis. J Clin Oncol. 2023;41(32):4993-5004. doi:10.1200/JCO.22.01972
Related Videos
Related Content