NCCN Guidelines for MPN Reflect New Drugs, Focus on Clinical Trials

Understanding of myeloproliferative neoplasms (MPNs), a group of blood cancers that occur when a person’s bone marrow makes too many blood cells, has increased since discovery of the JAK2 mutation in 2005.¹ Still, the first set of National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPNs, which include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), did not appear until 2017, and through 2022 there were few updates.

But since then, the NCCN Guidelines for MPNs have had multiple updates per year, with the latest in August 2024,² a sign of increased activity in the field. In an interview with The American Journal of Managed Care^® (AJMC^®), Aaron Gerds, MD, MS, who chairs the panel handling the MPN updates, confirms that the more frequent updates reflect new approvals and more options for patients.

Aaron Gerds, MD, MS | Image credit: Cleveland Clinic

“We are regularly looking at the published literature and updates in the field in order to make sure that these guidelines are very nimble, and that they are adjusted to reflect current practice,” said Gerds, who is associate professor of medicine and deputy director for clinical research at the Cleveland Clinic Taussig Cancer Institute. Some guidelines might be updated every 5 to 10 years; but if there’s nothing new, “there's not a lot of sense in updating things in a large way.”

Conversely, updates often occur when new therapies are approved or become available, Gerds said, as was the case in September 2023 when momelotinib (Ojjaara), the fourth Janus kinase (JAK) inhibitor, became available for the treatment of intermediate or high-risk MF, including primary MF or secondary MF, and post-PV, and post-ET in adults with anemia.³

The most recent update puts a major focus on clinical trials; in many circumstances, they are listed as the preferred option over FDA-approved therapies; in the AJMC interview, Gerds explains how a pair of phase 3 trials involving ruxolitinib combinations will produce results very soon.

The rest of the AJMC interview, lightly edited for clarity, appears below.

AJMC: In addition to recommendations for specific therapies, the latest NCCN Guidelines update makes multiple recommendations for use of next-generation sequencing (NGS), especially when evaluating higher-risk patients.² Although there is some variation across cancers, we still hear reports of challenges in reimbursement for NGS. What is the experience with MPNs?

Gerds: It goes without saying, but I'll say it anyway: There's quite a bit of tension between those who care for patients with cancers—not just blood cancers, but all cancers—and the people who pay for those treatments, the third-party insurance companies. Their goal is primarily to remain solvent, fiscally and to, quite frankly, make money. And our goal is to take care of patients.

Sometimes those things are at odds, because medicines and therapies and diagnostics in cancer medicine are incredibly expensive, and while they try to limit costs, we are always trying to push the boundaries of care to make our patients’ lives better—and there are many points of pain with this tension. One of the points of pain is next generation sequencing testing. Those of us in the field of myelofibrosis recognize that NGS testing is critical in the care of our patients. It is the best way to understand the prognosis for a given individual with myelofibrosis. Identifying the JAK/STAT mutation that's driving that pathway is important in diagnostics, and I think widely accepted by insurances, as well as being relevant for a patient's care. But in this recent update we also wanted to emphasize the critical importance of getting a full NGS panel, because genes outside the JAK/STAT pathway are important in identifying a prognosis in patients. It has become the standard of care to use models like the MIPS score, which has the genetics of the disease front and center in determining one's prognosis.⁴

AJMC: The first section of the latest revision includes language changes that reflect several changes since the last update in January 2024. What are the most important adjustments?

Gerds: In addition to the advent of new medications or large papers that might expand on medications’ indication for treatment in the guidelines, we're always going through to make sure the verbiage is most consistent with the current thinking within a disease space. We went through our guidelines with recent iterations, and tried to do a few things:

First, we tried to increase the emphasis on clinical trials as a therapy option, not just in second-line setting or third-line setting or extreme cases, but even in the frontline setting, as there are large numbers of frontline trials now being done for myelofibrosis. The available therapies are not good enough. They're great—they’ve changed the treatment landscape, but we need to do better, and we continue to do better. So, trials, even the frontline setting, we feel are incredibly important to emphasize.

Second, we updated language to be more precise about what we call our diseases—in particular, accelerated/blast phase disease.⁵ We wanted to make sure that was consistent throughout the guideline, and using those terms helps distinguish it from de novo acute myeloid leukemia (AML) or de novo AML; which is AML that did not come out of a preceding MPN and behaves very differently. The survivals are different. The genomic complexity of the disease is different, and the response to chemotherapy is very different than what we see with accelerated/blast phase MPN. And so we really wanted to emphasize that point, [as] this will feed back into treatment considerations as well as the design of clinical trials. I think that's a great example of how we've gone through the to make sure we're using terminology that emphasizes the points we're trying to make.

AJMC: It is apparent there are several places where the guideline lists clinical trials as the preferred option, followed by approved therapies.

Gerds: Most of the trials that we have in myelofibrosis are, quite frankly, the standard of care plus the new thing. And so, it makes sense to say, ‘Yes, we can safely say with a large degree of equipoise that these clinical trials are preferred over standard care because they're not radically different.’ They're not totally different, and would have that equipoise saying that, yes, it is fair to try these clinical trials, even before you do a standard of care therapy.

AJMC: The update also has a lot of emphasis on risk stratification. Can you discuss this point of emphasis?

Gerds: Risk stratification in myelofibrosis is important for 2 reasons. First, it is there to help educate our patients on what we expect to happen over time. The more important reason, or equally as important reason, I would say, is that it helps identify patients who we want to refer to transplantation, being that hematopoietic stem cell transplantation is the only curative therapy as of today. If we can better understand one's risk and what may happen in the next 2, 3, 5, or 10 years, it can help guide those patients towards transplantation.

Otherwise, the treatment of myelofibrosis is really a needs-based schema where, if a patient has symptoms or splenomegaly (an enlarged spleen), we try to address those with JAK inhibitors. If the patient has anemia, we're trying to address those things with anemia-supportive agents. But really, the emphasis on prognosis is to help counsel patients as well as identify those for transplantation. And this is all in the added context of the fact there are a large number of models out there that have been published and validated, and so it can get pretty confusing which one to pick when and for what situation. And so, our goal was to try to clarify that process as well.

AJMC: Ruxolitinib (Jakafi) is the first approved JAK inhibitor⁶; it has been around for a long time (approved in FM, PV, and graft-vs-host disease). As we know, there are a number of new therapies on the scene, with some very recently approved. What are the considerations for clinicians for selecting a new therapy over something that’s been prescribed for more than a decade? What are the decision points?

Gerds: So, there are now 4 JAK inhibitors that are FDA approved to treat myelofibrosis, and the thing that connects them all is they're all JAK2 inhibitors. They all inhibit wild-type JAK2 to similar IC50s (half-maximal inhibitory concentration, a measure of a drug’s efficacy).

But we spend a lot of time talking about the other parts of their mechanism, actually. Do they also inhibit JAK1, or IRAK1, or ACBR1, or these other targets—because that helps determine, or at least start to draw in a picture, of where these drugs might work the best. And then, we combine that with the clinical trial data. So, what were the inclusion criteria for the pivotal studies?

If you take the 2 together, you can start to piece together where these JAK inhibitors might be most beneficial. Of course, ruxolitinib is a fantastic medication. It is excellent at treating splenic symptoms, particularly in patients who have preserved platelet counts, as well as those who have minimal to no anemia. So, in that patient who's still proliferative, who has adequate marrow function but does have a big spleen and symptoms, ruxolitinib makes the most sense.

Pacritinib (Vonjo) has really shined in populations of patients who are more cytopenic, who have anemia, and certainly those who have severe thrombocytopenia, even where platelet counts are less than 50,000 (per µL).⁷

Based on the MOMENTUM study⁸ we see that momelotinib can be successful in patients who have baseline anemia, and fedratinib (Inrebic) through the JAKARTA2 trial⁹ has shown efficacy in the second-line setting, where patients have been previously treated with ruxolitinib and still have spleen volume and symptom burden have seen improvements on fedratinib. And so that starts to parse out where these therapies might be best suited.

The major challenge, though, is that the NCCN Guidelines are algorithms; there are direct lines, very black and white boxes for these things. And in reality, there are no “boxes.” There's a lot of overlap between the trials; there's a lot of overlap of where these drugs are efficacious or have been found to be efficacious, both in prospective and retrospective analyses. And so, we're trying to take a Venn diagram that is almost a singular circle and pull it apart and put in an algorithm. I think that's really the challenge with these guidelines, because they need to be algorithmic for that practicing physician. The physicians need to be able to pull them up quickly, run through and say, “OK, this is what my patient needs.” Certainly, when you get into the weeds of the data that's been published, it’s much more nuanced, but that's really hard to put in an algorithm. So, we're trying to take that nuance, the subtleties from the trials, and distill it into an algorithm.

AJMC: We discussed clinical trials and the fact that they are preferred in many cases. Given that, what's in the pipeline that you’re particularly enthused about? What readouts should we be waiting for?

Gerds: There are a large number of phase 3 trials that are in process right now. For myelofibrosis, the 2 that are furthest along are the MANIFEST-2 trial,^10,11 which is at a combination of ruxolitinib and pelabresib in the frontline setting for myelofibrosis, as well as the TRANSFORM-1 study,¹² which looked at ruxolitinib and navitoclax versus ruxolitinib alone in the frontline setting. We have preliminary data from the week 24 analyses, which were presented at last year's [American Society of Hematology] annual meeting, and both trials were positive for the primary endpoints, which was very exciting, of course—being new therapies in new combinations, we need to do better than just ruxolitinib alone.

We need that long-term data—what happens at week 48, maybe even 2 years, 3 years down the road. So how does the use of combination therapy really start to slay apart those curves for event-free survival, or even overall survival?

We also have a phase 3 trial that's ongoing in this primarily in the second-line setting with a drug called imetelstat (Rytelo), which was already FDA-approved to treat low-risk myelodysplastic syndromes.¹³ And that trial is, in fact, going for that overall survival primary endpoint. So can we improve survival in patients with the more recalcitrant, if you will, myelofibrosis. There are other randomized phase 3 trials with export molecules like selinexor (Xpovio), which is already approved to treat patients with multiple myeloma, but also has efficacy in myelofibrosis, among a few others.¹⁴ So, navtemadlin, which is an MDM2 inhibitor, is also in a phase 3 trial.¹⁵

The fact that we have multiple ongoing phase 3 trials in an effectively rare disease, I think, is really, really exciting. And I would not be surprised if you know, with the guidelines, we're scrambling to update them again in the next year to 2 years.

References

1. Merchant S. Chapter four—the JAK2 mutation. Intl Rev Cell Molecul Biol. 2021;365:117-162. doi:10.1016/bs.ircmb.2021.09.002
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Myeloproliferative Neoplasms Version 2.2024 — August 8, 2024. Accessed October 8, 2024. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf
3. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GSK. September 15, 2023. Accessed October 9, 2024. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia/
4. Boscar iE, Dalle Palle S, Vitulo N, et al. MIPs: multi-locus intron polymorphisms in species identification and population genomics. Scientific Reports. 2024;14:17870. Published August 1, 2024. Accessed October 8, 2024.
5. Arber DA, Orazi A, Hasserjian RP, et al. International consensus classification of myeloid neoplasms and acute leukemia: Integrating morphological, clinical, and genomic data. Blood 2022;140:1200-1228. https://www.ncbi.nlm.nih.gov/pubmed/35767897.
6. Deisseroth A, Kaminskas E, Grillo J, et al. US Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin Cancer Res. 2012;18(12):3212-3217. doi:10.1158/1078-0432.CCR-12-0653.
7. FDA approves drug for adults with rare form of bone marrow disorder. News release. FDA newsroom. March 1, 2022. Accessed October 10, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-adults-rare-form-bone-marrow-disorder
8. Gerds AT, Verstovsek S, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study. Lancet Haematol. 2023;10(9):e735-e746. doi:10.1016/S2352-3026(23)00174-6.
9. Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol. 2020;95(6):594-603. doi:10.1002/ajh.25777.
10. Harrison CN, Gupta VK, Gerds AT, et al. Phase 3 MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naïve myelofibrosis. Future Oncol.2022;18(27):2987-2997. doi:10.2217/fon-2022-0484.
11. Rampal RK, Grosicki S, Chraniuk D, et al. 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(suppl 1):abstr 628. doi:10.1182/blood-2023-179141
12. Pemmaraju N, Mead AJ, Somervaille TCP, et al. Transform-1: A randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with uUntreated myelofibrosisBlood. 2023;142(suppl 1):abstr 620. https://ash.confex.com/ash/2023/webprogram/Paper173509.html
13. Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10423):249-260. DOI: 10.1016/S0140-6736(23)01724-5
14. Study of Selinexor in Combination with Ruxolitinib in Myelofibrosis (SENTRY). Updated September 19, 2024. Accessed October 19, 2024. https://www.clinicaltrials.gov/study/NCT04562389
15. Verstovsek S, Al-Ali HK, Mascarenhas J, et al. BOREAS: a global, phase III study of the MDM2 inhibitor navtemadlin (KRT-232) in relapsed/refractory myelofibrosis. Future Oncol 2022; doi: 10.2217/fon-2022-0901.