Category Archives: Myelofibrosis

Is Treatment for Cytopenic Myelofibrosis Still an Unmet Clinical Need?

Posted on by

Madeline Caduc and Steffen Koschmieder

Nov 2023

Philadelphia-negative myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a group of clonal hematological disorders driven by mutated hematopoietic stem cells. MF, as de novo myeloid malignancy (primary MF: PMF) or secondary to an antecedent MPN (post-ET-MF or post-PV-MF), is a life-threatening condition associated with shortened survival and risk of leukemic transformation in about 20% of the patients. Clonal expansion of malignant myeloid stem- and progenitor cells and stromal changes along with increased proinflammatory cytokines production drive the remodeling of the bone marrow (BM) microenvironment and disrupt physiological hematopoiesis. Clinical manifestations of MF-associated progressive BM failure, such as cytopenia (anemia, thrombocytopenia), hepatosplenomegaly, constitutional symptoms (eg, weight loss, fever, night sweating), significantly impact patients’ quality-of-life (QoL) and correlate with poor prognosis for overall survival (OS).,

The identification of a constitutive JAK–STAT pathway activity and underlying somatic driver mutations in the janus kinase 2 (jak2), calreticulin (calr), and thrombopoietin receptor (mpl) genes has revolutionized the therapeutic landscape with the development of JAK inhibitors (JAKi).

Ruxolitinib, a dual JAK1/JAK2 inhibitor, was the first JAKi approved for treatment in patients with intermediate- or high-risk MF (U.S. Food and Drug Administration [FDA]) or MF with disease-associated splenomegaly or symptoms (European Medicines Agency [EMA]) and remains the standard of care. However, although 2 phase 3 clinical trials, COMFORT-I and –II, demonstrated that ruxolitinib induces rapid spleen volume reductions (SVR) as well as symptom improvement, treatment discontinuations are frequent (up to 60% in 3 y), because of grade of ≥3 cytopenia, and resulting in suboptimal symptom control, risk of disease relapse, and decreased survival.–

Nearly a decade later, the selective JAK2 and FMS-like tyrosine kinase 3 (FLT3) inhibitor fedratinib was approved for the treatment of intermediate and high-risk MF (FDA) or MF with disease-associated splenomegaly or symptoms (EMA). Although fedratinib was active in untreated patients but also patients with documented progression during ruxolitinib or intolerance to ruxolitinib, fedratinib induced comparable myelosuppression with anemia and thrombocytopenia as the most common causes for treatment discontinuation. Thus, although the development of JAKi has significantly improved MF treatment, cytopenic myelofibrosis still presents a significant unmet medical need.

Pacritinib, a potent JAK2 and interleukin-1 receptor associated kinase 1 (IRAK1) inhibitor, received FDA-approval for use in MF patients with platelet counts of ≤50 × 109/L, based on the results of the PERSIST-1 and PERSIST-2 studies. The efficacy and safety of pacritinib compared with physician’s choice of therapy (including ruxolitinib) is currently being further investigated in MF patients with severe thrombocytopenia in the phase 3 study PACIFICA (NCT03165734). Interestingly, a post hoc analysis of the PERSIST-2 study showed an anemia benefit in patients treated with pacritinib, which was attributed to activin A receptor type 1 (ACVR1) inhibition. However, further investigations are needed to unravel the detailed biological mechanisms involved, including the role of IRAK1 inhibition.

The pathophysiology of MF-related anemia has not been fully deciphered. In addition to progressive reticulin deposition, dysregulation of iron homeostasis has emerged as a pivotal process for disruption of normal erythropoiesis. Hepcidin, a key regulator of iron metabolism, was discovered to be elevated in MF patients, and this upregulation proved to be unresponsive to ruxolitinib treatment. Interestingly, the combined JAK1/2 inhibitor, Momelotinib (MMB), also inhibits ACVR1 and thereby decreases hepcidin, emerging as a promising therapeutic alternative for patients with MF-related anemia. MMB was assessed as treatment of intermediate- or high-risk MF patients in 2 phase 3 trials, SIMPLIFY-1 and SIMPLIFY-2. Although MMB met the primary endpoint in the SIMPLIFY-1 trial (noninferiority to ruxolitinib regarding spleen volume response), the key secondary endpoint was not met (noninferiority to ruxolitinib regarding symptom response). However, MMB activity demonstrated consistent anemia benefits including conversion to transfusion-independence (TI), SVR, and QoL improvement, when compared with baseline. The SIMPLIFY-2 trial evaluated the superiority of MMB over the best available therapy (BAT) in MF patients who had previously received ruxolitinib treatment. The defectiveness of currently available therapies for cytopenic MF was emphasized by the fact that 89% of the BAT patients continued treatment with ruxolitinib. However, the primary endpoint (superiority of MMB versus BAT regarding spleen volume reduction at week 24 [SVR24]) was not met, although the MMB group demonstrated a higher rate of conversion to TI, emphasizing its anemia-alleviating potential when compared with BAT. Of note, the lack of JAKi washout period before MMB-treatment start might have influenced the results.

Recently, MMB-induced anemia benefit was further investigated in the double-blind, (2:1) randomized clinical trial of MMB versus danazol, the MOMENTUM trial. This trial enrolled MF patients with failure to JAKi treatment, moderate-to-severe anemia (hemoglobin <10 g/dL), and a total symptom score (TSS) ≥10. The primary endpoint, a ≥50% reduction in the mean TSS at week 24, was met, as well as key secondary endpoints, including TI rate at week 24 and SVR24. Importantly, several of the symptoms were not directly correlated with anemia (eg, early satiety, abdominal discomfort, bone pain, and night sweats). Thus, inferiority of danazol might not be surprising. However, at the time of the study, danazol treatment was in alignment with the guidelines of the National Comprehensive Cancer Network and the European Society of Medical Oncology for the management of MF-associated anemia.

In the present HemaSphere issue, Mesa et al present novel data from the MOMENTUM trial, bridging the knowledge gap of how MMB impacts MF-associated symptoms. In line with the results of SIMPLIFY-1 and -2, MMB improved anemia and led to a higher proportion of patients achieving TI compared to the danazol group. Interestingly, some patients experienced fatigue relief without attaining TI. Although some anemia benefits might have not been captured by the strict TI endpoint of the study, these findings underscore the multifactorial pathogenesis of fatigue. Thus, MMB treatment–associated benefits may well extend beyond its proerythrogenic activity with the reduction of cytokines production as a possible mechanism for the reported TSS improvement. However, as pointed out by the investigators, although patient-reported fatigue was a secondary endpoint of MOMENTUM, the trial was not designed to explore the relationship between anemia and symptoms. Further investigations will be needed.

In addition to anemia and RBC transfusion–dependency, recent surveys emphasized severe thrombocytopenia (platelet count ≤50 × 109/L) as a critical negative prognostic factor, with higher rates of both hemorrhagic and thrombotic complications, as well as a higher risk for leukemic transformation. Furthermore, fatigue as a multifactorial and burdensome MF-symptom with significant repercussion on patients’ cognitive, physical, and social functioning was shown to be significantly increased in thrombocytopenic MF patients.

In a second publication in this HemaSphere issue, Kiladjian et al present data from their post hoc combined analysis of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials on the efficacy and safety of MMB in patients with thrombocytopenia. All patients with baseline platelet counts of <100 × 109/L were included and defined as the “sub-100 group.” Of note, patients with severe thrombopenia (<50 × 109/L) were not analyzed separately because of low patient numbers but were integrated within the sub-100 group. Overall, platelet counts were stable or increased in the MMB treated sub-100 group, enabling continuous adequate dosing beyond the initial 24-week-treatment period. Interestingly, this retrospective analysis of the SIMPLIFY trials indicates a reduced ruxolitinib effectiveness in patients with platelet counts below 100 × 109/L. The numerically higher TSS reduction, SVR, and conversation rate to TI in the MMB group may be because of a higher myelosuppressive activity of ruxolitinib, leading to more frequent dose reductions and treatment discontinuations. Thus, this post hoc analysis suggests that MMB may be superior to ruxolitinib, BAT, and danazol in patients with low platelet counts, without altering the safety profile. However, because of the descriptive nature of this analysis, prospective real world data will be required to confirm these results.

In summary, the new results of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials underline the potential of MMB to expand our treatment options for MF patients, particularly those with symptomatic and/or RBC transfusion–dependent anemia. MMB has recently been approved by the FDA for the treatment of intermediate- or high-risk MF in adults with anemia.

In addition, several new therapeutic agents are presently under clinical investigation, either as monotherapy or as add-on therapies to JAK inhibitor. Much of their success will depend on their ability to target the underlying disease pathophysiology, to lead to clinically meaningful long-term eradication of the malignant clone and cure of the patients from MF. Thus, the unmet clinical need for the treatment of cytopenic MF is lessened, but it still exists.

FDA Approval of Momelotinib May Establish New SOC for Myelofibrosis With Anemia

Posted on by

November 2, 2023

Courtney Flaherty

The JAK1/JAK2 and ACVR1 inhibitor momelotinib (Ojjaara) not only provides spleen volume and constitutional symptom benefits in patients with anemic symptomatic myelofibrosis that is noninferior to that achieved with available JAK inhibitors, but may meaningfully reduce disease-related anemia symptoms that standard-of-care agents or danazol do not address, according to Andrew T. Kuykendall, MD. He added that the agent’s recent approval in this population requires re-evaluation of current approaches for managing these aspects of the disease.

On September 15, 2023, the FDA approved momelotinib for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary or secondary myelofibrosis, and disease-related anemia.1,2 Findings from the phase 3 MOMENTUM trial (NCT04173494), as well as data from a subpopulation of adult patients with anemia from the phase 3 SIMPLIFY-1 trial (NCT01969838), supported the regulatory decision.

Twenty-five percent of patients with symptomatic and anemic myelofibrosis who were previously exposed to a JAK inhibitor experienced at least a 50% reduction in tumor symptom score (TSS) with momelotinib vs 9% of patients treated with danazol, which translated to a treatment difference of 16% (95% CI, 6%-26%; P < .01). Additionally, 30% of patients in the momelotinib arm achieved transfusion independence (TI) vs 20% of those in the danazol arm, which translated to a noninferiority treatment difference of 14% (95% CI, 2%-25%; P = .023). Spleen volume reduction and a decrease in anemia-related symptoms were also observed with momelotinib.3

“[With momelotinib], we’re extending the benefits of JAK inhibition to more people and we’re potentially helping [to ameliorate] anemia, which has been an area of unmet need for a long time for patients with myelofibrosis,” said Kuykendall, who is an assistant member of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

In an interview with OncLive®, Kuykendall discussed the importance of this approval for treating patients with anemic symptomatic myelofibrosis in clinical practice, key efficacy and safety data from the MOMENTUM trial that supported the decision, and unanswered questions regarding the agent’s potential role in other subsets within this population.

OncLive: What is the significance of the recent FDA approval of momelotinib for patients with myelofibrosis and anemia?

Kuykendall: This decision represents our further advancement in the perpetual story of [managing patients with] myelofibrosis [over] the past decade. On one hand, [we’re] trying to bring JAK inhibition to as many patients with myelofibrosis as possible. Ruxolitinib [Jakafi] really changed the game in myelofibrosis by allowing patients to [experience] profound improvement of splenomegaly and disease-related symptoms; it is also associated with a modest survival benefit. However, we continue to run into issues with patients who have anemia, which is most patients with myelofibrosis. [These patients, as well as those] who have low platelets, can’t experience the full benefit of JAK inhibition. The accelerated approval of pacritinib [Vonjo] helped with some aspects of that.

Now, momelotinib [provides] a full dose of a potent JAK inhibitor for patients who are anemic and may even be able to help with that anemia, as well. On the flip side, it looks like it can help with patients [who have] low platelets, as well. [The MOMENTUM trial] enrolled [patients] [with a] platelet count [of more than 25 x 109 cells/L].

What is unique about the mechanism of action of momelotinib compared with other JAK inhibitors?

All of the main approved agents in myelofibrosis are JAK2 inhibitors. However, their kinase inhibition profiles serve as differentiating factors. Momelotinib is a bit different in the sense that, like ruxolitinib, it [targets] JAK1 and JAK2. Pacritinib, and to a lesser extent, fedratinib [Inrebic], are more selective for JAK2. [Momelotinib] also inhibits ACVR1, which we believe plays a key role in modulating hepcidin and improving anemia. This potentially distinguishes momelotinib from ruxolitinib.

Now, instead of worsening anemia, which we often see happen with ruxolitinib or fedratinib, we’re able to get those symptom and spleen benefits [that come with] JAK1/JAK2 inhibition, and at the very least, mitigate some of the anemia we saw with ruxolitinib. [Momelotinib could] potentially lead to an overall improvement in anemia and fewer transfusions for patients.

Could you expand on the design of the MOMENTUM trial, and the patient population enrolled?

The MOMENTUM trial was the third phase 3 trial of momelotinib. Ultimately, the trial enrolled patients who had previously been exposed to ruxolitinib, were anemic, had some degree of myelofibrosis-related symptoms, and had splenomegaly. Patients didn’t have to be [treated with] ruxolitinib for a long time. They could have been on it for just about a month, [during which] they had some anemia. Those patients were randomly assigned 2:1 to either momelotinib or danazol, which we know is a control. This means that we use the agent for patients who are anemic.

What key efficacy findings were reported?

The primary end point of the trial was symptom improvement and aimed for a 50% reduction in TSS. Overall, we expected to see improvement with momelotinib over danazol, [However], we know that symptoms can be related not just to inflammatory cytokines or to splenomegaly but can also occur due to anemia. We expected danazol to help with some of those [symptoms]. Some key secondary end points [included] some improvement in splenomegaly reduction compared with danazol. Although the results didn’t meet the criteria for superiority, TI rate [with momelotinib] was nominally better than the rate [observed with danazol]. More patients on the momelotinib arm were TI after 24 weeks vs [those in] the danazol arm with essentially an equal number [transfusion dependent between groups] at baseline.

Spleen response rates [with momelotinib] are similar to what you might expect to see with ruxolitinib or another JAK inhibitor. However, momelotinib has been directly compared with ruxolitinib in the SIMPLIFY-1 trial, where treatment-naive patients were randomly assigned to momelotinib or ruxolitinib. In that trial, momelotinib was noninferior to ruxolitinib in terms of spleen responses. Therefore, we know it is a potent JAK inhibitor in terms of inducing spleen responses. It was exciting to see results play out like that in this pivotal trial.

What should be known about the safety profile of momelotinib?

[The toxicities associated with momelotinib] are relatively benign. When we think about JAK inhibitors, we consider the safety profiles. In general, these are palliative medications that we’re using to make people feel better and improve quality of life and functionality. If our ultimate goal is for people to feel better, we need these agents to be well tolerated. When one of our key findings is symptoms improving, you can see that these are well-tolerated medications. In the short term, patients are reporting that they feel better than they did previously after going on these medications.

In terms of things to watch out for, there’s a mild increase in gastrointestinal [GI] toxicity vs what was seen with danazol. Still, these rates are relatively low for those experiencing nausea, which is also usually low grade. This is probably lower than what we have seen in other trials with pacritinib and fedratinib that inhibit FLT3, as anything that inhibits FLT3 is associated with some degree of GI toxicity.

In previous trials, there was some concern for peripheral neuropathy, which wasn’t really seen in the MOMENTUM study. There were relatively low rates of anemia and thrombocytopenia. In fact, this agent is likely to improve, or at least stabilize, anemia and was leveraged safely in patients with a quite low platelet count. Overall, there’s not too much to be concerned about [regarding] hematologic adverse effects. [Additionally,] momelotinib actually had fewer adverse effects on the kidneys than danazol did.

With this approval, where do you see momelotinib fitting into the treatment paradigm in myelofibrosis?

The clearest answer is [that it will be used for] patients who are quite anemic and have struggled to continue treatment with ruxolitinib at adequate doses without needing transfusions or developing symptomatic anemia. That’s the ideal population. Certainly, you could think about using it outside of those bounds, as well. Anyone with anemia and some degree of splenomegaly symptoms could be afforded momelotinib as an option, given the concern that ruxolitinib or fedratinib treatment might drop hemoglobin [levels], pushing people into transfusion dependency.

In that anemic population, there are outstanding questions: What about patients who don’t have symptomatic splenomegaly and don’t have a ton of disease-related symptoms, but are anemic? Is this now going to be our treatment of choice for this cytopenic population? Momelotinib was nominally better than danazol [at reducing transfusion dependence], so are we going to now choose this over danazol in a patient without too many splenic symptoms? That’s tough to say right now, but you could make an argument for momelotinib in that space.

In patients who are not anemic and are being treated with ruxolitinib but need to move to a second-line agent, is [momelotinib an option] that you’re going to leverage, knowing that anemia is part of the natural history of this disease over time and that it may be reasonable to start this type of an agent earlier rather than later? There are many different areas where this could be a beneficial agent, but [its potential role in] the anemic population is very clear.

What is your main message for colleagues regarding this approval?

Momelotinib is another tool in the toolbox. [It’s approval] is another reason to differentiate and understand when and why you would use different JAK inhibitors since we now have 4 [available]. You have to understand why and when to use one agent over the other, when you’re going to switch from one to the other, when you’re going to dose modify, and which agents are best [for each case]. This is a good time to think about those questions and have a clear plan in mind. It’s great to have different options for patients, but knowing when to use them is going to ensure that we’re using them in the right way.

References

  1. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed October 4, 2023. 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
  2. Momelotinib (Ojjaara) Prescribing information. GlaxoSmithKline; 2023. Accessed November 2, 2023. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Ojjaara/pdf/OJJAARA-PI-PIL.PDF
  3. Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0

Read more

Pelabresib Generates Excitement in Myelofibrosis

Posted on by

November 3,  2023

Jordyn Sava

Multiple studies are evaluating pelabresib (CPI-0610) for the treatment of patients with myeloproliferative neoplasms (MPNs). With more data on the agent expected to be released from trials in this space toward the end of the year, Joseph M. Scandura, MD, PhD, reflected on its potential role for patients with myelofibrosis and studies evaluating the agent.

Pelabresib is an oral, small-molecule, investigational BET inhibitor. The agent works by downregulating NF-κB and signals other relevant genes involved in myelofibrosis disease pathways.

In the ongoing, global, nonrandomized, multicohort, open-label, phase 2 MANIFEST study (NCT02158858), investigators are assessing pelabresib as a monotherapy and in combination with ruxolitinib (Jakafi) in patients with myelofibrosis.1

The study is evaluating the efficacy of the JAK inhibitor combination therapy vs pelabresib alone for treatment-naïve or pretreated patient populations, and involved 4 separate cohorts. Patients with JAK inhibitor-pretreated myelofibrosis were given pelabresib, patients with ruxolitinib-pretreated myelofibrosis were given pelabresib plus ruxolitinib, patients with JAK inhibitor naïve myelofibrosis were given pelabresib plus ruxolitinib, and patients with essential thrombocythemia were given pelabresib alone.

According to data from the trial presented at the 2023 EHA Congress, by the data cutoff of July 29, 2022, 7 of the 20 patients enrolled in the study were treated for at least 6 months. Fourteen patients continued to receive pelabresib. Findings showed that pelabresib plus ruxolitinib demonstrated durable improvements in spleen volume and total symptom score among those enrolled. The confirmed complete response rate was 40% and the partial hematologic response rate was 20%, respectively.

Another study evaluating pelabresib is the ongoing, randomized, double-blind, phase 3 MANIFEST-2 trial (NCT04603495).2 Here, patients with JAK inhibitor-naïve myelofibrosis are being randomized 1:1 and treated with upfront pelabresib plus ruxolitinib vs ruxolitinib alone.

Patient enrollment in this study was completed in May 2023. Topline findings are expected to be released in late 2023.

In an interview with Targeted OncologyTM, Scandura, Weill Cornell Medicine, discussed research on pelabresib for the treatment of patients with MPNs.

Targeted Oncology: Can you discuss pelabresib and its mechanism of action?

Scandura: Pelabresib is a first-in-class oral inhibitor of BET proteins, primarily those containing the BD1 and BD2 domains. It’s being developed currently in myelofibrosis. It has been tested in other diseases, but it has shown significant activity in myelofibrosis. I believe that it’s going forward in that area and represents the first of what is potentially multiple drugs hitting these same epigenetic pathways.

What sets it apart from other agents for patients with MPNs?

Well, it’s the first drug that hits the BET inhibitors. It’s among the first epigenetic modifiers, and these are pathways that affect how genes are packaged and expressed, turned on, and turned off. In all myeloid malignancies, in fact in all cancers, epigenetic abnormalities are much more common than genetic abnormalities and exactly how to target them has been a challenge. This particular pathway has been shown to be kind of hyperactivated in myelofibrosis. This inhibitor has shown some activity, both in terms of single-agent use and in combination with standard JAK inhibitor therapy.

Can you explain some of the recent research on pelabresib?

John Mascarenhas, MD, [presented] an update of the long-term follow-up of patients treated with the combination of ruxolitinib with pelabresib–ruxolitinib being a first-in-class and standard-of-care JAK inhibitor. What he’s showing are the remarkable early responses that have been observed and are being maintained through the most recent follow-up. Then, Claire Harrison, MD, FRCP, FRCP, [presented] data on another arm of the phase 2 study where in pelabresib was added to ruxolitinib in people who are not achieving an adequate response.

I have presented an update on the translational work related to pelabresib trying to understand what some of these markers are, and these changes were observed in the bone marrow. From that standpoint, I think that’s where the excitement was generated with pelabresib. It’s 1 of the first agents that has been able to reverse fibrosis in the marrow in a sizable percentage of patients. Of course, this disease is myelofibrosis, so the idea of reducing fibrosis is appealing.

The reality of it is we don’t know, besides that kind of intuitive appeal, what it means when patients respond and have reversion of fibrosis in terms of long-term outcomes or in terms of what that goes along with our patients feeling better. [Those are] some of the other measures of response correlating with the marrow response.

What are some key takeaways regarding pelabresib and its development?

The first one is that we need to wait for the data to mature. My personal bias is all of these biomarkers are invaluable until we know outcomes such as survival or time to treatment failure or event-free survival. Until we know that, we are just kind of stuck in this circular loop of what should be, what we hope will be, what our intuitive beliefs are, but we do not really know what any of these things mean until we have those outcomes. That just takes time.

The nice thing is there are a number of phase 3 studies, randomized trials, collaborative studies. MANIFEST-2 is a randomized phase 3 study, and that will allow us to address and follow up on some of these findings, and hopefully get to those answers about whether or not these changes that we’re observing in the short-term are predicting these long-term beneficial outcomes. It just takes time for that data to mature.

REFERENCES:
Passamonti F, Patriarca A, Knapper S, et al. Pelabresib (CPI-0610) monotherapy in patients with high-risk essential thrombocythemia refractory or intolerant to hydroxyurea: preliminary results from MANIFEST study. Presented at: 2023 EHA Congress; June 8-11,2023;Frankfurt,Germany. Abstract S168.
Harrison CN, Gupta VK, Gerds AT, et al. Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis. Future Oncol. 2022;18(27):2987-2997. doi:10.2217/fon-2022-0484

Read more

 

DISC-0974 by Disc Medicine for Myelofibrosis: Likelihood of Approval

Posted on by

October 28, 2023

DISC-0974 is under clinical development by Disc Medicine and currently in Phase II for Myelofibrosis. According to GlobalData, Phase II drugs for Myelofibrosis have a 40% phase transition success rate (PTSR) indication benchmark for progressing into Phase III. GlobalData’s report assesses how DISC-0974’s drug-specific PTSR and Likelihood of Approval (LoA) scores compare to the indication benchmarks.

Smarter leaders trust GlobalData

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

DISC-0974 overview

DISC-0974 is under development for the treatment of chronic inflammation and hematological disorders such as anemia of chronic disease, anemia in chronic kidney disease, Iron refractory iron deficiency anemia (IRIDA), myelofibrosis, chronic idiopathic myelofibrosis (primary myelofibrosis), post-essential thrombocythemia myelofibrosis (post-et mf), post-polycythemia vera myelofibrosis (ppv-mf) and myeloproliferative disorders. The drug candidate acts by targeting hemojuvelin. It is administered through intravenous and subcutaneous routes.

Disc Medicine overview

Disc Medicine, formerly Gemini Therapeutics Inc, is a clinical-stage biopharmaceutical company that specialises in the discovery, development and commercialization of novel treatments for patients with severe hematologic disorders. The company pipeline includes bitopertin for the treatment of erythropoietic porphyrias, including erythropoietic protoporphyria and X-linked protoporphyria and Diamond-Blackfan Anaemia, or DBA; DISC-0974 for the treatment of anaemia of myelofibrosis and anaemia of chronic kidney disease, or CKD; and MWTX-003 for the treatment of polycythemia vera, or PV, and other hematologic disorders. The company’s preclinical programmes consist of DISC-0998, which is used to treat anaemia brought on by inflammatory disorders. Disc Medicine is headquartered in Cambridge, Massachusetts, the US.

Read more

Newer-Generation JAK Inhibitors Expand Myelofibrosis Treatment Paradigm

Posted on by

October 19, 2023

Ashling Wahner

The growing array of JAK inhibitors available to patients with myelofibrosis underscores the need for personalized treatment decisions in this patient population, which may depend on baseline cytopenias, disease characteristics, and the availability of second-line options for patients who progress on first-line ruxolitinib (Jakafi), according to Anthony M. Hunter, MD.

The pivotal phase 3 PERSIST-2 trial (NCT02055781) showed that 29% patients who received pacritinib (Vonjo) achieved a spleen volume reduction of at least 35% compared with 3% of those who received best available therapy, which included ruxolitinib.1 Additionally, momelotinib (Ojjaara), which was approved by the FDA in September 2023 for adult patients with intermediate- or high-risk primary or secondary myelofibrosis and anemia, is the newest JAK inhibitor to be approved for patients in this population.2

“Instead of just giving everybody the same treatment no matter what, we have room to pick and choose who will be a better [candidate] for which drug,” Hunter said in an interview with OncLive® during the 2023 SOHO Annual Meeting.

In the interview, Hunter discussed the roles for pacritinib, momelotinib, and fedratinib (Inrebic) in patients with myelofibrosis; treatment sequencing with newer-generation JAK inhibitors after ruxolitinib; and the importance of having several treatment options in the second-line setting and beyond.

Hunter is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and medical director of the Immediate Care Center at Winship Cancer Institute of Emory University, both in Atlanta, Georgia.

OncLive: What was the goal of your presentation on choosing and properly using JAK inhibitors in myelofibrosis?

Hunter: The goal [of my presentation] was to discuss the historical and emerging data with JAK inhibitors. We’ve had JAK inhibitors around for approximately 12 years, from the first one, ruxolitinib, but now, [we are] starting to see an increase in that arsenal, and our fourth JAK inhibitor, [momelotinib, was] approved [in September 2023].The goal was to review the data with these different JAK inhibitors we have already available or emerging right now; discuss some of the unique differences between them and where they may fit into specific subgroups of patients; and [discuss] the practical standpoints of how to use these drugs in clinical practice.

Considering the number of JAK inhibitors that are available, what factors guide your treatment decisions?

[We consider several factors] right now. One of the biggest factors we see that distinguishes a couple of the different JAK inhibitors is patients who have low blood counts or cytopenias at baseline. Standard patients with more elevated counts, or at least not significant cytopenias, are still using ruxolitinib, and we have fedratinib as well.

However, cytopenic patients who historically have been a tough group to treat with our original JAK inhibitors, now have some emerging options. Pacritinib is for patients with lower platelet counts, platelet counts of less than 50 x 109/L, who have historically been excluded [from treatment with JAK inhibitors]. In addition, [data are] showing that [pacritinib] has the potential [to improve] anemia as well. Additionally, momelotinib, [which was approved by the FDA in September 2023, is] an active agent in the setting of these anemic patients, with the potential to improve outcomes.

One of the biggest factors for choosing between these options is the presence of baseline cytopenias. All [these agents] show good activity in the settings of spleen responses and symptom reductions. [We don’t have a lot of] clear data about which subgroups of patients, aside from cytopenic patients in the front line, we should switch between [JAK inhibitors]. Otherwise, the rest of these [agents] are certainly options still. Then, certainly in the second-line setting, we have data with pacritinib, momelotinib, and fedratinib all having some activity after progression on ruxolitinib.

How might the use of pacritinib expand to benefit patients with higher platelet counts?

The National Comprehensive Cancer Network Guidelines for Myeloproliferative Neoplasms have been updated and have included pacritinib as an option for patients with a platelet count of over 50 x 109/L. In more anemic patients, we see anemia responses with pacritinib, so it has a role in that population. A sometimes tougher group is patients with a platelet count between 50 x 109/L and 100 x 109/L, who are able to use drugs like ruxolitinib or fedratinib.

When we start to see thrombocytopenia develop on treatment, [these agents may] start to hit those low platelet levels as well. It’s hard to maintain continuous and effective dosing with some of these patients. Even in patients with more modest levels of thrombocytopenia, there may be some role for pacritinib.

How are JAK inhibitors currently sequenced after ruxolitinib in the first-line setting?

We have seen with ruxolitinib, in multiple real-world cohorts and clinical trials, that outcomes once patients have progressed on ruxolitinib, whether that be [because of] intolerance or resistance to treatment, are quite poor, with survival in the 12- to 16-month range in most studies. Historically, there have not been great data about how to treat these patients. Studies suggest that novel agents, which have included second-line JAK inhibitors, have shown more promise than conventional agents like hydroxycarbamide. The [phase 3] MOMENTUM [NCT04173494] and SIMPLIFY 2 [NCT02101268] studies with momelotinib, PERSIST-2 and other studies with pacritinib, and the [phase 2] JAKARTA-2 study [NCT01523171] with fedratinib are all clinical trials that investigated these agents in patients who had previously been exposed, or at least included patients who had been exposed, to prior ruxolitinib.

We see activity with all those different agents. More advanced patients potentially get more cytopenias and anemias. Some of these newer agents that are a bit more designed for that patient population may have a bigger role there, but certainly fedratinib has also [been associated with] great data in the second-line setting in this population.

What is your main message for colleagues regarding the use of JAK inhibitors in myelofibrosis?

We have options now. For a long time, we only had 1 agent, for the most part. We’ve now had a couple more approved in the past few years, so we’re starting to get to a point now where we can pick and choose a little. We can match [treatments] to clinical features, like cytopenias, potentially, as well as comorbidities and other disease- or non-disease–related aspects that will give us more leeway to treat patients more effectively in a more personalized approach. Also, [there is the] potential to sequence these options, so we have more effective options for patients who progress on first-line treatment.

References

  1. CTI BioPharma announces FDA accelerated approval of VONJO (pacritinib) for the treatment of adult patients with myelofibrosis and thrombocytopenia. CTI BioPharma Corp. News release. February 28, 2022. Accessed October 2, 2023. https://www.prnewswire.com/news-releases/cti-biopharma-announces-fda-accelerated-approval-of-vonjo-pacritinib-for-the-treatment-of-adult-patients-with-myelofibrosis-and-thrombocytopenia-301492159.html
  2. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed October 2, 2023. 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

Read more

FDA Grants Approval to GSKs Ojjaara A GameChanger in Myelofibrosis Treatment

Posted on by
by Yasmim Mendonça
 September 18, 2023

As of September 18, 2023, the United States Food and Drug Administration (FDA) has granted approval to GSK’s groundbreaking medication, Ojjaara (momelotinib), for the treatment of intermediate or high-risk myelofibrosis in adults suffering from anemia. This approval encompasses both primary myelofibrosis and secondary myelofibrosis, including post-polycythemia vera and post-essential thrombocythemia cases. Ojjaara is the sole authorized treatment that effectively addresses the primary symptoms of myelofibrosis, such as anemia, constitutional symptoms, and splenomegaly, making it a game-changer in the field of medicine.

Myelofibrosis, a form of blood cancer, affects a significant number of individuals in the United States, with an estimated 25,000 patients grappling with this condition. The approval of Ojjaara marks a monumental milestone for GSK, as it introduces a formidable rival to the widely-used Incyte drug, Jakafi. With this groundbreaking development, patients diagnosed with myelofibrosis now have an additional treatment option that holds immense promise in effectively managing their condition and improving their quality of life.

Read more

Momelotinib Receives FDA Approval for Myelofibrosis With Anemia

Posted on by

Ariana Pelosci

The News

The FDA has approved momelotinib (Ojjaara) for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary and secondary myelofibrosis, who are experiencing anemia, according to a press release from GSK.1

The approval was based on results from the phase 3 MOMENTUM trial (NCT04173494), which was previously presented at the 2022 American Society of Clinical Oncology Annual Meeting, with other supporting data coming from a subpopulation of the phase 3 SIMPLIFY-1 trial (NCT01969838). 2,3

Momelotinib, a once daily oral JAK1/2 inhibitor, is the only approved treatment for this indication.

Expert Perspective

“I think [momelotinib] will make an immediate impact. There clearly are individuals now who are on JAK inhibitors like ruxolitinib [Jakafi] or fedratinib [Inbrec] who have significant anemia who will immediately be potential candidates,” Ruben A. Mesa, MD, said in an interview with CancerNetwork® prior to the approval. “We’ll see how the [National Comprehensive Cancer Network] guidelines form but there’s a case to be made for consideration [for momelotinib] as the initial JAK inhibitor selected for people who have significant anemia.”

Mesa is the president of the Enterprise Cancer Service Line and senior vice president at Atrium Health; executive director of the National Cancer Institute-designated Atrium Health Wake Forest Baptist Comprehensive Cancer Center; and vice dean for Cancer Programs at Wake Forest University School of Medicine

The MOMENTUM Trial

The MOMENTUM trial included 195 patients who were randomly assigned 2:1 to receive either momelotinib (n = 130) at 200 mg per day plus placebo or danazol (n = 65) at 600 mg per day plus placebo. At week 24 patients in the danazol arm were allowed to crossover to the momelotinib arm. The primary end point was total symptom score at week 24, and the secondary end points included transfusion independence and splenic response rate.

In the momelotinib arm, 27.7% of patients discontinued treatment for several reasons including adverse effects (AEs; n = 16), patient decision (n = 6), or death (n = 4). In the danazol arm, 41.5% of patients discontinued treatments because of AEs (n = 11), patient decision (n = 5), or death (n = 3). Additionally, 4 patients crossed over to the momelotinib arm early.

The median age in the momelotinib arm was 71.0 years vs 72.0 years in the danazol arm, 60.8% vs 67.7% were male, and 82.3% vs 76.9% were White, respectively. In terms of myelofibrosis subtype, 60.0% of those in the momelotinib arm had a primary subtype vs 70.8% in the danazol arm, 20.8% vs 16.9% had post-polycythemia vera, and 19.2% vs 12.3% had post-essential thrombocytopenia.

At week 24, the total symptom score response rate was 24.6% (95% CI, 17.49%-32.94%)in the momelotinib arm vs 9.2% (95% CI, 3.46%-19.02%) in the danazol arm (P = .0095). Moreover, 40.0% (95% CI, 31.51%-48.95%) of patients in the momelotinib arm had a 25% reduction in splenic volume vs 6.2% (95% CI, 1.70%-15.01%; P <.0001) in the danazol arm. Additionally, 35% reduction in spleen volume was observed in 23.1% (95% CI, 16.14%-31.28%) in the momelotinib arm and 3.1% (95% CI, 0.37%-10.68%; P = .0006) in the danazol arm.

At baseline, the transfusion independence rate at baseline was 13% in the momelotinib arm vs 15% in the danazol arm. Comparatively, the rate week 24 was 31% in the momelotinib arm vs 20% in the danazol arm (P = .0064).

SIMPLIFY-1 Trial

In this randomized, multicenter study, momelotinib was investigated vs ruxolitinib (Rituxan) in patients who had not received prior treatment with a JAK inhibitor. A total of 432 patients were analyzed with patients received 200 mg orally daily of momelotinib or 20 mg of ruxolitinib once per day.

A 50% of more reduction in the total symptom score was observed in 28.4% of patients receiving momelotinib vs 42.2% receiving ruxolitinib (P = .98). Momelotinib improved the transfusion rate, transfusion independence, and transfusion dependence (P ≤ .19).

Safety

In terms of safety findings from the MOMENTUM trial, the most common grade 3 or higher nonhematologic AEs included acute kidney injury (3.1% vs 9.2%), nausea (2.3% vs 3.1%), and dyspnea (2.3% vs 1.5%) in the momelotinib and danazol arms, respectively. Hematologic AEs of grade 3 or higher included anemia (60.8% vs 75.4%), thrombocytopenia (27.7% vs 26.2%), and neutropenia (12.3% vs 9.2%) in the momelotinib and danazol arms, respectively.

Grade 3 or higher AEs occurred in 53.8% vs 64.6%, and serious AEs occurred in 34.6% vs 40.0% of patients in the momelotinib and danazol arms, respectively. Investigators reported a hazard ratio (HR) of 0.734 (95% CI, 0.382-1.409; P = .3510) for overall survival overall and 0.506 up to week 24 (95% CI, 0.238-1.076; P = .0719).

Safety data from the SIMLIFY-1 trial indicated that AEs occurred in 7% of patients who received momelotinib vs 3% who received ruxolitinib. In 10% of patients, treatment-related neuropathy occurred with momelotinib treatment vs 5% with ruxolitinib.

References

  1. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia, News release. GSK. September 15, 2023. September 15, 2023.
  2. Mesa RA, Gerds AT, Vannucchi A, et al. MPN-478 MOMENTUM: phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. J Clin Oncol. 2022;40(suppl 16):7002. doi:10.1200/JCO.2022.40.16_suppl.7002
  3. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor–naïve patients with myelofibrosis. J Clin Oncol. 2017;34(suppl 34):3844-3850. doi:10.1200/JCO.2017.73.4418

Read more

Ezobresib by Bristol-Myers Squibb for Myelofibrosis: Likelihood of Approval

Posted on by

September 14, 2023

Ezobresib is under clinical development by Bristol-Myers Squibb and currently in Phase II for Myelofibrosis. According to GlobalData, Phase II drugs for Myelofibrosis have a 40% phase transition success rate (PTSR) indication benchmark for progressing into Phase III. GlobalData’s report assesses how Ezobresib’s drug-specific PTSR and Likelihood of Approval (LoA) scores compare to the indication benchmarks. 

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

Ezobresib overview

Ezobresib (BMS-986158) is under development for the treatment of solid tumors including triple-negative breast cancer, small-cell lung cancer, epithelial ovarian cancer, peritoneal cancer, renal cell carcinoma, fallopian tube cancer, Burkitt’s lymphoma/leukemia, Uveal melanoma, Uterine carcinosarcoma, NUT-midline carcinoma, Non-small cell lung cancer, metastatic hormone refractory (castration resistant, androgen-Independent) prostate cancer, blood cancer (hematologic malignancies), primary myelofibrosis (PMF), post-essential thrombocythemia (ET) or post-polycythemia vera (PV) myelofibrosis. It is administered orally as a capsule. The drug candidate acts by targeting bromodomain and extra-terminal (BET) proteins. It was under development for Ewing sarcoma.

Bristol-Myers Squibb overview

Bristol-Myers Squibb (BMS) is a specialty biopharmaceutical company that is engaged in discovery, development, licensing and manufacturing, marketing, distribution and sale of medicines and related medical products to patients with serious diseases. Its primary focus is on cancer, cardiovascular, immunology and fibrotic therapeutic projects. The company offers its products across the world to wholesalers, retail pharmacies, medical professionals, hospitals and government entities. BMS provides its products in the US, Europe, and Japan. The company conducts research to focus on the discovery and development of novel medicines that address serious diseases in areas of significant unmet medical need. BMS is headquartered in New York City, New York, the US.

Read more

Research Nurse Breaks Down Myelofibrosis-Related Anemia

Posted on by

Brielle Benyon

Anemia is a common and potentially dangerous condition that can occur in patients with myelofibrosis, a type of myeloproliferative neoplasm. While anemia is a blanket term that describes low hemoglobin levels, myelofibrosis-related anemia behaves quite differently than anemia in patients with a blood cancer diagnosis, explained Sharon Bledsoe.

Bledsoe, a senior research nurse at The University of Texas MD Anderson Cancer Center in Houston, recently explained myelofibrosis-related anemia, including its cause and treatment.

CURE®: What causes anemia in patients with myelofibrosis?

Myelofibrosis is basically a disease in which the bone marrow gets replaced by connective tissue in a process called fibrosis. The bone marrow’s main objective is to produce blood cells, and in producing the blood cells — the red blood cells, the white blood cells and the platelets. When the fibrosis interferes with the production of the cells, scar tissue starts to form in the bone marrow, and the bone marrow is the soft spongy tissue in the center of the bones.

As the scar tissue starts to grow, the bone marrow loses its ability to make enough healthy blood cells. So, it produces too many abnormal blood cells. The lifespan of a true red blood cell or of a normal human red blood cell is 120 days, which is about roughly four months. When you have a patient dealing with myelofibrosis, with the scarring and all of that, they’re producing the red blood cells, but they’re not maturing; when they’re not mature, they die off faster. So, they’re producing a whole lot a whole lot, but they’re dying fast. Then you have the anemia that starts because they’re not living for enough time, so they’re not getting four months of life; within days, weeks, they’re dying off.

How is myelofibrosis-associated anemia treated?

When patients’ (hemoglobin levels) start to get low, we start to monitor their trends. We monitor their hemoglobin; we start to monitor in to see if they’re if they are going to need a transfusion. And if they need transfusions, how often are they needing the transfusions? So we’re going to monitor all of that, whether they need the transfusions and how often they need the transfusions.

That’s one way that it’s treated.

And then doctors may put them on drugs that will help the anemia, drugs like danazol and Jakafi (ruxolitinib). When those red blood cells are being produced so quickly, there’s not enough room within the bone marrow, so (they) go into the spleen, or into the liver, which is now causing them to have enlarged spleens and enlarged liver. And sometimes, because it can’t be treated, the spleen has to be removed.

(Jakafi) can take the spleen size down. However, with (Jakafi), you fall into the area where they can get skin cancers, secondary skin cancers, squamous cell carcinoma, basal cell carcinoma and things like that; you have to really, really watch for that. In treating the anemia, you have to watch for so many other things that may crop up.

What is the difference between myelofibrosis-related anemia and general anemia that is experienced in patients without an MPN?

There is a major difference, because anemia that a person would have that doesn’t have cancer presents differently than the anemia (related to MPNs). For a person who has a blood cancer, their anemia is going to come with other things (such as) possibly filling up faster (when eating), night sweats (and) extreme fatigue. And some of them have (feelings of) wanting to faint because the hemoglobin is so low.

In a person that has just routine anemia, they won’t have those types of symptoms, they’ll just probably feel a little tired or a little sluggish.

What advice do you have for patients with myelofibrosis who may be experiencing anemia?

We tell the patients to let us know if you have increased fatigue, let us know if any of your symptoms change, you have increased fatigue, you have increased night sweats, you start having fevers or things like that, let us know if any of those things are taking place. That way, I can give that information to the to the oncologist and then they know what to do for the patient.

Make sure that you are proactive as a patient, if there’s something that’s wrong, and you know that it hasn’t been an issue before, make sure that you follow up and follow through, don’t just accept (symptoms). If you have to go to 5 doctors, go to as many as it takes to get the diagnosis, because with time, time loss is not time that can be regained. So, you need to be proactive and monitor your care and know what your norms are and what’s not normal for you.

Read more

Current Approaches to Diagnose and Treat Primary Myelofibrosis

Posted on by

Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Rami Komrokji, MD, discussed elements to diagnosing myelofibrosis and how to approach risk stratification before treatment.

KOMROKJI: MF could be either primary de novo or coming from secondary from essential thrombocythemia [ET] or polycythemia vera [PT]. [Concerning] the major criteria listed [by the World Health Organization (WHO)], I always bring up the 2 points that not every fibrosis in the bone marrow is myelofibrosis.1 You can see it in lymphomas, hairy cell leukemia, connective tissue disease, etc, and you don’t need fibrosis in the early stages of myelofibrosis to make the diagnosis. The classical megakaryocytic atypia is enough and in the prefibrotic MF, that’s enough to diagnose the disease.

Prefibrotic MF is a relatively new entity that we talk about. Many patients in practice are labeled as ET, and sometimes it’s hard to tease those [differences] out. But those are the patients who we would think have ET, and in 3 to 4 years, they have overt MF. Usually, it will it take a decade to get there, but if a patient had ET and then in 3 or 4 years was in [overt] MF, those probably were patients with prefibrotic MF. There are few clues…most of the time, those patients will have high LDH [lactate dehydrogenase], on the bone marrow there will be more hypercellular granulocytic hyperplasia. There is more clustering of the megakaryocytes.

Currently, we manage them almost the same, but those are the patients who will transform earlier, at higher risk of leukemia. Maybe in the future, those are the patients we will target with some more interventions to try to prevent the overt MF.

The presence of a clonal marker excludes other diseases. [However], myelodysplastic syndrome [MDS] with fibrosis is sometimes hard to distinguish. Fibrosis can be seen in MDS; it’s typically associated with bad outcomes and the new WHO classification with the blast increase has MDS with fibrosis [as a] category on its own. In the clinical phenotype, they typically don’t have the hepatosplenomegaly as much as constitutional symptoms. They’re cytopenic, more like MDS. If a good pathologist sees myeloid or erythroid dysplasia, that will favor MDS with fibrosis. The megakaryocytes are tricky because you always see megakaryocytic atypia in MPNs [myeloproliferative neoplasms], and it depends on how experienced the hematopathologist is. If they are mistakenly calling them dysplasia, that could be deceiving. There are some minor criteria: the anemia, leukocytosis, splenomegaly, LDH, and leukoerythroblastosis.

What is the role of risk stratification when treating patients with MF?

Once we establish the diagnosis, we want to risk stratify the patients and there are many models in MF, 3 or 4 clinical and 2 molecular. I like the MIPSS70 [MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis] most because it’s comprehensive and it was designed to look at the question of transplant or not in younger patients not counting the age as a factor.2 Anemia, transfusion dependency, thrombocytopenia, and leukocytosis… [lead to poor prognosis]. Circulating blasts, unfavorable karyotype, [etc], all of those are weighed in these models. Molecular models…account for bad mutations like ASXL1, SRFS2, or absence of calreticulin. But at the end, we are putting the patients into a spectrum of a low-risk disease, where the survival spans many years, to a high-risk disease where the survival is less than 2 years.

Why is it important to use prognostic models for MF?

The disease risk value in practice is deciding on transplant. If somebody is not eligible for stem cell transplant [SCT], you may argue that those models are not that important. Somebody who’s very low risk will rarely be symptomatic, because if they have any symptoms, they probably move up to intermediate-1 risk.

If somebody’s survival estimate is 2 to 3 years, or an intermediate-2 or higher risk by any of those models, we think of the SCT earlier on in the course of the disease [to consider if they are] eligible for transplant by functional status and comorbidities, not necessarily by age. The second thing is [having] enough disease risk to justify the SCT. In patients who have higher risk, the timing of the transplant is probably early on. In patients with lower risk, even if they are eligible for SCT, the optimal timing is probably to try to delay the SCT. It’s always a hard decision because you don’t want to go too early [because of] upfront transplant-related mortality. But you also never want to go into an MPN accelerated phase or acute myelocytic leukemia from MPN because those diseases have terrible outcomes.

What recommendations are there for treatment of higher-risk myelofibrosis?

Once we label the patients intermediate or higher risk, we are assessing the symptoms and deciding on treatment. We rarely see patients who just [have] transfusion-dependent anemia. Those patients are probably not the classical candidates for JAK2 inhibitors, at least the classical ruxolitinib [Jakafi] or fedratinib [Inrebic].

[For] most patients…you’re treating either constitutional symptoms or splenomegaly. For those patients, JAK2 inhibitors are reasonable. The National Comprehensive Cancer Network guidelines split that choice of JAK2 inhibitor based on the platelet count.3 If it’s below 50 × 109/L, pacritinib [Vonjo] is the choice; if it’s above 50 × 109/L, [the choice is] ruxolitinib or fedratinib. Most [physicians] are more used to ruxolitinib, [it has] more data…but fedratinib is a reasonable option as well. Sometimes I think even a platelet cutoff of 100 × 109/L would be reasonable to consider pacritinib; the platelet cutoff of 50 × 109/L was for the truly unmet need and accelerated approval of pacritinib.

If patients are candidates for SCT, many times we do start the JAK2 inhibitors before the SCT because the SCT will still take 3 to 4 months to happen. If patients have a big spleen [and] poor performance from the disease, shrinking the spleen and getting them ready for SCT is reasonable.

The 3 available JAK2 inhibitors, ruxolitnib, fedratinib, and pacritinib…have different targets. Ruxolitinib targets JAK1/JAK2, [and has] potent JAK1 [activity]. Pacritinib has different targets; it doesn’t have any JAK1 activity. It has some ACVR1 [activity] so some anemia response can be explained through that [and] other inflammatory pathways like IRAK1. Fedratinib also has some FLT3 activity and some JAK1 activity. Momelotinib has JAK1 and ACVR1 activity.

The choices are based on the cytopenia profile. Fedratinib most of the time is positioned as second line after ruxolitinib in patients that are still proliferative. Ruxolitinib is the first line in patients that are proliferative, not cytopenic. Pacritinib is for thrombocytopenia and when we have approval for momelotinib, hopefully that will be for the anemia phenotype.

References:

1. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8(2):15. doi:10.1038/s41408-018-0054-y

2. Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis. J Clin Oncol. 2018;36(4):310-318. doi:10.1200/JCO.2017.76.4886

3. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 2.2023. Accessed September 7, 2023. https://tinyurl.com/yw9ka77m

Read more