Category Archives: Myelofibrosis

Hobbs Examines Frontline JAK Inhibition for Intermediate-Risk Myelofibrosis

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Targeted Oncology Staff

CASE SUMMARY

  • A 68-year-old woman presented to her physician with symptoms of mild fatigue, moderate night sweats, and abdominal pain/fullness lasting 4 months; she also reported increased bruising and an unexplained 12-lb weight loss.
  • Her spleen was palpable 8 cm below the left costal margin.
  • Karyotype: 46XX
  • Bone marrow biopsy results: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
  • Genetic testing results: JAK2 V617F mutation; CALR negative
  • A blood smear revealed leukoerythroblastosis.
  • Laboratory values:
    • Red blood cell count: 3.40 × 1012/L
    • Hemoglobin level: 13.2 g/dL
    • Hematocrit: 36%
    • Mean corpuscular volume: 94 fL
    • White blood cell count: 23.0 × 109/L
    • Platelet count: 450 × 109/L
    • Peripheral blood blasts: 1%
  • Diagnosis: primary myelofibrosis
  • Risk:
    • International Prognostic Scoring System: intermediate-2
    • Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis in adults 70 and younger: intermediate

TARGETED ONCOLOGY: How do the 3 Janus kinase ( JAK) inhibitors that are approved in this setting compare with each other?

HOBBS: Ruxolitinib [Jakafi] was the first JAK inhibitor [to be approved].1 I think they got lucky that it got approved way before fedratinib [Inrebic]2 and pacritinib [Vonjo],3 even though I think it’s worth noting [that] fedratinib and pacritinib… started their process of clinical trials a long time ago. Unfortunately, they ended up getting held up during their trials.

The indications of these 3 drugs are fairly similar: intermediate- or high-risk myelofibrosis (for pacritinib, specifically for patients with platelet counts of less than 50 × 109/L).4-6 For ruxolitinib, the [starting dose] is based on platelet count, not on hemoglobin level.4

In practice, probably a lot of physicians don’t adhere strictly to the platelet criteria, and in a patient who is a little frail or cytopenic or who has anemia, you could maybe start at a lower dose and then escalate, depending on how they tolerate the treatment. Fedratinib is given as a [once-daily] dose of 400 mg, and it was studied in patients with a platelet count of at least 50 × 109/L.5 The dose of pacritinib is 200 mg twice daily.6 So ruxolitinib is the only one where you really [adjust] the dose a lot.

CASE UPDATE

The patient is not interested in transplant; a decision was made to initiate ruxolitinib.

What clinical trial data supported the use of ruxolitinib?

It’s amazing that these data are 11 years old. The studies were published in The New England Journal of Medicine. These data came from phase 3 randomized studies that compared ruxolitinib with placebo in COMFORT-I [NCT00952289] and ruxolitinib with best available therapy in COMFORT-II [NCT00934544].

The COMFORT-I and COMFORT-II studies demonstrated very similar things, [with ruxolitinib leading] to a significantly improved decrease in spleen volume [the percentage of patients with at least a 35% reduction; reductions of 41.9% and 28% were seen in the experimental arms of COMFORT-I and COMFORT-II, respectively]. Most patients on ruxolitinib had some improvement in splenomegaly, even if they didn’t meet the arbitrary 35% spleen volume reduction [cutoff].7,8

Similarly, patients on ruxolitinib compared with both placebo and best available therapy had a significant improvement in symptoms.7,8 In my experience, for patients who have lots of symptoms like itching and so on, there’s really nothing that can make those symptoms go away [as well as] the JAK inhibitors do.

The COMFORT studies used the Myeloproliferative Neoplasm Symptom Assessment Form plus other measures. These studies demonstrated that there was an improvement in symptoms like fatigue and appetite issues, and there was also overall improvement in global health status and functional status.7,8

The long-term data from the COMFORT studies have shown a survival benefit in the patients who were treated with ruxolitinib [median overall survival (pooled data from both studies), 5.3 years vs 3.8 years for the experimental and control arms, respectively].7,9

I think it’s interesting to think about why that was. Was it because of less transformation to leukemia, or was it because of an improved functional status and the ability to eat, drink, and be more functional and have a decreased inflammatory state? I think that is still unclear.

What was the relationship between spleen response and survival among patients treated with ruxolitinib?

Even though we don’t know the mechanism that’s driving the survival benefit, we do know that spleen response did correlate with outcomes [in a multicenter study of ruxolitinib]. Patients who had a spleen response seemed to do better than those who didn’t.10 And I think that’s intuitive. Patients who have more resistant disease obviously aren’t going to do as well.

What was the relationship between ruxolitinib dose and response (spleen volume or total symptom score) in the COMFORT-I trial?

An important point is that if you give a low dose of a JAK inhibitor, it’s not going to be that effective. That was definitely true for the spleen. Ruxolitinib was more effective at higher doses for spleen volume reduction. Interestingly, for symptom improvement, some patients had a good response with respect to some of their symptoms with a lower dose, but to get the maximal spleen response, you needed a higher dose. The responses didn’t always track exactly together.11

How was ruxolitinib tolerated in these studies?

It was, in general, well tolerated. But not surprisingly, ruxolitinib was associated with higher rates of anemia, thrombocytopenia, and neutropenia compared with placebo [and best available therapy].7,8

What data inform the use of ruxolitinib in patients with a platelet count in the range of 50 × 109/L to 100 × 109/L?

We know how to use ruxolitinib, [but] we use it on-label, [so when a patient’s platelet count is] below 100 × 109/L, we [don’t know] what to do. Do we give 5 mg? We know that a lower dose of ruxolitinib is not that effective. There was a study called EXPAND [NCT01317875], a phase 1b dose-finding study that evaluated different starting doses of ruxolitinib in patients with low platelet counts.

The patients were divided into a group of patients with platelet counts of 75 × 109/L to 99 × 109/L and another group of patients with platelet counts of 50 × 109/L to 74 × 109/L. They demonstrated that 10 mg twice daily was the maximal safe dose for both groups and showed that patients were able to stay on that dose.12,13

Similar to the COMFORT studies, the results of the EXPAND study showed that even if patients had low platelets, if they were treated with a slightly higher dose of ruxolitinib, they ended up having a pretty good response in terms of symptoms as well as in terms of spleen volume [Table].12,13 These data highlight that it’s probably safe to give ruxolitinib at lower platelet counts and also demonstrate that the higher dose, more than 5 mg, is associated with a greater improvement in spleen [volume reduction] in particular.

What data inform the use of ruxolitinib in patients with anemia of grade 3 or 4?

[Nearly half of the] patients on the COMFORT-I study had anemia at baseline.7,8 Importantly, efficacy was maintained despite anemia, and although some patients had to adjust their dose or receive a transfusion, [less than 1% of patients] had to discontinue ruxolitinib because of anemia.7 I would imagine that in the real world that would probably be different.

Some ruxolitinib studies have shown that if a patient develops anemia while on ruxolitinib, it’s not as bad as if they have anemia de novo, especially if that happens early in treatment.14 Of course, if a patient has been on ruxolitinib for a year or 2 and all of a sudden [develops] anemia, that’s different and probably related to disease progression.

It’s important to note that if you put a patient on ruxolitinib, they [can] become a little bit anemic. Some of them will [be anemic] the first month and then find their new baseline, which isn’t always exactly where they were before but is a little higher than the nadir. But that decrease at the beginning of treatment is not as concerning as that anemia that we see in patients who present up front with anemia.

How does a patient’s baseline hemoglobin level influence your decision of whether to give ruxolitinib?

I feel comfortable giving the drug. I would probably not give the on-label dose on the basis of their platelet count because especially those patients who are in the 7 [g/dL hemoglobin] range, I’m going to make them transfusion dependent.

But it’s something that warrants a conversation. It depends on how symptomatic that patient is. If a patient has horrible night sweats and is bothered by their spleen, they may not be as bothered by their anemia. But I do struggle with that, so if the patient is not that symptomatic, maybe I won’t push that JAK inhibitor as much or the dose as much.

It depends on the situation. Many times, I’ll do the JAK inhibitor alongside an erythropoiesis-stimulating agent [ESA] or something like that. I don’t love the recommendation to just give the [on-label] dose and give transfusions. I would prefer not to have to give transfusions.

Q:If the erythropoietin level is less than 500 mU/mL, do you give ruxolitinib? Do you add other agents?

I’ll try danazol or an ESA. Personally, I haven’t had that much success with ESAs in myelofibrosis. I’ve used luspatercept-aamt [Reblozyl] off-label, both with ruxolitinib and by itself, but…some of the insurances require that I try the ESA first.

Q:Would you consider using lenalidomide (Revlimid)?

I rarely end up using it. It is a little better tolerated than thalidomide [Thalomid]. It’s definitely an option, especially for those patients with thrombocytopenia [because] you don’t have much else to do. But I don’t find [these drugs] to be the most well tolerated. But that is definitely a recommendation. You can use [lenalidomide] to try to help with anemia.

REFERENCES

1. Deisseroth A, Kaminskas E, Grillo J, et al. U.S. 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

2. FDA approves fedratinib for myelofibrosis. FDA. Updated August 16, 2019. Accessed May 16, 2023. https://tinyurl.com/5ej7s4tx

3. FDA approves drug for adults with rare form of bone marrow disorder. News release. FDA. March 1, 2022. Accessed May 16, 2023. https://tinyurl.com/4jcus8km

4. Jakafi. Prescribing information. Incyte Corporation; 2023. Accessed May 16, 2023. https://tinyurl.com/ua3rzhwr

5. Inrebic. Prescribing information. Bristol Myers Squibb; 2023. Accessed May 16, 2023. https://tinyurl.com/ms6emc6k

6. Vonjo. Prescribing information. CTI BioPharma Corp; 2022. Accessed May 16, 2023. https://tinyurl.com/5bpdwhku

7. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557

8. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. doi:10.1056/NEJMoa1110556

9. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. doi:10.1186/s13045-017-0527-7

10. Palandri F, Palumbo GA, Bonifacio M, et al. Durability of spleen response affects the outcome of ruxolitinib-treated patients with myelofibrosis: results from a multicentre study on 284 patients. Leuk Res. 2018;74:86-88. doi:10.1016/j.leukres.2018.10.001

11. Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther. 2013;7:13-21. doi:10.2147/OTT.S53348

12. Vannucchi AM, Te Boekhorst PAW, Harrison CN, et al. EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis. Haematologica. 2019;104(5):947-954. doi:10.3324/haematol.2018.204602

13. Gugleilmelli P, Kiladijan JJ, Vannucchi A, et al. The final analysis of Expand: a phase 1b, open-label, dose-finding study of ruxolitinib (RUX) in patients (pts) with myelofibrosis (MF) and low platelet (PLT) count (50 × 109/L to < 100 × 109/L) at baseline. Poster presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Accessed May 16, 2023. https://tinyurl.com/bdzymsst

14. Gupta V, Harrison C, Hexner EO, et al. The impact of anemia on overall survival in patients with myelofibrosis treated with ruxolitinib in the COMFORT studies. Haematologica. 2016;101(12):e482-e484. doi:10.3324/haematol.2016.151449

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Dr Halpern on the MANIFEST Trial of Pelabresib and Ruxolitinib in Myelofibrosis

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Anna B. Halpern, MD

Anna B. Halpern, MD, physician, assistant professor, Clinical Research Division, Fred Hutch, assistant professor, hematology, University of Washington School of Medicine, discusses key efficacy data from the phase 1/2 MANIFEST trial (NCT02158858) investigating the BET inhibitor pelabresib (CPI-0610) plus ruxolitinib (Jakafi), and highlights the agents clinical significance in patients with myelofibrosis.

The global, open-label, nonrandomized, multicohort study evaluated the efficacy of the JAK inhibitor combination therapy vs pelabresib alone for treatment-naive or pretreated patient populations, Halpern begins. The trial involved 4 separate cohorts. These cohorts included the use of pelabresib in patients with JAK inhibitorpretreated myelofibrosis, pelabresib plus ruxolitinib in patients with ruxolitinib-pretreated myelofibrosis, pelabresib plus ruxolitinib in patients with JAK inhibitor–naïve myelofibrosis, and pelabresib alone in patients with essential thrombocythemia.

Halpern reports that results from the JAK inhibitor–naïve cohort showed that pelebresib plus ruxolitinib reduced spleen volume by at least 35% in 68% of patients, emphasizeing that total symptom score decreased by at least 50% in 56% of patients at 24 weeks. The data cutoff date for these findings was July 29, 2022.

Moreover, exploratory analysis revealed that 28% of patients had a grade 1 or greater improvement in fibrosis, while 29.5% experienced a greater than 25% reduction in JAK2 V617F VAF by week 24, Halpern details. These outcomes are of particular interest because they may indicate the disease-modifying ability of this combination, Halpern explains.

Based on these findings, the ongoing randomized, double-blind, phase 3 MANIFEST-2 trial (NCT04603495) is evaluating upfront pelabresib plus ruxolitinib vs ruxolitinib alone in a larger cohort of patients with JAK inhibitor–naïve myelofibrosis, Halpern concludes. Enrollment to this study was completed in May 2023, and topline findings are anticipated to report out in late 2023.

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FDA Grants Fast Track Designation to Myelofibrosis, Nasopharyngeal Cancer Therapies

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July 21, 2023

By Matthew Shinkle

The FDA granted fast track designation to two oncology therapies.

Selinexor (Karyopharm Therapeutics) — a selective inhibitor of nuclear export — received the designation for treatment of myelofibrosis, including primary myelofibrosis, post-essential thrombocythemia myelofibrosis and post-polycythemia vera myelofibrosis.

“Selinexor’s unique mechanism of action, XPO1 inhibition, is a novel and potentially fundamental mechanism in myelofibrosis,” Reshma Rangwala, MD, PhD, chief medical officer of Karyopharm, said in a company-issued press release.

The company initiated a pivotal phase 3 trial to assess the efficacy and safety of once-weekly selinexor in combination with ruxolitinib (Jakafi, Incyte) for JAK-naive patients with myelofibrosis. Initial data are expected in 2025.

BRG01 (Biosyngen) — an adoptive immune cell therapy — received the designation for treatment of certain patients with relapsed or metastatic nasopharyngeal carcinoma. The designation applies to use of the agent by patients with Epstein-Barr virus-positive disease.

FDA granted orphan drug designation to BRG01 earlier this year.

  • Karyopharm receives FDA fast track designation for selinexor for the treatment of myelofibrosis (press release). Available at: https://investors.karyopharm.com/2023-07-17-Karyopharm-Receives-FDA-Fast-Track-Designation-for-Selinexor-for-the-Treatment-of-Myelofibrosis. Published July 17, 2023. Accessed July 19, 2023.
  • Biosyngen’s first-in-class cell therapy BRG01 receives FDA fast track designation (press release). Available at: https://www.biosyngen.com/index.php?m=home&c=View&a=index&aid=107. Published July 10, 2023. Accessed July 19, 2023.

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BMS-986158–Based Combos May Provide Another Viable Treatment Approach in Myelofibrosis

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August 4, 2023

Courtney Flaherty

Haifa Kathrin Al-Ali, MD, provides background on the phase 1/2 study of BMS-986158, presents initial efficacy and safety data from the study, and discusses her hope that novel combination regimens like these could achieve the challenging goal of disease modification in myelofibrosis in the future.

The investigational, oral BET inhibitor BMS-986158 administered with either first-line ruxolitinib (Rituxan) or second-line fedratinib (Inrebic) showcased early efficacy and tolerability in patients with intermediate- or high-risk myelofibrosis. These data suggest that strategies combining BET and JAK inhibition can not only address myelofibrosis-related symptoms but may show potential for disease modification, according to Haifa Kathrin Al-Ali, MD.

Findings from the dose-escalation portion of the phase 1/2 CA011-023 trial (NCT04817007) were reported at the 2023 EHA Congress, and showed that both regimens had manageable toxicity profiles. In part 1A of the study, 82% of patients given BMS-986158 plus ruxolitinib experienced an any-grade treatment-related adverse effect (TRAE); this percentage was 75% in part 1B, which evaluated BMS-986158 plus fedratinib. Dose-limiting toxicities (DLTs) occurred in 2 patients in part 1A and 3 patients in part 1B.

Early efficacy data demonstrated that first-line BMS-986158 plus ruxolitinib led to spleen volume reduction (SVR) that became particularly robust by week 24. By week 48, 80% of patients (95% CI, 28%-100%) given the first-line ruxolitinib combination (n = 5) and 50% of those given the second-line fedratinib regimen experienced an SVR of at least 35%. In the ruxolitinib arm, the mean spleen volume change was –46.7% at week 12, –59.9% at week 24, and –56.3% at week 48; in the fedratinib arm, these percentages were –29.1%, -30.8%, and -33.0%, respectively.

“There is still a way to go, but these preliminary data are quite encouraging,” said Al-Ali, a professor of Translational Oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany.

In an interview with OncLive®, Al-Ali provided background on the phase 1/2 study of BMS-986158, presented initial efficacy and safety data from the study, and discussed her hope that novel combination regimens like these could achieve the challenging goal of disease modification in myelofibrosis in the future.

OncLive: What was the rationale for investigating the use of BET inhibitors as monotherapy or in combination with JAK inhibitors in myelofibrosis?

Al-Ali: We know that in patients [with myelofibrosis] there is a NF-κB–mediated pro-inflammatory cytokine profile. [This] leads to a dysregulated bone marrow microenvironment and osteoblastic differentiation, which contributes to the bone marrow fibrosis. It’s rational to use BET inhibitors because they have been shown to reduce or inhibit the expression of BET-targeted oncogenes like c-MYC and MYC.

Please describe the design of this study. Which patients were included this analysis, and what were the key objectives of the research?

This is an open-label, phase 1b/2 study. It mainly included patients with myelofibrosis who had splenomegaly and [had] either intermediate-1 [disease] plus symptoms, intermediate-2 [disease], or high-risk [disease, according to the Dynamic International Prognostic Scoring System]. The trial consisted of a dose-escalation phase followed by a dose-expansion phase. In the dose-escalation phase, there were also 2 parts. Part 1A [involved] first-line treatment with the BET inhibitor plus ruxolitinib in patients who had no previous exposure to ruxolitinib. [Part 1B consisted of] the second-line combination, [where] the BET inhibitor was combined with 400 mg of fedratinib and [was administered] once daily [to] patients with either intolerance or resistance to ruxolitinib.

This was a phase 1 study. [At the 2023 EHA Congress,] we presented the data from the dose-escalation phase, so the primary objective is always safety. The secondary objective was efficacy in terms of SVR. There were some exploratory analyses on JAK2 allele burden as well as bone marrow fibrosis.

According to data presented at the congress, what should be known about the safety of BMS-986158?

Regarding safety, [we] found that both the first-line combination with ruxolitinib or the second-line combination with fedratinib were feasible, tolerable, and the safety profiles were manageable. The main AE was thrombocytopenia, which is a class effect; it’s manageable and transient with dose modification or dose holding. The second major AEs were gastrointestinal [toxicities, including] diarrhea and nausea. Generally, these [effects] were mild, never led to the discontinuation of patients from the trial and were quite manageable.

What were the efficacy findings reported with these combinations?

Regarding efficacy, there are very promising results [showing] SVR of at least 35% from baseline by MRI. In the first-line cohort, there was a rapid and relevant reduction from baseline spleen volume [of at least 35%] in [73%] of patients [at week 12]. This seemed to be sustainable. Looking at SVR at week 24, 100% of patients [experienced] SVR. This is a phase 1 [study], and we should be careful, but these are encouraging results.

[Similar results were seen] with the second-line treatment, although the [duration of] follow-up was shorter. At week 12, at least [38%] of the patients [experienced] more than a 35% reduction in spleen volume. These are also encouraging results.

Finally, evidence for disease modification might be seen regarding JAK2 allele burden reduction. [This was] seen quite early, starting by cycle 6 in all the patients [with] JAK2-mutated [disease]. Additionally, in patients with follow-up bone marrow biopsies that could be evaluated, there seems to be a significant reduction in at least 1 grade of fibrosis by week 12 or week 24. [The study includes a] small number of patients, and these are preliminary, encouraging data. This bone marrow fibrosis regression seems to be associated with a hematological, [specifically] anemic, response.

You mentioned that potential evidence for disease modification may have been observed with this in the form of JAK2 allele burden reduction. In myelofibrosis, what efforts are currently underway to develop disease-modifying therapies that go beyond standard approaches focused on symptom management?

One of the major challenges [in myelofibrosis] is to see [clear evidence of successful] disease modification. All the biomarkers you can measure, like bone marrow fibrosis or a reduction in allele mutational burden, should have a clinical outcome correlation. This is a big challenge.

In the future, it is crucial to move away from only SVR and symptom improvement. We have great drugs that could do that. We have to wait for data from phase 3 randomized trials, and we need time to learn and [understand] the benefit of these combination treatments. My wish is to [achieve] sustainable, durable, clinical responses for patients with these combinations, but this is still an area with a lot of unanswered questions.

Are any next steps planned for the investigation of BMS-986158 in this disease?

The next step [for this research] is going further with the trial. The expansion phase has started for the first-line combination treatment in patients who are ruxolitinib naïve. The same will hopefully be happening for the second-line treatment. If these all [show] positive signals, we will move to a phase 3 clinical trial.

What is your main takeaway message for colleagues regarding this presentation?

The takeaway message is that it is feasible to have these combinations. We have learned how to dose [them] and how to manage AEs, which is the first step [for] every treatment. We have [also] shown encouraging preliminary clinical data regarding SVR, [as well as] some encouraging translational aspects like reduction in JAK allele burden or improvement in bone marrow fibrosis.

Overall, what was most exciting about this year’s EHA Congress?

[This year’s EHA Congress has] been particularly exciting. It is almost [solely] a myeloproliferative neoplasm congress because [there are] so many new, exciting datasets [being presented]—not only for a myelofibrosis, but also for polycythemia vera and essential thrombocythemia. At the end of the day, the most important winners will be the patients.

Reference

Ayala R, Lopez N, Abulafia AS, et al. BMS-986158, a potent BET inhibitor, as monotherapy and in combination with ruxolitinib or fedratinib in intermediate- or high-risk myelofibrosis (MF): results from a phase 1/2 study. Presented at the 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S213.

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Momelotinib Outperforms Danocrine in Myelofibrosis Symptom Mangament

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August 3, 2023

Brielle Benyon

Patients with previously treated myelofibrosis (a type of myeloproliferative neoplasm) tended to benefit more regarding symptom, spleen and anemia outcomes when administered a regimen of momelotinib compared with those given Danocrine (danazol), according to updated findings of the recently completed phase 3 MOMENTUM trial.

“Momelotinib was associated with durable symptom, spleen, and anemia benefits, late responses after week 24 and favorable safety through week 48. These results highlight the potential benefits of treatment with momelotinib in patients with myelofibrosis, particularly those with anemia,” the researchers wrote in their findings, which were published in the journal The Lancet Hematology.

The study involved 195 adults with post-polycythemia vera or post-essential thrombocythemia myelofibrosis that were previously treated with a JAK inhibitor for 90 days or more. Two-thirds of participants (130 patients) were randomly assigned to receive momelotinib, while the other third (65 patients) were randomly assigned to receive Danocrine.

After 24 weeks, all patients were eligible to receive momelotinib, and 93 (72%) and 41 (63%) in the momelotinib and Danocrine groups, respectively, entered the momelotinib open-label extension period.

Among the patients who continued on momelotinib treatment and were evaluable based on total symptom score criteria, 30 (45%) patients in the original momelotinib group and 15 (50%) in the Danocrine groups responded to treatment, meaning that their disease shrank or disappeared from the therapy.

A total of 45 patients (34.62%) in the momelotinib group died of any cause compared with 26 (40%) in the Danocrine group.

Momelotinib works by inhibiting JAK2 signaling pathway. Of note, JAK2 is a genetic mutation that is commonly found in patients with myeloproliferative neoplasms and leads to scarring in the bone marrow. This scarring inhibits the marrow’s ability to produce healthy blood cells — a condition known as myelofibrosis.

Long-term follow-up revealed no new side effects from momelotinib, with the most common non-blood-related side effects from the drug being diarrhea (45 patients [26%] in the momelotinib group) and weakness or lack of energy (28 [16%]). The most common moderate to severe (grade 3 or 4) side effects were thrombocytopenia (33 [19%]) and anemia (30 [18%]). A total of 79 patients (46%) given momelotinib experienced at least one serious side effect, and 30 patients (18%) died from a treatment-emergent side effect, with two fatal treatment-emergent side effects considered to be potentially linked to momelotinib.

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Systemic Inflammatory Indices for Predicting Prognosis of Myelofibrosis

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Published August 2, 2023

Tuba Ersal, Vildan Özkocaman, İbrahim Ethem Pınar, Cumali Yalçın, Bedrettin Orhan, Ömer Candar, Sinem Çubukçu, Tuba Güllü Koca, Fazıl Çağrı Hunutlu, Şeyma Yavuz, Rıdvan Ali & Fahir Özkalemkaş

The impact of inflammatory markers such as systemic immune-inflammation (SII) index and systemic inflammation response index (SIRI) on myelofibrosis (MF) prognosis was evaluated for the first time in this study. Data from 60 patients diagnosed with MF between March 2011 and September 2022 were retrospectively analyzed. In addition to disease-related markers, the impact of SII and SIRI on prognosis was evaluated. In our study, the overall median survival (OS) was 64 months. OS was significantly shorter in patients older than 65 years, with high ferritin and lymphocyte levels, transfusion dependence at diagnosis, platelet count below 100 × 109/L, Hb level below 8 g/dl, and high risk according to the dynamic international prognostic scoring system (DIPSS)-Plus score. When these variables were included in the multivariate Cox regression model, it was found that being older than 65 years, having a high ferritin value, being at high risk according to the DIPSS-plus score and Hb values below 8 increased the risk of death. Platelet-to-lymphocyte ratio (PLR) and SII index were lower in patients with a fatal outcome. No statistically significant relationship was found between SIRI and mortality. The findings of this study showed that low PLR and high ferritin were associated with poor prognosis in MF. Elevated SII and SIRI, evaluated for the first time in patients with myelofibrosis, did not predict prognosis. Since non-inflammatory variables play a role in the pathogenesis of MF, bone marrow indicators and systemic inflammation indicators derived from hematologic parameters may not be accurate.

Introduction

Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasms (MPN) characterized by anemia, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms, and acute myeloid leukemia progression1. Most patients carry a mutation in the JAK-2, CALR, or MPL genes2, which contributes to the JAK-2-signal-transducer-and-activator-of-transcription signaling pathway and the high inflammatory state characteristic of these diseases. Inflammation plays a crucial role in the development and progression of MPN.

The prognosis of MF varies greatly. While some patients only have a few months to survive, others live for more than 20 years. The three leading causes of death are hemorrhage, infection brought on by bone marrow loss, and transformation into acute leukemia3.

A good risk stratification model provides information about the prognosis of patients, affecting the decision whether the patient is included as a candidate for allogeneic stem cell transplantation and thereby the treatment. To evaluate the mortality risk of MF patients, the dynamic international prognostic scoring system (DIPSS)4 or DIPSS-plus is generally used5.

It is well established that inflammation affects all phases of tumor growth and can increase the risk of developing a tumor (triggering the first genetic mutation, tumor development, metastasis, and progression). Therefore, inflammation parameters are strong candidates for predicting cancer prognosis. Numerous inflammatory indicators have recently been linked to a poor prognosis for cancer, including C-reaction protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR)6,7,8. The systemic immune-inflammation (SII), which was first used in hepatocellular cancer in 2014 as a new inflammation marker based on peripheral neutrophil, platelet, and lymphocyte counts9 and the systemic inflammation response index (SIRI), which was developed to predict survival in patients with pancreatic cancer and based on peripheral neutrophil, monocyte, and lymphocyte counts10, have also been used as inflammatory biomarkers to predict prognosis in many cancer types11,12,13,14.

In this study, in addition to the potential prognostic markers examined in other retrospective studies to date, we investigated the prognostic value of SII and SIRI in MF for the first time in the literature.

Materials and methods

The data of 60 patients who were followed up with the diagnosis of MF between March 2011 and September 2022 at Bursa Uludag University Hematology Department Clinic were retrospectively analyzed. All patients met the 2016 World Health Organization criteria for PMF15 or the 2008 international working group for myelofibrosis research and treatment (IWG-MRT) criteria for SMF16. Patients were divided into four groups as low, intermediate-1, intermediate-2, and high-risk groups according to DIPSS and DIPSS-plus scores. The effect of age, MF subtype, JAK-2 mutation status, erythrocyte transfusion dependence, presence of constitutional symptoms, splenomegaly, leukocyte, hemoglobin, platelet, CRP, mean corpuscular volume, mean platelet volume (MPV), red blood cell distribution width (RDW), LDH, ferritin levels, TS and CAR, PNI, NLR, PLR, leukocyte to lymphocyte ratio (WLR), ferritin to lymphocyte ratio (FLR), lymphocyte to LDH ratio (LLR), DIPSS and DIPSS-plus risk group, and SII and SIRI, which were examined for the first time in MF, on prognosis was investigated in all patients. SII was calculated as platelet count × neutrophil count/lymphocyte count in peripheral blood and SIRI was calculated as neutrophil count × monocyte count/lymphocyte count. Mortality was defined as patients who died during follow-up. Our study was conducted under the institutional research committee’s ethical standards and according to the 1964 Helsinki Declaration. This study was approved by the clinical research ethics committee of Bursa Uludag University Faculty of Medicine (Decision No: 2022-18/20).

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics for Windows Version 25.0 (Statistical Package for the Social Sciences, IBM Corp., Armonk, NY, USA). Descriptive statistics were presented as n and % for categorical variables and mean ± SD, median (IQR) for continuous variables. Data were analyzed in terms of normality assumptions. For continuous variables with Kolmogorov–Smirnov values p > 0.05, independent samples t-test was used as the parametric test to evaluate the difference in mortality between the groups. Chi-square test was used to compare categorical variables. Three receiver operating characteristic (ROC) curve analysis was performed for SII and ferritin values to predict mortality. Kaplan–Meier method was used to compare survival times between various variables. Finally, multivariate Cox regression results of various clinical factors on mortality risk were presented. p < 0.05 was considered statistically significant in all analyses.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study.

Results

Sixty patients made up the study population, with 53.3% of the females and 46.7% of the males. Median age at diagnosis of 63 years. Most patients (76.6%) and those with splenomegaly (93.3%) had anemia at the time of diagnosis. Of these patients, 41.6% had massive splenomegaly. There were 41.6% of cases of constitutional symptoms, with weight loss being the most prevalent (61.5%) and high fever being the least prevalent (11.5%). Thrombosis was present in 16.6% of patients (n = 10). Four patients had cerebral vascular thrombosis, five had portal system thrombosis (three portal vein thrombosis, two splenic infarction), and one had deep vein thrombosis. JAK-2 mutation positivity was detected in 30 (58.8%) of 51 patients who underwent genetic screening. The rate of transformation to acute leukemia was 8.3%. Table 1 shows the distribution of the demographic and clinical findings of the patients.

Table 1 Demographic and clinical characteristics of the patients.
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As seen in Table 2, median overall median survival (OS) was 64 months (95% CI 54.88–73.10). Two-year OS was 73.6%, while five-year OS was 55.6%. No difference was found between the MF subtypes (p = 0.825). Median OS was significantly different between the age groups (p = 0.005) (Fig. 1). Median survival was 73.7 months in patients under 65 years of age (95% CI 68.07–79.32) compared to 44.6 months in patients over 65 years of age (95% CI 10.66–78.53). Two-year OS and five-year OS were 83.3% and 74.1% in patients under 65 years of age compared with 56.4% and 25.6% in patients over 65 years of age.

Table 2 OS comparisons according to patient variables.
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Figure 1
figure 1

Overall survival of patients.

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A significant difference was found in OS with respect to DIPSS-plus risk groups (p < 0.001). Median survival was 73.7 months (95% CI 47.43–99.66) in the low-risk group, 72.1 months (95% CI –) in the intermediate-1 risk group, 59.7 months (95% CI 31.17–82.22) in the intermediate-2 risk group, and 9.6 months in the high-risk group (95% CI 8.06–11.4). A statistically significant difference was also found in median OS between the high-risk group and all other risk groups (p < 0.001). Two-year OS and five-year OS were 100% and 83.3% in the low-risk group, compared with 92.3% and 84.6% in the intermediate-1 risk group. In the intermediate-2 risk group, two-year OS was 76.3% and five-year OS was 49.9%. In the high-risk group, all patients died within two years.

PLR (p = 0.048), SII (p = 0.018) and lymphocyte count (p = 0.033) showed a statistically significant difference between patients with and without mortality. PLR and SII were lower in patients with mortality compared to patients without mortality, while ferritin and lymphocyte levels were higher. No significant difference was found in survival with respect to other variables (neutrophils, platelets, NLR, LLR, WLR, FLR, RDW, MPV, CRP, LDH, spleen size, serum iron, iron binding capacity, TS, PNI, CAR).

A significant relationship was found between OS and Hb levels below 8 g/dL (p = 0.027), transfusion dependency (p < 0.001), and platelet count below 100 × 109/L (p = 0.002), while no statistically significant relationship was found between OS and MF subtypes, positive or negative JAK-2 mutation status, presence of constitutional symptoms, TS < 20%, Hb < 10 g/dL, leukocyte count > 25 × 109/L, degree of collagen and reticulin fibrosis, and DIPSS risk groups.

Univariate analysis results showed that age, ferritin, transfusion dependency, platelet count, DIPSS-plus risk group, Hb, and SII index variables were statistically significant for mortality risk (p < 0.05). The variables that were significant in univariate analyses were included in the multivariate Cox regression model. According to the results of the multivariate Cox regression model, it was found that being over 65 years of age (HR 7.29; 95% CI 2.44–21.75; p < 0.001), increased ferritin values (HR 1.00; 95% CI 1.00–1.01 p = 0.002), high-risk DIPSS-plus (HR 12.63; 95% CI 1.30–122.30 p = 0.029), and hemoglobin values below 8 increased mortality risk (OR 0.32; 95% CI 0.11–0.94 p = 0.038) (p < 0.001, − 2 loglikelihood = 158,326) (Table 3).

Table 3 Multivariate Cox regression results for various clinical variables.
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The predictive power of SII for mortality was statistically significant (p = 0.032). In the ROC analysis conducted to evaluate SII in predicting mortality, the area under the curve was 0.677 (95% CI 0.528–0.827) and the cut-off value for SII was 1246.78 (Fig. 2). For this value and below, sensitivity was 57.6% and specificity was 55.5%. The predictive power of ferritin was not statistically significant for mortality (p = 0.097) (Table 4, Fig. 3).

Figure 2
figure 2

ROC curve of SII levels for predicting mortality.

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Table 4 Predictive power of SII and Ferritin in differentiating mortality.
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Figure 3
figure 3

ROC curve of Ferritin levels for predicting mortality.

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Discussion

Accurate risk assessment is crucial for developing the best treatment strategy in MF, which is one of the BCR-ABL-negative MPNs accepted as a model of inflammation-related cancer development, especially in young patients. Widely accepted scoring systems require genetic evaluation and tests may be difficult to access in some centers. The current study assessed prognostic indicators in patients with MF. To the best of our knowledge, this is the first study to have examined the relationship between SII and SIRI and mortality in MF patients in the literature. Inflammatory indicators and parameters that could affect prognosis were assessed in 60 patients.

Indices such as SII and SIRI are thought to be associated with the prognosis of various tumors. A meta-analysis by Yang et al. evaluating 22 studies including 7657 patients revealed that high SII was clearly associated with lower OS, time to recurrence, progression-free survival, cancer-specific survival, relapse-free survival, and disease-free survival17. These results suggest that high SII may be a potential prognostic marker in patients with various cancers and may be associated with poor overall outcomes. A study by Geng et al. in patients with esophageal cancer showed that median OS was significantly higher in patients with low SIRI18.

In this study, the relationship between MF and SII was evaluated for the first time in the literature; and paradoxically, mortality was found to be lower in patients with MF compared to patients without MF (p = 0.018). This discrepancy results from patients with a fatal course having higher lymphocyte numbers and lower platelet counts. SII lost its relevance when these variables were incorporated into the multivariate Cox regression model. Additionally, SIRI was also examined for the first time in MF patients and found not to be associated with mortality (p = 0.492).

Anemia is a disease characteristic most consistently associated with poor prognosis in MF5,19,20,21. The most commonly used threshold in prognostic models is 10 g/dL. Transfusion dependence has had poor prognostic significance in MF22,23,24. There is ongoing debate about the relationship between transfusion dependence and poor prognosis in chronic MPN. Some authors argue that transfusion dependence affects survival through the adverse effects of chronic erythrocyte transfusion, such as iron overload and transfusion-related immunomodulation. In the present study, when the Hb cut-off point was taken as 10 g/dL, no difference was found between the groups in terms of survival (p = 0.168). However, when the cut-off point was taken as 8 g/dL, a significant difference was found in median OS (p < 0.027). Hb level ≤ 8 g/dL was determined as a marker of poor prognosis. When included in the multivariate Cox regression model, Hb < 8 g/dL increases the risk of mortality (HR 0.32; 95% CI 0.11–0.94 p = 0.038).

Some studies have found that thrombocytopenia was associated with poor prognosis5,20,21,25, but it was noted that low platelet counts are frequently associated with anemia and collinearity in multivariate regression models may make it difficult to characterize thrombocytopenia as an independent prognostic factor19. In the present study, platelet count was lower in patients with a mortal course, but the difference was not statistically significant (p = 0.085). When the cut-off value for platelet count was taken as 100 × 109/L, a significant difference was found in median OS (p = 0.002). Median OS was significantly shorter in patients with platelet count below 100 × 109/L (72.1 months versus 17.1 months).

The transfusion dependency at diagnosis or during MF is an indicator of poor prognosis22,23. In our patients, median OS was 73.7 months in the group without transfusion dependence and 17.1 months in the group with transfusion dependence, which was significantly lower (p < 0.001).

Consistent with previous studies, age was associated with OS in both univariate analysis and multivariate Cox regression analysis. When the cut-off point for age was taken as 65 years, a significant difference was found in OS between the groups (p = 0.005). When included in the multivariate Cox regression model, it was found that mortality risk was significantly higher in those older than 65 years (HR 7.29; 95% CI 2.44–21.75; p < 0.001).

Currently, the most widely used prognostic scoring system in MF is DIPSS-plus. DIPSS-plus was used in 967 consecutive patients at the Mayo Clinic and resulted in median survival of 1.8, 3.6, 7.8, and 17.5 years for high, intermediate-2, intermediate-1, and low-risk patients, respectively26. When the patients in this study were divided into risk groups according to DIPSS-plus, a statistically significant difference was found between the median OS times (p < 0.001). Median OS was 73.7 months in the low-risk group, 72.1 months in the intermediate-1 risk group, 59.7 months in the intermediate-2 risk group, whereas it was 9.6 months in the high-risk group (p < 0.001). In the multivariate Cox regression analysis, a significant difference was found between the low-risk group and the high-risk group persisted (HR 12.63; 95% CI 1.30–122.30 p = 0.029), while the significance between the low-risk group and intermediate-1 and intermediate-2 risk groups disappeared (p = 0.151, p = 0.570, respectively).

With respect to iron metabolism, studies have shown that high ferritin value and low TS are associated with low OS in MF. Lucijanic et al. evaluated the prognostic impact of low TS in 87 patients with PMF. Low TS was found to have a detrimental effect on the survival of PMF patients, independent of anemia and ferritin levels27. In the present study, ferritin level was found to be higher in patients with mortality (p = 0.024) and when included in the multivariate Cox regression model, it was found that an increase in ferritin levels increased the risk of mortality (HR 1.00; 95% CI 1.00–1.01 p = 0.002). However, there was no statistically significant relationship between TS, serum iron level, iron binding capacity, RDW, and mortality. Numerous studies have been published in the literature showing the link between several inflammation markers, including NLR and PLR, and a poor prognosis for cancer7,8,28. In a study evaluating NLR and PLR in MF, these values were found to be significantly higher in patients compared to healthy controls. In univariate analyses, shorter overall survival was observed in patients presenting with high NLR and low PLR29. In the same study, increased RDW was associated with survival (p = 0.039). In MF, high CRP is associated with features of more advanced disease and a trend toward worse clinical outcomes as part of individual parameters or different prognostic scores30,31,32. In this study, no correlation was found between CRP and NLR and survival. Consistent with the literature, survival was shorter in patients with low PLR values (p = 0.048).

CAR has recently been recognized as an inflammatory biomarker and prognostic factor in several malignant neoplasms33,34. However, a study evaluating CAR in patients with MF reported that higher CAR was associated with lower OS35. PNI is an index reflecting a patient’s inflammatory, nutritional, and immune status. In a study evaluating PNI in MF patients, low PNI predicted worse survival independent of DIPSS36. In the present study, however, CAR and PNI had no effect on survival.

The mean LDH level was higher (p = 0.108) and spleen size was larger (p = 0.122) in patients with a mortal outcome, but this was not statistically significant.

This study has certain limitations. The study was conducted retrospectively and in a single-center.

In conclusion, the results obtained in this study show that elevated SII and SIRI, which have prognostic significance for many cancers, cannot be used as markers for poor prognosis in MF. Since the pathology of MF directly involves the bone marrow unlike solid organ cancers, these inflammation markers may be insufficient to predict prognosis. Further clinical studies are needed to confirm these results.

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Survival Expectation After Thrombosis and Overt-Myelofibrosis in Essential Thrombocythemia and Prefibrotic Myelofibrosis: A Multistate Model Approach

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July 28, 2023

Alessandra Carabbio, Alessandro Maria Vannucchi, Elisa Rumi, Valerio De Stefano, Alessandro Rambaldi, Giuseppe Carli, Heinz Gisslinger, Francesco Passamonti, Juergen Thiele, Naseema Gangat, and Tiziano Barbui

Ample evidence has been provided that accurate discrimination between essential thrombocythemia (ET) and early prefibrotic primary myelofibrosis (pre-PMF) has an impact not only on presenting laboratory data but also on complications, like thrombosis, progression to overt myelofibrosis (MF), transformation to blast phase (BP), and overall survival [1,2,3,4,5,6,7,8]. However, studies estimating the epidemiology of these critical events in the two entities have mainly focused on one isolated outcome at a time, without considering the entire spectrum of multiple intermediate disease states, possibly affecting probabilities and risk factors of the outcome of interest. This situation calls for a multistate model approach, a technique that allows a more in-depth insight into intermediate factors likely influencing the progressive transitioning from one status to another.

The aim of the present investigation was to estimate the probabilities that intermediate-state passages, including thrombosis, overt MF, and BP, impact the final absorbing state (death) in ET versus pre-PMF. To this purpose, retrospective data from two multicenter and well-documented studies [1, 9] were used: (i) ET patients (n = 791) from a multicenter international study of 891 cases, selected for the availability of complete disease history [1] and (ii) pre-PMF patients (n = 382) from four different Italian centers [9]. Both studies were approved by all institutional review boards or ethical committees of participating centers.

At the time of diagnosis, treatment-naïve ET and pre-PMF patients revealed different hematologic and clinical characteristics (Table S1). A parametric Markov multistate model [10] was applied to analyze data on survival considering intermediate states that are part of the natural history of ET and pre-PMF. The model included five states with ten possible transitions (Fig. S1): all patients begin in the initial state of diagnosis (ET, panel A, n = 791 or pre-PMF, panel B, n = 382) and then they could transit through the occurrence of an incident thrombotic event (Table S2) and/or the evolution to overt MF and/or BP (transient states) before death (absorbing state).

In ET, transition-1 from diagnosis to thrombosis included 101/791 patients (12.7%), but this status was transient in 21/101 patients that moved to death (21%) after a median time of 4.0 years (IQR: 1.6–6.4), 3/101 (6%) and in 1/101 (2%) to MF and BP, after a median time of 4.7 and 5.2 years, respectively. Remarkable was that in pre-PMF, the direct transition to thrombosis was found in 13.9%, a figure not different from ET (i.e., 12.7%). Conversely, pre-PMF substantially differed from ET for a higher rate of direct transition to overt MF or BP, that was 13 and 4% vs. 4 and 0.6%, respectively.

After 10 years, the state occupation probability of being event-free was 70 and 50% in ET and pre-PMF, respectively, and progressively decreased, particularly in pre-PMF (Fig. S2), due to earlier mortality, particularly for a greater probability of hematological evolutions. This trend was even more evident for death; regardless of the pathways through hematological evolutions, deaths were double in pre-PMF than ET, reaching 30, 60, and 80% vs. 15, 30, and 60% at 5, 10, and 20 years, respectively.

Probabilities to direct transition to thrombosis (n = 101 in ET and n = 53 in pre-PMF) and overt MF (n = 29 in ET and n = 51 in pre-PMF) are compared in Fig. 1. The trend of experiencing thrombosis directly after ET diagnosis showed to increase in the first 10 years (10%) and to decline subsequently (less than 5% at 30 years). On the contrary, in the first decade after diagnosis (<5%), the same probability grew slowly in pre-PMF while subsequently rose up to crossing the ET trend (8% after 30 years). Instead, the direct transitions from pre-PMF to overt-MF had an opposite trend: in the first 10 years, it reached a peak of 11%, while in ET, the trend was less pronounced, reaching a probability not exceeding 2.3% in the same period post-diagnosis.

Fig. 1: Direct transition probabilities to thrombosis and evolution in overt MF.
figure 1

Direct transition probabilities over time from diagnosis of ET or pre-PMF to thrombosis (A) and overt MF (B). Transition probabilities are defined as the probability of going from a given state to the next state in a Markov process. Direct transitions refer to all the 791 and 382 ET and pre-PMF patients, respectively, initially at risk; thus, they represent the probability that a patient can first experience thrombosis or evolve into overt MF.

The performance of the IPSET-thrombosis score [11] was tested in both ET and pre-PMF for the direct transition to thrombosis. In ET, considering the low-risk group as a reference, the intermediate and high-risk groups determined by IPSET-thrombosis were confirmed to predict the thrombotic risk (HR = 2.08, 95% CI = 1.28–3.37, p = 0.003 and HR = 3.13, 95% CI = 1.82–5.40, p < 0.001, respectively). In pre-PMF, the same model was unpowered to reach statistical significance in the intermediate-risk group (HR = 2.50, 95% CI = 0.87–7.21, p = 0.089), while it was in the high-risk category (HR = 3.93, 95% CI = 1.52–10.11, p = 0.005).

Concerning survival, most of the deaths in ET and pre-PMF occurred directly from diagnosis (Fig. 2). The intermediate events that most influenced death were thrombosis (25.3%) in ET and BP (23.8%) in pre-PMF. In comparison with ET, the probability of direct transition from diagnosis to death in patients with pre-PMF increased linearly over time (Fig. 2) and was twofold higher, reaching values of 15, 30, and 60% at 5, 10, and 20 years, respectively. Of note, the probability of death in ET patients with an intermediate thrombosis state maintained a fourfold higher value over time than the ones without thrombosis. As expected, the probabilities of death in MF or BP status were higher and occurred faster, and not substantially different in ET or pre-PMF.

Fig. 2: Transition probabilities to death in ET and pre-PMF.
figure 2

Comparison of the direct and indirect (via thrombosis, evolution in MF or BP) transition probabilities to death (absorbing state) over time from diagnosis of ET (dash lines) or pre-PMF (solid lines).

We confirmed the good performance of the IPSET-survival score [12] to differentiate the risk of direct mortality in ET (intermediate: HR = 4.38, 95% CI = 1.63–11.73, p = 0.003 and high-risk: HR = 20.17, 95% CI = 7.71–52.78, p < 0.001, compared to low-risk). The IPSET-survival score was equally well performing in pre-PMF (HR = 3.52, 95% CI = 1.22–10.12, p = 0.019 and HR = 13.37, 95% CI = 4.63–38.57, p < 0.001, for intermediate and high-risk groups, respectively, compared to low-risk). However, the discriminatory power of the IPSET-survival in ET was lower when the multistate model evaluated the mortality mediated by the thrombosis state; only high-risk patients were discriminated (HR = 19.27, 95% CI = 2.46–51.01, p = 0.005), whereas the intermediate-risk group was not significantly different from the low-risk one (HR = 3.84, 95% CI = 0.55–26.12, p = 0.194). Thus, in addition to the IPSET-survival risk factors (i.e., age ≥60 years, previous thrombosis, and white blood cells count ≥11 × 109/L) we found that platelets count ≥1000 × 109/L (HR = 5.74, 95% CI = 1.79–18.40, p = 0.003) and arterial vs. venous thrombosis in the follow-up (HR = 4.43, 95% CI = 1.04–18.91, p = 0.044) were independent predictors. The low number of deaths after thrombosis (12/105, 11%) in pre-PMF did not allow us to analyze the IPSET-survival performance in this transition.

The present multistate analysis, provides new insights for a better understanding of ET and pre-PMF disease processes. For example, in pre-PMF, the probability of thrombosis in the first decade was lower (<5%) due to a strong competitor represented by the evolution in MF (up to 11%). Consequently, occupation of thrombosis state in the first decade was lower in pre-PMF than in ET patients but became comparable in the last decades of observation (13 and 14% in ET and pre-PMF, respectively), supporting our previous cumulative estimates obtained with conventional methodology [1]. This notion might have practical implications to differentiate treatments during the course of the two entities by preferring antithrombotic prophylaxis according to IPSET thrombosis in ET that kept its discriminatory power also in this multiple competing adjustment analysis. In pre-PMF, therapy of first choice might be directed to prevent myelofibrosis evolution, provided agents able to do that are positively evaluated in appropriate clinical trials.

Regarding BP evolution, we highlight that the direct transition from the diagnosis was predominant in ET (n = 6/7, 86%), and it was modestly influenced by the pathway through thrombosis (n = 1/7, 14%). Unfortunately, we could not provide sufficient information on the role of cytoreductive therapy in these transitions due to the unreliable timing of drug administration.

Mortality prediction in ET was the topic addressed in a previous study [12]. On the basis of the hazard ratio estimates from Cox regression models, the IPSET-survival model was constructed, and 867 ET patients were allocated into three risk categories with significantly different survival [12]. In the present analysis, in a selected group of patients (n = 791) from the same database, we re-evaluated the risk factors of death considering the possible influence of the intermediate states that occurred before death, and confirmed the performance of the IPSET-survival scoring system for the prediction of direct mortality. However, we also found that the effect on mortality exerted by the intermediate thrombosis state was not negligible (accounting for 25% of deaths) and fourfold higher than in patients without incident thrombosis. Whether the reduction of vascular complications may impact survival remains to be demonstrated in appropriate prospective studies. Furthermore, we found two additional independent predictors of mortality in thrombosis-mediated transition, namely platelet count >1000 × 109/L (HR = 5.74, 95% CI = 1.79–18.40, p = 0.003), in line with a previous observation [13], and the incident arterial vs. venous thrombosis (HR = 4.43, 95% CI = 1.04–18.91, p = 0.044).

Limitations of this study concern its retrospective design and a possible bias related to the reporting accuracy of events, in terms of completeness and timing. In addition, since in these databases, the administration times of the cytoreductive drugs (hydroxyurea in absolute prevalence) were not well specified, we could not reliably evaluate the influence of the pharmacological cytoreduction on the post-diagnosis events. Furthermore, given that current results were obtained in the same ET database used for IPSET scores, a possible “self” confirmation bias could not be excluded. However, our aim was not to confirm the overall performance of the two scores, but to evaluate whether the transition from one state to another could have affected the overall survival or the cumulative incidence of thrombosis in a different way.

Strengths of the study are the relatively large number of patients for rare diseases such as ET and pre-PMF and the clinical and hematological diagnostic accuracy of the two entities and outcomes.

In conclusion, this multistate analysis provides novel information on the temporal probability of intermediate critical events occurring in ET and pre-PMF, and their impact on mortality. This knowledge might inform clinical practice and could also make more feasible the design of clinical trials.

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Karyopharm Receives FDA Fast Track Designation for Selinexor for the Treatment of Myelofibrosis

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– Regulatory Designation Includes Primary Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis and Post-Polycythemia Vera Myelofibrosis –

– Pivotal Phase 3 Study of Selinexor and Ruxolitinib in Treatment-Naïve Myelofibrosis Initiated in June 2023 –

NEWTON, Mass., July 17, 2023 /PRNewswire/ — Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced that the United States Food and Drug Administration (FDA) has granted Fast Track Designation to the development program of selinexor for the treatment of patients with myelofibrosis, including primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis.

“Fast Track Designation for selinexor highlights its potential to address the unmet medical need in myelofibrosis, an important acknowledgement as we continue our pivotal Phase 3 study,” said Reshma Rangwala, MD, PhD, Chief Medical Officer of Karyopharm. “Selinexor’s unique mechanism of action, XPO1 inhibition, is a novel and potentially fundamental mechanism in myelofibrosis. We have been highly encouraged by the efficacy and safety data observed to date [in our Phase 1 study] with selinexor in combination with ruxolitinib in patients with treatment-naïve myelofibrosis and believe selinexor has the potential to shift the treatment paradigm. We look forward to continued interaction with the FDA as we advance the development of this promising treatment for patients in need.”

In June 2023, Karyopharm initiated a pivotal Phase 3 clinical trial (XPORT-MF-034) (NCT04562389) to assess the efficacy and safety of once-weekly selinexor 60 mg in combination with ruxolitinib in JAKi-naïve patients with myelofibrosis. Updated data from the Phase 1 study were presented at the American Association for Cancer Research Annual Meeting 2023, American Society of Clinical Oncology 2023 and European Hematology Association 2023, which showed rapid, deep and sustained spleen responses and robust symptom improvement in patients treated with selinexor 60 mg in combination with ruxolitinib as of the April 10, 2023 cut-off date.  Top-line data from the Phase 3 study is expected in 2025. The Company plans to expand its clinical development program in myelofibrosis by investigating selinexor in other JAKi-naïve settings, such as novel combinations, to benefit the greatest number of patients.

Fast Track Designation is intended to facilitate development and expedite review of drugs to treat serious and life-threatening conditions so that an approved product can reach the market expeditiously. Features of Fast Track Designation include frequent interactions with the FDA review team, and if relevant criteria are met, eligibility for Priority Review and Rolling Review.

Further information about the Phase 3 study can be found at www.clinicaltrials.gov.

About Karyopharm Therapeutics
Karyopharm Therapeutics Inc. (Nasdaq: KPTI) is a commercial-stage pharmaceutical company pioneering novel cancer therapies. Since its founding, Karyopharm has been an industry leader in oral Selective Inhibitor of Nuclear Export (SINE) compound technology, which was developed to address a fundamental mechanism of oncogenesis: nuclear export dysregulation. Karyopharm’s lead SINE compound and first-in-class, oral exportin 1 (XPO1) inhibitor, XPOVIO® (selinexor), is approved in the U.S. and marketed by the Company in three oncology indications and has received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including Europe and the United Kingdom (as NEXPOVIO®) and China. Karyopharm has a focused pipeline targeting multiple high unmet need cancer indications, including in multiple myeloma, endometrial cancer, myelodysplastic neoplasms and myelofibrosis. For more information about our people, science and pipeline, please visit www.karyopharm.com, and follow us on Twitter at @Karyopharm and LinkedIn.

Forward-Looking Statements
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the ability of selinexor to treat patients with myelofibrosis; and expectations related to the clinical development of selinexor and potential regulatory submissions of selinexor. Such statements are subject to numerous important factors, risks and uncertainties, many of which are beyond Karyopharm’s control, that may cause actual events or results to differ materially from Karyopharm’s current expectations. For example, there can be no guarantee that Karyopharm will successfully commercialize XPOVIO or that any of Karyopharm’s drug candidates, including selinexor and eltanexor, will successfully complete necessary clinical development phases or that development of any of Karyopharm’s drug candidates will continue. Further, there can be no guarantee that any positive developments in the development or commercialization of Karyopharm’s drug candidate portfolio will result in stock price appreciation. Management’s expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: the adoption of XPOVIO in the commercial marketplace, the timing and costs involved in commercializing XPOVIO or any of Karyopharm’s drug candidates that receive regulatory approval; the ability to obtain and retain regulatory approval of XPOVIO or any of Karyopharm’s drug candidates that receive regulatory approval; Karyopharm’s results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, including with respect to the need for additional clinical studies; the ability of Karyopharm or its third party collaborators or successors in interest to fully perform their respective obligations under the applicable agreement and the potential future financial implications of such agreement; Karyopharm’s ability to enroll patients in its clinical trials; unplanned cash requirements and expenditures; development or regulatory approval of drug candidates by Karyopharm’s competitors for products or product candidates in which Karyopharm is currently commercializing or developing; the direct or indirect impact of the COVID-19 pandemic or any future pandemic on Karyopharm’s business, results of operations and financial condition; and Karyopharm’s ability to obtain, maintain and enforce patent and other intellectual property protection for any of its products or product candidates. These and other risks are described under the caption “Risk Factors” in Karyopharm’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2023, which was filed with the Securities and Exchange Commission (SEC) on May 4, 2023, and in other filings that Karyopharm may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and, except as required by law, Karyopharm expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

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Anemia-Focused Treatment Approaches Represent Future Directions in Myelofibrosis

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July 12, 2023

Ashling Wahner

JAK inhibitor add-on agents may address an unmet need for patients with myelofibrosis with disease- or treatment-related myelofibrosis, according to Anna B. Halpern, MD, who noted that standard myelofibrosis treatments can cause adverse effects that interfere with patient quality of life (QOL).

“Myelofibrosis is generally a [relatively] rare disease,” Halpern said in an interview with OncLive®. “Having a second opinion at a center that treats a lot of myelofibrosis and has much clinical trial availability is a great option for any patient, particularly if they have higher-risk disease features.”

In the interview, Halpern discussed strides in the treatment of myelofibrosis with anemia, the shifting role of ruxolitinib (Jakafi) in this disease, and the importance of providing patients with access to clinical trials, as they may benefit from investigational treatment approaches.

Halpern also highlighted the potential benefits of moving JAK inhibitors to the upfront setting, as evidenced in cohort 3 of the phase 2 REFINE trial (NCT03222609), in which navitoclax plus ruxolitinib generated a spleen volume reduction of at least 35% (SVR35) at week 24 in subgroups of patients with JAK inhibitor–naïve myelofibrosis with historically poor prognoses, including patients at least 75 years of age (SVR35, 50%), those with a high Dynamic International Prognostic Scoring System score (SVR35, 33%), and those with HMR mutations (SVR35, 47%).1 Furthermore, she explained clinical outcomes with ruxolitinib plus pelabresib (CPI-0610) in the phase 1/2 MANIFEST trial (NCT02158858), which showed that the combination elicited an SVR35 at 24 weeks in 68% of patients with JAK inhibitor–naïve disease.2

Halpern is a physician and an assistant professor in the Clinical Research Division at Fred Hutchinson Cancer Center, as well as an assistant professor of hematology at the University of Washington School of Medicine, both in Seattle.

OncLive: How does the mechanism of action of JAK-STAT inhibitors like momelotinib contribute to their potential to ameliorate disease-related anemia?

Halpern: Disease-related anemia is partially mediated through the hepcidin pathway. JAK-STAT signaling drives overproduction of inflammatory cytokines, leading to elevated hepcidin dysregulated iron metabolism. Through the inhibition of JAK-STAT signaling, JAK inhibitors have the potential to intervene in this pathway and improve anemia.

How does the clinical benefit seen with momelotinib compare with that seen with standard agents like ruxolitinib and danazol in the anemic myelofibrosis setting?

In a study that compared momelotinib with ruxolitinib in the upfront or JAK inhibitor–naïve setting, momelotinib was better than ruxolitinib at improving anemia-related outcomes, [such as] improving or decreasing transfusion dependence, increasing transfusion independence at week 24, and decreasing the need for red blood cells. Ruxolitinib was probably better for controlling symptoms, and [the agents] were generally similarly [effective] at controlling spleen [size].

Regarding the comparison [of momelotinib] with danazol, the phase 3 MOMENTUM trial [NCT04173494] was a randomized trial of momelotinib vs danazol. This was for patients who had previously been treated with a JAK inhibitor. [In this trial], momelotinib was superior to danazol in multiple outcomes, including symptom response score, at 25% vs 9% respectively, spleen response, at 23% vs 3% respectively, and transfusion independence, at 40% vs 13%, respectively. Overall, momelotinib probably has several advantages compared with danazol.

What unmet needs exist for patients with myelofibrosis, and what should be done to address these?

One of the biggest unmet needs I see often in clinic is anemia. [Anemia occurs] both because of disease and because it’s a treatment-emergent effect with some JAK inhibitors. Ruxolitinib primarily interferes with erythropoietin signaling in the JAK-STAT pathway, which is essential for erythropoiesis. We see anemia, both because of disease and ruxolitinib, that is challenging to treat. This is a big unmet need, particularly as anemia is correlated with QOL. It’s not the only aspect correlated with QOL in patients with myelofibrosis. Their inflammatory and cytokine profile, which JAK inhibitors can control, is also important. [Anemia is] just 1 component.

Another big unmet need is treating high-risk disease and preventing progression of disease and leukemic progression. That’s a big issue because we’re not yet sure whether our therapies are disease modifying.

What efforts are being made to move ruxolitinib and navitoclax to the frontline setting?

At the 2022 ASH Annual Meeting and Exposition, many exciting therapies in myelofibrosis, both standalone and JAK inhibitor add-ons, were presented. The data we saw at ASH with navitoclax were encouraging. An arm in the REFINE trial [investigated] ruxolitinib and navitoclax in a JAK inhibitor–naïve cohort. This study was interesting because we saw changes in bone marrow fibrosis as well as reduction in the variant allele frequency [VAF] of the driver gene mutation in many patients. Those outcomes are particularly of interest because they have the potential to be biomarkers for disease modification or the disease-modifying ability of this drug combination.

It’s hard to study whether the longer-term outcomes are correlates for leukemia, progression, and survival, so we need [outcomes] in the shorter term to study. The 2 candidates of bone marrow fibrosis and VAF are strong. We’ll look forward to larger trials with these [agents] in the upfront setting.

What did the MANIFEST trial reveal about the efficacy and clinical significance of pelabresib plus ruxolitinib?

The MANIFEST trial [investigated] the BET inhibitor pelabresib plus ruxolitinib. There were multiple arms, [including a] JAK inhibitor–naïve cohort, an upfront treatment arm. We saw a good reduction in spleen volume, as well as symptom score. Considering the outcomes that may correlate with disease modification, improvement in bone marrow fibrosis and reduction in VAF, we saw that 28% of patients had 1 or greater grade 1 improvement in fibrosis, and 29.5% had an over 25% reduction in the JAK2 V617F VAF. This is promising for this combination. Now, the randomized, double-blind, phase 3 MANIFEST-2 trial [NCT04603495] is evaluating this combination in the upfront setting in a larger cohort.

What new JAK inhibitor add-ons coming down the pike in myelofibrosis are you excited to see?

It’s hard to know. We have a lot of data in phase 2 trials investigating different cohorts of different patients. In oncology, sometimes we can have many promising data in phase 1 and 2 trials, but those do not always bear fruit or come out as clearly in randomized phase 3 trials. It’s hard to compare the results of these trials, even though they have similar eligibility criteria and outcomes. I will need to wait for the phase 3 trials to know how these drugs will go.

What is your main message for colleagues regarding emerging therapies in myelofibrosis?

We have had several new drugs approved for myelofibrosis in the past few years, which is wonderful. We always like to have many treatment options for patients. However, we have much room to go. If possible, referring patients early on to our center or other centers that have many clinical trials for myelofibrosis is wonderful. That way, they have access both to standards of care and treatments coming down the pipeline. We can help study whether these treatments will improve unmet needs and help modify the natural history of this disease, which is our goal. Referral to us, even just for a second opinion, [is important], so we can help guide treatment and think about [whether patients are] eligible for any of these clinical trials.

What ongoing myelofibrosis clinical trials at Fred Hutchinson Cancer Center are you excited about?

DISC-0974 is in an early-phase trial [NCT05320198]. We don’t have any data yet. However, this trial is open at our center, and it’s interesting. DISC-0974 is a first-in-class anti-HJV monoclonal antibody that is a key regulator of hepcidin production in humans. This is a monthly subcutaneous injection for only 6 injections, and it prevents signaling in the HJV pathway, which results in suppressed hepcidin and improved erythropoiesis. This is [a particular focus in the] issue of anemia in myelofibrosis. This is an add-on agent to a patient’s ruxolitinib, JAK inhibitor, or hydroxyurea. They stay on their baseline treatment, and we add this on for anemia.

These drugs that are [being investigated] and targeting the hepcidin pathway, both in this disease as well as in other myeloid neoplasms, like myelodysplastic syndrome, are exciting. I’m hopeful that this different mechanism of action with non-overlapping toxicities with traditional JAK inhibitors could be an interesting treatment approach for anemia. This trial is currently open, so we are happy to see any patients with anemia on their current therapies.

References

  1. Passamonti F, Foran JM, Tandra A, et al. The combination of navitoclax and ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis mediates responses suggestive of disease modification. Blood. 2022;140(suppl 1):583-585. doi:10.1182/blood-2022-157949
  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. Published online March 7, 2023. doi:10.1200/JCO.22.01972

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Pelabresib Combo Improves Spleen/Symptom Burden in JAKi-Naïve Myelofibrosis

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July 9, 2023

Russ Conroy

Combination treatment with pelabresib (CPI-0610) and ruxolitinib (Jakafi) was well tolerated and demonstrated enduring improvements in spleen and symptom burden among patients with JAK inhibitor treatment–naïve patients with myelofibrosis, according to findings from arm 3 of the phase 2 MANIFEST study (NCT02158858).

At week 24, 68% (95% CI, 57%-78%) of patients who received the combination achieved a spleen volume reduction of at least 35% (SVR35), which included a median SVR of –50% (range, –84% to 28%). Additionally, SVR35 responses at 24 weeks were observed in 70% and 67% of patients with intermediate-1– and intermediate-2– or high-risk disease based on Dynamic International Prognostic Scoring System (DIPSS) criteria, respectively, and 82% and 66% of patients based on International Prognostic Scoring System (IPSS) criteria. Kaplan-Meier estimates indicated that 93.5% (95% CI, 87.4%-99.7%) of those with a SVR35 response maintained their response at 36 weeks after onset.

A total symptom score reduction of at least 50% (TSS50) was reported in 56% (95% CI, 45%-67%) of patients at week 24, with a best TSS50 response at any time of 83% and a median change in TSS of –59% (range, –100% to 225%). Additionally, 43% of patients had a TSS50 response at 48 weeks, which included a median change in TSS of –54.8% (range, –100% to 307.1%).

At 24 weeks, study treatment yielded an absolute change in hemoglobin levels from baseline between –1 and at least 1.5 g/dL in 55% of patients; hemoglobin levels improved in 36% of patients, including a mean change of 1.3 g/dL and a median of 0.8 g/dL. Moreover, 24% of patients had a mean hemoglobin increase of at least 1.5 g/dL from baseline over any 12-week period while forgoing red blood cell transfusions.

“To our knowledge, the MANIFEST trial in JAK inhibitor treatment-naïve patients is the first study with a rational combination of BET [inhibitor] pelabresib and ruxolitinib that showed clinically meaningful durable improvements in splenomegaly and symptoms, was associated with biomarker findings indicating potential disease modification, and demonstrated a generally favorable safety profile,” the study authors stated. “This combination has the potential to improve the standard of care for treatment-naïve patients with myelofibrosis and warrants further investigation.”

Investigators of the global, open-label, nonrandomized phase 2 MANIFEST study evaluated pelabresib in combination with ruxolitinib in a cohort of JAK inhibitor treatment-naïve patients with myelofibrosis. Patients received an initial dose of 125 mg of pelabresib once daily for 14 days followed by a 7-day pause in combination with continuous ruxolitinib twice a day. Patients could receive a maximum pelabresib dose of 175 mg once daily.

The study’s primary end point was SVR35 from baseline to 24 weeks measured by imaging. The secondary end point was TSS50, and exploratory end points included bone marrow fibrosis improvement based on blinded central hematopathologist review following European consensus guideline criteria for reticulin fibrosis grading and improvement in anemia and transfusion requirements.

Patients who had not been exposed to treatment with JAK inhibitors and BET inhibitors and had confirmed diagnoses of primary myelofibrosis, or post–essential thrombocythemia or post–polycythemia vera myelofibrosis were eligible for enrollment on the trial. Additional eligibility criteria included having a spleen volume of at least 450 cm3, intermediate-2– or high-risk disease based on DIPSS criteria, and at least 2 measurable symptoms using the Myelofibrosis Symptom Assessment Form v4.0.

Overall, 84 patients received at least 1 dose of the study treatment, 53 of whom remained on treatment at the time of data cutoff. The median patient age was 68 years (range, 37-85), and 70% were male. Additionally, 24% had intermediate-1, 61% had intermediate-2, and 16% had high-risk disease by DIPSS criteria. In terms of mutations, investigators most frequently observed JAK2V617F (74%), ASXL1 (46%), CALR (21%), and MPL (8%).

Blinded central pathology review of bone marrow samples indicated at least 1 grade improvement in reticulin fibrosis at week 24 in 28% of evaluable patients, including 7% who had improvements of 2 grades. Among 24 patients with grade 1 or 2 reticulin fibrosis at baseline, 4 had worsening conditions, including 2 patients each with grade 1 and 2 fibrosis. Investigators observed no significant relationship between reticulin fibrosis improvement and clinical end points in the study,

Overall, 96% of patients experienced at least 1 treatment-emergent adverse effect (TEAE), and 63% had grade 3 or higher TEAEs. The most frequent hematologic TEAEs included thrombocytopenia (52%) and anemia (42%), and the most common nonhematologic TEAEs included diarrhea (35%), fatigue (33%), musculoskeletal pain (30%), respiratory tract infection (29%), and constipation (25%).

Pelabresib dose reductions were necessary among 37% of patients, and 36% had ruxolitinib dose reductions due to TEAEs. There were 5 deaths during study treatment or within 30 days following the final pelabresib dose, including 4 determined to be unrelated to pelabresib treatment. One patient died to multiorgan failure due to sepsis secondary to pneumonia, which investigators deemed to be related to pelabresib.

Reference

Mascarenhas J, Kremyanskaya M, Patriarca A, et al. MANIFEST: pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve myelofibrosis. J Clin Oncol. Published online March 7, 2023. doi:10.1200/JCO.22.01972

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