Category Archives: Myelofibrosis

Transfusion Independence With Momelotinib Impacts OS in Myelofibrosis

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Targeted Oncology Staff

DISCUSSION QUESTION

  • How do the most recent data on Janus kinase (JAK) inhibitors support/change your approach to treating patients?​

DRAUPADI TALREJA, MD: I’m all for momelotinib [Ojjaara]. I was never for ruxolitinib [Jakafi] but there was nothing else available, so I used it.

HARIS ALI, MD: Would you use momelotinib in the majority of your patients or just on certain patients with moderate or severe anemia?

TALREJA: I will use it for them because it reduces the spleen anyway; all [JAK inhibitors] reduce the spleen beautifully. Because it does not cause anemia and can make them transfusion independent, if they have symptoms, a big spleen, and anemia, I have many reasons to use momelotinib. So I’m going to go there, and I’m going to [use less] ruxolitinib.

ALI: Maybe the once-daily dose might be helpful as well.

ARATI CHAND, MD: Was the SIMPLIFY-1 study [NCT01969838] powered for superiority or noninferiority?

ALI: It was powered for noninferiority for [spleen volume reduction] and symptoms, and superiority for the transfusion independence.1

CHAND: What about the adverse event [AE] profile?

ALI: Ruxolitinib has a bit more thrombocytopenia and anemia, and momelotinib has some more gastrointestinal [AEs] and nausea. Otherwise, they were quite comparable.1

CHAND: It looks less toxic compared with ruxolitinib. I would probably change and start using more momelotinib now that is available. Earlier, we didn’t have anything except ruxolitinib and fedratinib [Inrebic]. Pacritinib had such a restricted indication that you could only use it for those patients with very thrombocytopenic myelofibrosis. I think I would definitely start my new patients on momelotinib.

ALI: Would that be regardless of the hemoglobin and platelet count?

CHAND: I think so. It looks like it’s better tolerated. Patients are different, so there may be patients who don’t tolerate this. But in that case, it would make sense to switch and see if they tolerate ruxolitinib better. Efficacy is one thing, but tolerance is also important, especially for treatments that have to be given over prolonged periods of time.

GEORGE HAJJAR, MD: The dosing is also an issue. Adjusting the dose of ruxolitinib is very frequent, depending on the platelet count and hemoglobin level. It’d be interesting to know how many patients got the full dosing of ruxolitinib in that trial vs momelotinib.

ALI: The correct dosing is also important, but it usually goes by the package insert, like 20 mg [twice daily ruxolitinib] for patients with greater than 200 × 109/L platelets, or [15 mg twice daily for patients with between 100 × 109/L and 200 × 109/L platelets].2

HAJJAR: Dose adjustments are always frequent. If we see platelet count drop, we have to tell the patient to decrease the dose, which will be a pain.

ALI: [In the COMFORT-I trial (NCT00952289)], although anemia was a big factor, discontinuation of ruxolitinib because of anemia was in less than 1% of the patients.3 Regardless, patients felt better with the improvement in the symptoms and the spleen symptoms. For whatever reason, that was not the one of the common reasons for discontinuation. I think one of the most common was thrombocytopenia; it wasn’t anemia.

One thing with momelotinib is that it has a lot of drug interactions with OATP1B1/B3 inhibitors, including with statins and different drugs.4 It’s something to watch out for, because hepatic dysfunction was another reason for the hold and [we need to] look at it further. Drug interactions may be the one thing to look out for in a patient, as most of the patients over 65 will be on 5 or 6 different medication for different comorbidities.

CHAND: Was that interaction only for 1 statin or for all statins? Because [many patients] are on a statin now.

ALI: That’s right, so dose reduction might be needed for the statins. There’s a whole drug list with OATP1B1/B3 inhibitors, so you just have to watch for that, but it has more than 1 statin listed there.

DISCUSSION QUESTION

  • How do the overall survival (OS) data influence your choice of therapy?​

ALI: We looked into an OS advantage with ruxolitinib.5 We don’t have too much survival data with [momelotinib] but we do have with the transfusion independence vs non-independence.6 How does that affect your therapy?

TALREJA: I think OS [could be] better with momelotinib. With ruxolitinib, the only good thing is they feel good. It’s their quality of life that helps them live longer. I don’t think ruxolitinib does anything to the bone marrow to reduce the myelofibrosis, so I think momelotinib is a much better drug.

ALI: Would everyone say the same thing about momelotinib for OS compared with other JAK inhibitors including ruxolitinib?

CHAND: I don’t know if you can say that momelotinib has superior OS [based on the trials], but it is basically dependent on transfusion burden. Regardless of what medication you are on, if you’re transfusion dependent, your survival is poor, and if you’re transfusion independent, you’re going to do better in the long run.

ALI: You’re right. Anemia is a big [factor]; if we’ll look at the HR…among all the other risk factors like age or low platelet count, anemia is the biggest factor and transfusion dependence [is based on] patients who are more anemic, so there is definitely poorer survival in those patients.

SWARNA CHANDURI, MD: Is this because this drug works on the hepcidin as an inhibitor? Is that the reason why this is better tolerated and [leads to] less dependence on the transfusions?

ALI: Yes, [inhibiting] the hepcidin pathway, and further reduction to ACVR1 leads to [transfusion independence].7

CHANDURI: If this drug has the additional quality of [ruxolitinib] and improving it, then it is a better drug than ruxolitinib. But the main thing is that is why patients with anemia do better.

References:

1. 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;35(34):3844-3850. doi:10.1200/JCO.2017.73.4418

2. Jakafi. Prescribing information. Incyte; 2021. Accessed December 18, 2023. https://tinyurl.com/3t6dd8jj

3. 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

4. Ojjaara. Prescribing information. GlaxoSmithKline; 2023. Accessed December 18, 2023. https://tinyurl.com/4wc5dmet

5. 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

6. Mesa R, Harrison C, Oh ST, et al. Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. Leukemia. 2022;36(9):2261-2268. doi:10.1038/s41375-022-01637-7

7. Oh ST, Talpaz M, Gerds AT, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020;4(18):4282-4291. doi:10.1182/bloodadvances.2020002662

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Management of Ruxolitinib in MF Allows for Continued Survival Benefit

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Targeted Oncology Staff

In the second article of a 2-part series, Pankit Vachhani, MD, highlights the impact ruxolitinib has had, and continues, to have in treatment for patients with myelofibrosis and how physicians should manage this treatment for their patients.

CASE

  • A 68-year-old woman presented to her physician with symptoms of mild fatigue.
  • Her spleen was palpable 6-7 cm below the left costal margin​.
  • Medical history: No known comorbidities
  • Next-generation sequence testing: JAK2 V617F mutation​
  • Karyotype: 46XX​
  • Bone marrow biopsy: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis​
  • Blood smear: leukoerythroblastosis​
  • Diagnosis: Primary myelofibrosis​ (MF)
  • Dynamic International Prognostic Scoring System: intermediate-1​
  • Mutation-enhanced International Prognostic Score System 70: intermediate risk
  • The patient was not interested in transplant​.
  • A decision was made to initiate ruxolitinib (Jakafi).

Targeted Oncology: For patients with MF, what were their symptom responses while on ruxolitinib (Jakafi)?

PANKIT VACHHANI, MD: The patient’s symptom responses were recorded using different Quality of Life questionnaires from COMFORT-II study [NCT00934544].1 Patients on ruxolitinib did better with overall quality of life or functioning, as well as in some individual categories like pain, fatigue, and dyspnea. We also had data from COMFORT-I [NCT00952289], which used a symptom assessment form, [that showed similar results].2

How did the survival data compare between these 2 trials?

COMFORT-I had an inherent crossover designed into it. After 6 months, or 24 weeks, patients who got placebo could cross over to ruxolitinib, and the majority did so.2 Despite that, [we saw] the overall survival [OS] favored the patients who were originally randomized to ruxolitinib vs those who were originally randomized to placebo. That HR of 0.69 [95% CI, 0.50-0.95; P = .025] tells the story, in this case, and the OS data from COMFORT-II had an HR of 0.48 [95% CI, 0.28-0.85; P = .009]….3 These data are all pointing towards a survival advantage for patients who go on ruxolitinib. It’s important to note that there are survival data, but it was not the primary end point; it was the secondary endpoint, and it has been studied elsewhere as well.

How did the duration of treatment with ruxolitinib impact results for these patients?

[With ruxolitinib, we all ask] when should we begin treatment. Well, this was studied indirectly. The patients who went on the COMFORT studies were pooled together, so all the patients who were on ruxolitinib between these 2 studies were pulled together and [patients given] placebo and best available therapy were pooled on the other side.4 In terms of OS, if ruxolitinib was begun within 12 months of their MF diagnosis, those patients did the best in terms of survival, compared with patients who began ruxolitinib a little bit later, [at least] more than a year after diagnose [odds ratio (OR), 2.08; 95% CI, 1.12-3.90]. That’s an important point, which is [suggesting that] maybe beginning ruxolitinib treatment early might be associated with a better survival outcome. Similarly, the spleen volume responses…were also better for those who begin ruxolitinib earlier rather than later [at 47.6% vs 32.9%, respectively (P = .06)], which is also important to keep in mind [when treating these patients].4

What are the major hematologic adverse events (AEs) physicians should be aware of when using ruxolitinib?

In both COMFORT-I and COMFORT-II, cytopenias were some of the more common AEs. Grade 3/4 anemia, for example, with ruxolitinib was seen in 45% and 42% [of patients] and thrombocytopenia in 13% and 8%, [respectively].1,2 These can be managed through either transfusion, a drug hold, or maybe dose reductions, but the point is that [these AEs are] ruxolitinib related, [possibly due to the] inhibition of the JAK-STAT pathway.

The concern that I’ve heard from many is if [the patient] starts off with anemia, are they not responding as well [to ruxolitinib] compared with those who don’t start off with anemia? Or just the fact that ruxolitinib can cause anemia, does it make the overall outcomes worse? The answer is that ruxolitinib will lead to comparable outcomes, whether [the patient] has anemia or not.2 The spleen responses will be comparable, similarly and the symptom responses will be comparable. The underlying point is that the efficacy is maintained in patients with new onset anemia. We must separate drug-induced anemia of ruxolitinib, with the bad effects of anemia from MF, as these are 2 different types.

References:

1. 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):787-98. doi:10.1056/NEJMoa1110556

2. 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

3. Cervantes F, Vannucchi AM, Kiladjian JJ, et al; COMFORT-II investigators. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013;122(25):4047-53. doi:10.1182/blood-2013-02-485888

4. Verstovsek S, Kiladjian JJ, Vannucchi A, et al. Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT‐I and COMFORT‐II studies. Cancer. 2023;129:1681-1690. doi:10.1002/cncr.34707

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Komrokji Analyzes Strategies to Address Anemia With Ruxolitinib in Myelofibrosis

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Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Rami Komrokji, MD, discussed issues related to dosing and management of patients receiving ruxolitinib for myelofibrosis.

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: 46,XX
  • Bone marrow biopsy results: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
  • Genetic testing results: JAK2 V617F mutation; CALR mutation negative
  • A blood smear result 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 years or younger: intermediate
  • The patient refused stem cell transplant and received ruxolitinib (Jakafi).

Targeted Oncology: What effect did the titrated dose of ruxolitinib have on spleen volume and total symptom score in the COMFORT-I trial (NCT00952289)?

KOMROKJI: The spleen volume [reduction] is dose dependent [Figure 11]. You will rarely see a meaningful spleen reduction at below 10 mg twice a day, and it takes 3 to 4 months. That becomes the challenge. For the patients who [have] borderline [cytopenia], the more you’re going to push those [patients] to get the spleen response, the more they are going to [develop cytopenia]. The symptom improvement can be seen daily at 5 mg or 10 mg twice a day and [comes] faster. You could achieve that with a lower [dosage] than the spleen response [Figure 21]. Ruxolitinib is typically given twice a day because it has a short half-life. Sometimes in real-life practice, especially if the patients [were prescribed] a certain [dosage] of the pill, until we get the other [dosage of the] pill, we sometimes do it once a day or we tell them to cut the pill and do it twice a day. But ideally, it should be done twice daily.

What hematologic toxicities were observed with ruxolitinib in the COMFORT-I and COMFORT-II (NCT00934544) trials?

This drug, in general, is safe. The major issues with ruxolitinib are anemia, thrombocytopenia, and less often neutropenia, and those are very predictable, particularly the anemia. It’s almost a 2 g/dL hemoglobin [level] drop by week 8. If you started somebody with hemoglobin [level] of 13 g/dL…[by] month 2, it will be 11 g/dL. But for many of those patients, their symptoms are better and their spleen [enlargement] is gone, so they don’t mind the 11-g/dL [hemoglobin level]. If somebody started with hemoglobin [level] of 9 g/dL or 8 g/dL and [it is] dropping to 7 g/dL, then they will probably need transfusions.

The only way to mitigate the cytopenia most of the time is dose reductions. Sometimes for anemia, we add ESAs [erythropoiesis-stimulating agents]. The COMFORT-I trial did not allow adding any ESAs. The COMFORT-II trial from Europe had a small subset who had ESA addition.2 Technically, ruxolitinib inhibits the JAK/STAT pathway where erythropoietin signals through, but because it has a short half-life, it’s a reversible inhibition. There is a window of time where the ESA can work. Sometimes we do that in practice to mitigate anemia.

There is no difference in the response based on [grade 3 or 4] anemia, so whether the patients [had anemia] or not, in terms of their spleen and symptoms, they improved.3 Sometimes we used to push the dose before having the newer JAK2 [Janus kinase 2] inhibitors, and I used to struggle with this. The University of Texas MD Anderson Cancer Center [in Houston] had a philosophy of starting the patients on the higher dose even if they [have] transfusion [dependence]; then you back off. We escalated the dosing a little more, but at least the spleen and symptom improvement, even in the setting of anemia, can be achievable. I struggle with rendering somebody [with] transfusion [dependence] especially now that we have other choices.

What else should physicians keep in mind when using ruxolitinib?

If someone gets admitted for pneumonia or surgery, especially if they are on higher dosing and [are] responding, those drugs cannot be stopped cold turkey, particularly ruxolitinib and probably fedratinib [Inrebic] as well, because patients will have rebound cytokines. And if they are sick with pneumonia, they will [risk experiencing] SIRS [systemic inflammatory response syndrome] or septic shock. Even if they are going to surgery, we try not to interrupt if they can take [medication] orally. If your patients are not able to take oral medications, sometimes we bridge them with steroids as they are admitted.

If the case patient’s baseline hemoglobin level of 13 g/dL reduced to below 8 g/dL, is that a sign of ruxolitinib failure or progression?

That’s not typical, but I’ve seen some patients who will get profound cytopenia [later], so whether it’s a red flag or just sensitivity, I don’t know. Sometimes it depends on the timing. If somebody was on ruxolitinib for…a couple of years and I see this anemia, that’s…a red flag [ for] if there is anything changing the disease. If it was the first few months of ruxolitinib, I would assume it’s more likely to be ruxolitinib related. I would try to back off the dosing, [do] the classical things in medicine, make sure that the patient does not bleed [in case] something else was going on. But it will probably be somebody who is more sensitive. With that degree of drop, if I cannot get a spleen response or constitution symptoms relieved with a lower dose than nowadays, sometimes we would consider shifting to other JAK2 inhibitors if it was ruxolitinib related and I could not manage the symptoms with a lower dose.

How do you address the increased risk of skin cancer with ruxolitinib?

There are not very conclusive data, but there are data all over the place that any patients [with myelofibrosis] are at higher risk of skin cancer. For both hydroxyurea [Hydrea] and ruxolitinib, [it’s] a little higher than in patients who were not on treatment.4,5 Practicing in Florida adds another risk factor [for our patients developing skin cancer]. We tell them to get a baseline [dermatology exam] when we are starting and then get surveillance every 6 months. We don’t have many alternatives for treatment because both hydroxyurea and ruxolitinib increase the risk. There is no literature to say it’s dose dependent. I’ve rarely stopped the treatment because most of the time, if you’re doing surveillance, you can detect those early, but I’ve had patients who had bad…squamous cell carcinoma that [required] resection…. I held the treatment and tapered down, not knowing what else to do, because it…was extensive. There is literature, but there is no guidance.

What is the lowest dose of ruxolitinib you would use before making a switch?

The dosing of ruxolitinib is dependent on what I’m trying to achieve. If I’m going for a spleen response, I want them at least to be on 10-mg dosing because I rarely see a spleen response below 10 mg twice daily. [With] symptom improvement and [if] they’re feeling better [with] 5 mg to 10 mg, I settle and may not push the dosing more.

How do you safely switch from ruxolitinib to pacritinib (Vonjo)?

In terms of shifting, there is not much guidance, but we always taper down the ruxolitinib. We don’t stop it. If we’re shifting to pacritinib, [physicians] do different things. We taper down the ruxolitinib and sometimes put them on a bridge of steroids. I’ve had some colleagues who overlapped them in the first couple of weeks. Pacritinib has a much longer half-life, so it takes longer to kick in.6 With ruxolitinib, you see symptom control in a week or 2; with pacritinib, it takes 3 to 4 weeks. The approach is not to stop immediately…. Tapering ruxolitinib is 100% agreed on, particularly if you are stopping because of cytopenias, [but if] the patients were responding, that rebound will be even worse than [for] somebody who’s [experiencing progression]. The alternative strategies are to put them on a steroid bridge or overlap them…for a week or two and then stop the ruxolitinib completely. There is not much guidance if somebody was on pacritinib if you’re bridging them to something else, [and the same applies] with fedratinib. Pacritinib has less or no JAK1 effect, so in my experience, stopping it immediately is more tolerable. You don’t have to taper it. But we do with fedratinib. There are not many data yet with momelotinib [Ojjaara].

For patients who do not respond to management of anemia and require transfusions every 2 weeks, would you be concerned about iron overload?

There is not much literature about iron overloading in myelofibrosis, but it’s [a] very similar story to MDS [myelodysplastic syndrome]. Myelofibrosis is an inflammatory condition, so patients could have a high baseline [level] of ferritin. To [identify] somebody [having] iron overload, you have to get to the threshold of 15 to 20 units of blood transfusions.

The responses to ESA are [fewer] than in MDS because those patients have a higher endogenous serum erythropoietin level; you rarely see responses. There have been studies looking at…combination ruxolitinib/danazol and ruxolitinib/thalidomide…with modest activity.7,8 There is an ongoing phase 3 trial [INDEPENDENCE; NCT04717414] looking at ruxolitinib vs ruxolitinib/luspatercept-aamt [Reblozyl] because in the phase 2 trial [ACE-536-MF-001; NCT03194542], it seemed…that luspatercept can work in myelofibrosis to help with ruxolitinib-induced anemia.9 If patients have lower-risk myelofibrosis or I estimate their survival to be in years and they [have] high transfusion burden, I may consider some iron chelation. The problem [is] that the decision has to be individualized because even in MDS, we do the same because those iron chelations come with their own adverse events and toxicities. The subcutaneous pump is not easy for patients, and the oral ones have renal insufficiency, etc. But in selected cases, you could consider it.

If a patient with baseline hemoglobin level of 8 g/dL receives ruxolitinib and develops transfusion dependence, at what point do you consider it to be ruxolitinib failure?

[With] momelotinib approved, it will probably start taking that area of patients who [have anemia] at baseline because momelotinib does have anemia response in almost 25% of patients.10 I would say [to wait] 3 to 4 months for the main thing you are [managing]. If you’re [managing] the spleen and constitutional symptoms [and] you don’t see the spleen response by 3 to 4 months, then that’s failure. The [time to consider it] intolerance to treatment if they develop profound cytopenias is 2 to 3 months as well. I look at…am I achieving the primary end point? Did I at least reduce the spleen [size] by 25%? Is the patient feeling better at 4 months? If yes, I would continue. The other part I look at is if I make the patient [have] transfusion [dependence], are they having severe cytopenias? Sometimes you can start making the call on that at 2 months.

What approaches to controlling anemia related to myelofibrosis are most promising?

Whatever you use for anemia, [approximately] 30% response is the best [we’ve achieved]. In my experience of patients who [have cytopenia] without any spleen or constitutional symptoms, the most success had been with thalidomide plus prednisone, [where] 1 of 4 patients would respond. But if there was a response, some of the responses were very durable. You do the steroids the first 3 months, you take them off, [and] then you continue to thalidomide. I’ve had patients on [JAK inhibition] for 7 or 8 years. With the newer JAK2 inhibitors, pacritinib and momelotinib, the story is changing a little bit, particularly if they have spleen and constitutional symptoms. Then you are [managing] both. We still have to see data on somebody who [has cytopenia] without any spleen or constitutional symptoms [and] how much they will benefit from something like momelotinib or pacritinib for anemia.

REFERENCES

1. 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

2. McMullin MF, Harrison CN, Niederwieser D, et al. The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis. Exp Hematol Oncol. 2015;4:26. doi:10.1186/s40164-015-0021-2

3. 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

4. Lin JQ, Li SQ, Li S, et al. A 10-year retrospective cohort study of ruxolitinib and association with nonmelanoma skin cancer in patients with polycythemia vera and myelofibrosis. J Am Acad Dermatol. 2022;86(2):339-344. doi:10.1016/j.jaad.2021.10.004

5. Hydrea. Prescribing information. Bristol Myers Squibb; 2021. Accessed November 20, 2023. https://tinyurl.com/dt9v7jft

6. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818

7. Gowin K, Kosiorek H, Dueck A, et al. Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis. Leuk Res. 2017;60:31-35. doi:10.1016/j.leukres.2017.06.005

8. Duan M, Zhou D. Improvement of the hematologic toxicities of ruxolitinib in patients with MPN-associated myelofibrosis using a combination of thalidomide, stanozolol and prednisone. Hematology. 2019;24(1):516-520. doi:10.1080/16078454.2019.1631509

9. Gerds AT, Harrison C, Kiladjian JJ, et al. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis: results from the ACE-536-MF-001 study. J Clin Oncol. 2023;41(suppl 16):7016. doi:10.1200/JCO.2023.41.16_suppl.7016

10. Gerds AT, Verstovsek S, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study. Lancet Haematol. 2023;10(9):e735-e746. doi:10.1016/S2352-3026(23)00174-6

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New therapies against myelofibrosis, a blood cancer that risks evolving into acute leukemia – breaking latest news

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Myelofibrosis is a chronic myeloproliferative neoplasm which every year is diagnosed in approximately one thousand Italians, mostly in their sixties, but many cases occur in young people. There are therapies capable of keeping the disease under control even for years, but two important problems remain open: preventing the disease from evolving into acute myeloid leukemia (this happens in approximately 10% of patients) and preventing excessive enlargement of the spleen, very frequent, which entails serious consequences for patients. A step forward comes from one study presented at the annual meeting of the American Society of Hematology, underway in San Diego (California), whose main author is Francesco Passamonti, director of Hematology at the IRCCS Polyclinic Foundation of Milan: Obtaining a response on the spleen in a high percentage of patients and managing to maintain it for a long time implies well-being for the patient and a greater share of control over the disease – comments the expert -. This is why this result is important.

What is myelofibrosis

Myelofibrosis is a bone marrow disease characterized by the presence of alterations in the blood count (anaemia, thrombocytopenia, leukopenia or leukocytosis), accompanied by an increase in the spleen (splenomegaly) and the presence of symptoms such as fever, night sweats and a drop in weight. a rare pathology that determines the gradual appearance in the bone marrow of a fibrous tissue that no longer allows it to function correctly, with a consequent alteration in the production of blood cells – explains Passamonti – The disease is due to the presence of acquired genetic mutations in the JAK2 genes , MPL and CALR. These mutations determine the clinical manifestations of the disease, also releasing pro-inflammatory substances and a survival advantage for the diseased cells which then populate the marrow and spleen. In the early stages, myelofibrosis remains asymptomatic and the diagnosis may be made incidentally after a blood test performed for other reasons. Most patients are diagnosed in more advanced stages and manifest themselves with even serious symptoms such as anemia, enlargement of the spleen (splenomegaly) and thrombosis. It is therefore important to have new drugs available that can combat more advanced disease.

Enlarged spleen and other symptoms

The enlargement of the spleen affects approximately 8 out of 10 patients and causes symptoms such as digestive difficulties, sensations of heaviness, discomfort in the abdomen, early satiety and alterations in normal intestinal functions. In some cases the spleen is so enlarged that it occupies a large part of the abdomen and compresses the lungs (causing a dry cough). In some cases, its surgical removal is necessary. Other extremely debilitating symptoms, which can prevent you from carrying out normal daily and work activities and having a normal social and relational life, are fatigue or asthenia, a chronic sense of tiredness, to which fever, night sweats, itching can be added. widespread throughout the body (which worsens with contact with water, also known as aquagenic itching) and weight loss due to lack of appetite and digestive difficulties adds Passamonti.

The therapies

The therapies available today make it possible to extend the survival of patients and reduce debilitating symptoms, allowing, in most cases, a return to daily and work activities and a normal social life, but the only treatment that allows for definitive recovery is bone marrow transplant from a healthy donor, reserved for certain phases of the disease, for those in good general condition and under 70-75 years of age. The disease is progressive with an increase in the size of the spleen, a progressive decline in hemoglobin and platelets and increasingly disabling symptoms – says Passamonti -. It can also progress to acute leukemia. Based on the clinical characteristics of the pathology and the age of the patient, the risk of worsening of myelofibrosis is calculated: depending on the level of risk, a decision can be made for simple observation without therapy up to an allogeneic bone marrow transplant. Today, effective drugs such as JAK inhibitors (ruxolitinib and fedratinib) are available in Italy, aimed at those genetic alterations that we know are responsible for the neoplasm, allowing patients to extend their survival and reduce debilitating symptoms, allowing, in most cases, the return to daily and work activities and a normal social life. However, they have limitations: The response of the drugs on the spleen is limited and, even when they work, the validity of the treatment decreases over time – continues the expert -. And the transplant is a complex procedure, which cannot be offered to the majority of patients.

The new TRANSFORM-1 study

In short, we need new treatments that have a greater effect on the spleen and control symptoms in the long term. And they fit into this context data from the TRANSFORM-1 study, presented at the American Hematology Conference. This is a phase three trial (the last before the final approval and entry onto the market of a medicine) which enrolled over 250 patients with myelofibrosis who had not yet received any therapy, but who needed to start one . One half received the current standard treatment (ruxolitinib) and the other half ruxolitinib plus the new drug navitoclax. Navitoclax is an oral therapy which, by hitting a precise target (the BCL-2/BCL-XL proteins which promote tumor activity), causes the death of diseased cells which would otherwise live too long – clarifies Passamonti -. was administered as first line treatment with the goal of shrinking the spleen by more than 35% (measured by nuclear magnetic resonance imaging). The milestone, after six months of treatment, was reached in 63% of patients with the combination navitoclax and ruxolitinib and in 31% of those receiving standard care alone. The response was obtained in 76% and 41% in the two populations respectively. Furthermore, loss of response was recorded in 18% of patients with the combination and in 26% with ruxolitinib alone.

Chronic myeloproliferative neoplasms

In hematology, great progress in the last 20 years has been achieved thanks to the discovery of genetic mutations underlying numerous diseases and often responsible for tumor proliferation, as well as its resistance to treatment – comments Paolo Corradini, president of the Italian Society of Hematology (Sie) -. Scientific research then began to create drugs that only affected DNA alterations, sparing healthy cells. This has also led to important results in chronic myeloproliferative neoplasms, such as myelofibrosis, polycythemia vera (characterized by the progressive increase in red blood cells) and essential thrombocythemia involving the excessive increase in the number of platelets. They are rare diseases, which together cause around a thousand new cases to be recorded in Italy every year. They can accompany the patient for years without worsening, requiring only periodic checks or therapies, more or less aggressive depending on the case. The important role of our country in the TRANSFORM-1 trial demonstrates, once again, the high quality of Italian hematology.

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MorphoSys’ Pelabresib Improves All Four Hallmarks of Myelofibrosis in Phase 3 MANIFEST-2 Study

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Pelabresib and ruxolitinib combination significantly reduced spleen size, with an SVR35 response rate nearly double that of placebo plus ruxolitinib

Showed a strong positive trend in reducing symptom burden and a twofold increase in patients achieving both SVR35 and TSS50 versus placebo plus ruxolitinib

Improved measures of anemia, including higher hemoglobin response rates, fewer patients requiring transfusions and fewer anemia adverse events versus placebo plus ruxolitinib

Improved bone marrow fibrosis by at least one grade in more patients versus placebo plus ruxolitinib

Demonstrated safety results consistent with prior clinical trials, with fewer grade ≥3 adverse events compared with placebo plus ruxolitinib

MorphoSys will host an investor event to review findings on Monday, December 11

MorphoSys AG (FSE: MOR; NASDAQ: MOR) today announced comprehensive results from the Phase 3 MANIFEST-2 study investigating pelabresib, an investigational BET inhibitor, in combination with the JAK inhibitor ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis. These findings were presented in an oral presentation at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.

Myelofibrosis is characterized by four hallmarks: an enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms. In MANIFEST-2, all hallmarks were improved with the pelabresib and ruxolitinib combination versus placebo plus ruxolitinib, which is the standard of care in myelofibrosis. Ruxolitinib dosing was similar in both arms of the study and was determined based on its approved myelofibrosis indication.

“The MANIFEST-2 results demonstrated clear benefits across the four hallmarks of myelofibrosis, including a significant reduction in spleen size – a key finding given the known association between spleen volume reduction and patient survival,” said Raajit K. Rampal, M.D., Ph.D., Director, Center for Hematologic Malignancies, and Director, Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center. “The comprehensive results presented at ASH also show that the pelabresib combination improves anemia, disease-associated symptoms and bone marrow fibrosis, and that it is well-tolerated. These findings point to pelabresib and ruxolitinib as a potential paradigm-shifting first-line treatment of this debilitating disease.”

MANIFEST-2 Comprehensive Findings

MANIFEST-2 is a global, multicenter, double-blind, Phase 3 study of 430 JAK inhibitor-naïve adults with myelofibrosis, randomized 1:1 to receive the pelabresib and ruxolitinib combination or placebo plus ruxolitinib. MANIFEST-2 is one of the largest studies in this disease to date.

Strong Reductions in Spleen Size and Symptoms

In the MANIFEST-2 study, pelabresib and ruxolitinib demonstrated a near doubling in the proportion of patients achieving a ≥35% reduction in spleen volume (SVR35) at 24 weeks, the primary endpoint, versus placebo plus ruxolitinib (p<0.001).

For the first key secondary endpoint assessing symptom reduction, absolute change in total symptom score (TSS) at 24 weeks, there was a strong numerical improvement for patients receiving pelabresib and ruxolitinib versus placebo plus ruxolitinib. The response rate for the second key secondary endpoint, proportion of patients achieving ≥50% reduction in symptom score (TSS50) at 24 weeks, was also numerically greater for patients receiving pelabresib and ruxolitinib. Significant improvements in both key secondary endpoints were observed with the pelabresib combination for patients classified as intermediate-risk (Dynamic International Prognostic Scoring System [DIPSS] Int-1 and Int-2), who account for over 90% of the MANIFEST-2 population.

The proportion of patients achieving both SVR35 and TSS50 at 24 weeks was doubled with pelabresib and ruxolitinib versus placebo plus ruxolitinib (40.2% vs. 18.5%, respectively).

Details are included in the table below.

Endpoint Pelabresib + Ruxolitinib
(N=214)		 Placebo +
Ruxolitinib
(N=216)		 Difference
SVR35 65.9% 35.2% 30.4%*
P-value: p<0.001
Absolute Change in TSS -15.99
(Mean Baseline: 28.26)		 -14.05
(Mean Baseline: 27.36)		 -1.94**
P-value: 0.0545
TSS50 52.3% 46.3% 6.0%*
P-value: 0.216

*Difference calculated using Cochran–Mantel–Haenszel (CMH) common risk difference

**Least square mean estimate

Improvement in Anemia

Patients receiving pelabresib in combination with ruxolitinib reported fewer anemia adverse events (43.9%, grade ≥3: 23.1%) compared with placebo plus ruxolitinib (55.6%, grade ≥3: 36.4%). Additionally, by week 24, fewer patients in the pelabresib and ruxolitinib arm required red blood cell transfusions compared with the placebo arm (30.8% vs. 41.2%, respectively).

A greater proportion of patients achieved a hemoglobin response — defined as a ≥1.5 g/dL mean increase in hemoglobin levels over baseline in the absence of transfusions during the previous 12 weeks — with pelabresib and ruxolitinib versus placebo plus ruxolitinib (9.3% vs. 5.6%, respectively). Average hemoglobin levels were greater in patients receiving pelabresib and ruxolitinib than in those receiving placebo plus ruxolitinib, starting at week 9 and continuing to week 24. Anemia benefits were observed across all studied patient risk groups.

“Anemia can reduce patients’ quality of life by causing severe fatigue and necessitating blood transfusions,” said Professor Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom. “In MANIFEST-2, patients receiving the combination therapy showed clear benefits on anemia, including greater hemoglobin levels, fewer red blood cell transfusions and fewer anemia and fatigue adverse events. Given its strong efficacy, safety profile and signs of disease modification, the pelabresib and ruxolitinib combination has the potential to become the new standard of care in the first-line treatment of myelofibrosis.”

Improvement in Bone Marrow Fibrosis

Bone marrow fibrosis, or the replacement of bone marrow with fibrous scar tissue, is a central pathological feature of myelofibrosis. In MANIFEST-2, fibrosis was improved by at least one grade in a greater proportion of patients receiving pelabresib and ruxolitinib (38.5% vs. 24.2% with placebo plus ruxolitinib) and worsened by at least one grade in a smaller proportion of patients receiving pelabresib and ruxolitinib (16.3% vs. 28.3% with placebo plus ruxolitinib) at 24 weeks. Bone marrow fibrosis is graded on a scale from 0 (normal) to 3 (most severe) based on fiber density; studies suggest a correlation between the grade of bone marrow fibrosis and patient prognosis.

Biomarker Analysis Suggests Disease Modification

In a biomarker analysis, average plasma levels of inflammatory cytokines (IL-8, IL-6, TNF-α and NF-κB-regulated cytokines) were reduced in patients receiving pelabresib and ruxolitinib compared with placebo plus ruxolitinib at 24 weeks. Increased cytokine levels are associated with all four disease hallmarks; increased IL-8 levels are also associated with worse survival outcomes. These biomolecular improvements suggest early evidence of a disease-modifying effect.

Well-Tolerated Safety Profile

Overall, grade ≥3 treatment-emergent adverse events (TEAEs) were reported less frequently with pelabresib and ruxolitinib than with placebo plus ruxolitinib (49.1% vs. 57.5%, respectively).

In the pelabresib and ruxolitinib arm, the most common (≥10%) hematologic TEAEs were anemia (43.9%; grade ≥3: 23.1%), thrombocytopenia (32.1%; grade ≥3: 9.0%) and platelet count decrease (20.8%; grade ≥3: 4.2%). In the placebo plus ruxolitinib arm, the most common hematologic TEAEs were anemia (55.6%; grade ≥3: 36.4%), thrombocytopenia (23.4%; grade ≥3: 5.6%) and platelet count decrease (15.9%; grade ≥3: 0.9%).

The most common (≥10%) nonhematologic TEAEs in the pelabresib and ruxolitinib arm were diarrhea (23.1%; grade ≥3: 0.5%), dysgeusia (18.4%; grade ≥3: 0.5%), constipation (18.4%; grade ≥3: 0%), nausea (14.2%; grade ≥3: 0.5%), cough (12.7% grade ≥3: 0), asthenia (11.8% grade ≥3: 0.5%), fatigue (11.8%; grade ≥3: 0.5%), dizziness (11.3%; grade ≥3: 0%), headache (11.3% grade ≥3: 0.5%) and COVID-19 (11.3%; grade ≥3: 0%). The most common nonhematologic TEAEs in the placebo plus ruxolitinib arm were constipation (24.3%; grade ≥3: 0%), diarrhea (18.7%; grade ≥3: 1.4%), fatigue (16.8%; grade ≥3: 0.9%), COVID-19 (15.9%; grade ≥3: 1.9%), nausea (15.0%; grade ≥3: 0%), asthenia (13.6%; grade ≥3: 0%), dyspnea (13.1%; grade ≥3: 0.9%), cough (11.2%; grade ≥3: 0%) and headache (10.7%; grade ≥3: 0%). Discontinuation rates due to adverse events were 10.7% with pelabresib and ruxolitinib and 6.5% with placebo plus ruxolitinib.

The safety profile of the pelabresib and ruxolitinib combination therapy was consistent with previous clinical studies. No new safety signals were observed.

“The four hallmarks of myelofibrosis – enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms – have a strong impact on a patient’s life. In MANIFEST-2, the combination of JAK and BET inhibition addressed all four of these hallmarks with the potential to modify the course of the disease,” said Tim Demuth, M.D., Ph.D., MorphoSys Chief Research and Development Officer. “We are confident that the comprehensive data package will provide impactful insights into the promising and well-tolerated combination of pelabresib and ruxolitinib. Our goal now is to bring this first-line therapy to patients with intermediate- and high-risk myelofibrosis as quickly as possible. We look forward to meeting with regulatory agencies regarding these data and are diligently preparing regulatory filings with the intention of submitting applications to the U.S. Food and Drug Administration and the European Medicines Agency in the middle of 2024.”

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Karyopharm Shares Data at ASH 2023 Showing Strong SVR and TSS Durability Observed from Phase 1 Study of Selinexor 60mg and Ruxolitinib in JAK Inhibitor (JAKi)-Naïve Myelofibrosis Patients, with no SVR or TSS Progressions Observed As of the Data Cutoff(1)

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Biomarker Data from Phase 1 Study of Selinexor in Combination with Ruxolitinib in Treatment-Naïve Myelofibrosis (MF) Suggestive of Disease Modification

Data Reinforce the Potential for Selinexor in Combination with Ruxolitinib to Become a Novel, First-Line Treatment for JAKi-Naïve Patients with MF

NEWTON, Mass., Dec. 10, 2023 /PRNewswire/ — Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced long-term follow up of treatment-naïve patients with myelofibrosis (MF) who participated in the Phase 1 portion of its study evaluating once-weekly selinexor in combination with ruxolitinib (NCT04562389). The data, featured in an oral presentation at the 65th American Society of Hematology Annual Meeting and Exposition (ASH 2023), show patients treated with 60mg selinexor, and who achieved ≥35% reduction in spleen volume (SVR35) at week 24, continued to remain in radiographic response. In addition, all patients who achieved TSS50 at Week 24 remained in response as of the data cut-off.

The data included in the oral presentation for ASH 2023 were based on the Phase 1 portion of the Phase 1/3 study evaluating the safety and efficacy of once-weekly selinexor in combination with ruxolitinib in patients with treatment-naïve MF (NCT04562389). As of August 1, 2023, 24 patients had been assigned to either selinexor 40mg (N= 10) or 60mg (N=14), in combination with ruxolitinib. The maximum duration of follow-up was 78 weeks with a median duration of 32 weeks for SVR35 durability, and a maximum duration of follow-up was 64 weeks with a median duration of 51 weeks for TSS50 durability.

An exploratory biomarker analysis showed a reduction of variant allele frequency (VAF) at week 24 for all three MF driver genes (CALR, MPL, and JAK2) and rapid and sustained reduction of pro-inflammatory cytokine production. Early cytokine reduction at Week 4 was associated with spleen volume reduction (SVR) at Week 24 and was sustained until the end of treatment. The clinical efficacy associated with biomarkers impacting MF biological hallmarks may suggest disease modification.

“The growing body of data from this study suggests that selinexor in combination with ruxolitinib may provide spleen reduction, symptom improvement, long-term durability and disease modification, expanding the benefit this combination may provide to patients with treatment-naïve myelofibrosis, ” said Reshma Rangwala, MD, PhD, Chief Medical Officer of Karyopharm. “We’re excited about the potential to change treatment paradigms for these patients – and expand the number of patients who benefit from first-line therapy.”

The safety profile was consistent with previous data cuts with no new safety signals observed as of Aug 1st.

“The current standard of care is not associated with consistent molecular or pathologic responses,” said Dr. Sri Tantravahi, University of Utah. “The long-term findings are very exciting as they underscore the potential for durable, clinically relevant responses and modification of disease course. The wait for new options has been long and difficult for the myelofibrosis community, and we welcome this important research to help advance the understanding of XPO1 and JAK inhibitor combinations as a meaningful treatment option for patients.”

“We are encouraged by the attention MPNs (Myeloproliferative Neoplasms) are getting in recent years from companies like Karyopharm,” said Kapila Viges, Chief Executive Officer of MPN Research Foundation. “With patients waiting for more answers to these chronic yet serious blood cancers, we look forward to the data readouts at ASH this year. Efforts to develop better therapies and now combinations of therapies bring hope to the myelofibrosis community and open the potential for more options in the treatment paradigm. For patients, options matter.”

About XPOVIO® (selinexor)

XPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor and the first of Karyopharm’s Selective Inhibitor of Nuclear Export (SINE) compounds to be approved for the treatment of cancer. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in multiple oncology indications, including: (i) in combination with Velcade® (bortezomib) and dexamethasone (XVd) in patients with multiple myeloma after at least one prior therapy; (ii) in combination with dexamethasone in patients with heavily pre-treated multiple myeloma; and (iii) in patients with diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. XPOVIO (also known as NEXPOVIO® in certain countries) has received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including but not limited to the European Union, the United Kingdom, China, South Korea, Canada, Israel and Taiwan. XPOVIO and NEXPOVIO is marketed by Karyopharm’s partners, Antengene, Menarini, Neopharm and FORUS in China, South Korea, Singapore, Australia, Hong Kong, Germany, Austria, Israel and Canada.

Please refer to the local Prescribing Information for full details.

Selinexor is also being investigated in several other mid- and late-stage clinical trials across multiple high unmet need cancer indications, including in endometrial cancer and myelofibrosis.

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Navitoclax Combo Significantly Reduces Spleen Volume in Myelofibrosis

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Silas Inman

Combining navitoclax with ruxolitinib produced significant reductions in spleen volume by at least 35% at week 24 (SVR35W24) compared with ruxolitinib plus placebo but did not lead to significant changes in total symptom score (TSS) in those with myelofibrosis, according to data from the phase 3 TRANSFORM-1 study (NCT04472598) presented during the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.1

After a median follow-up of 14.9 months (range, 0.0-29.5), navitoclax and ruxolitinib elicited a SVR35W24 for 63.2% of patients compared with 31.5% for placebo plus ruxolitinib, marking a significant overall difference of 31.0% (95% CI, 19.5%-42.5%; P <.0001). At week 24, there was a mean -9.7 change in TSS with navitoclax/ruxolitinib from baseline (95% CI, -11.8 to -7.6) compared with a change of -11.1 for placebo plus ruxolitinib (95% CI, -13.2 to -9.1), which was not statistically significant (P = .2852).

“The spleen volume reduction was doubled and highly statistically significant. There’s no question there, but for the secondary end point, the total symptom score, both groups have the reduction, but it was not statistically significant,” said lead investigator Naveen Pemmaraju, MD, Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “There may be multiple reasons for that. Ruxolitinib alone is a nice drug for symptom improvement, but when you add in a second drug, you’re improving the outcomes for the patient but maybe introducing a bit more toxicity. The statistical significance may not have come out because of that.”

Oral navitoclax is a BCL-XL, BCL-2, and BCL-W inhibitor, which may impart unique efficacy for myeloproliferative neoplasms (MPN). “It turns out in MPN and myelofibrosis that the BCL-XL pathway appears to be a bit more important than the BCL-2,” said Pemmaraju. “In myelofibrosis, BCL-XL appears to be upregulated and so in vitro studies showed that either the navitoclax by itself or even better in combination with the ruxolitinib can overcome JAK resistance and add benefit.”

In the combination arm, navitoclax was administered at a starting dose of 200 mg if platelet counts were above 150 x 109 per liter or, if not, at 100 mg, which was later escalated to 200 mg if tolerated and after platelet counts reached greater than 75 x 109 per liter. This methodology was implemented to avoid thrombocytopenia, which was observed in earlier trials with the agent. Ruxolitinib was administered at the standard dose in each arm, although Pemmaraju noted with necessary dose reductions the relative dose intensity was lower. There were 125 patients in the combination arm and 127 in the control group.

In the combination arm, the median age of patients was 70 years (range, 42-87) compared with 69 years (range, 37-85) in the control group. The time from diagnosis to study entry was 8 months (range, 0.3-181.6) in the combination arm and 6 (range, 0.3-198.8) in the control group. Most patients had primary myelofibrosis, at 50% in the investigational arm and 57% in the control group. Other types included transformed version of myelofibrosis, namely those post polycythemia vera and post-essential thrombocythemia. The median spleen volume at entry was 1441 cm3 (range, 419-8020) in the combination group and 1639 cm3 (range, 219-5664) in the control arm.

The median TSS in the combination arm was 21 (range, 0.1-60.6) compared with 24 (range, 6.7-61.6) in the control group. A minority of patients were transfusion dependent at baseline, at 4% in the combination group and 3% in the control arm. The most common risk score was intermediate-2, at 83% in the combination group and 87% in the control. JAK2 V617F was the most common driver mutation, with approximately two-thirds having this mutation in each group. Nearly half of patients had mutations associated with high molecular risk. “These high molecular risk mutations are very important,” said Pemmaraju. “Earlier studies may not have captured this, and we were fortunate to capture this in the majority of patients.”

There was a significantly higher rate of SVR35 with the combination at all time points throughout the study. Across the full-time scale of the study, 76.8% of those in the combination arm experienced a SVR35 compared with 41.7% with ruxolitinib plus placebo, which was a meaningful 34.6% reduction (95% CI, 23.6%-45.6%; P <.0001). The median time to first SVR35 response was similar between groups, at 12.3 (range, 10.1-48.3) vs 12.4 (range, 11.3-72.3) weeks, for the combination and control arms, respectively. Fewer patients lost SVR35 in the combination group (18.8%) compared with the control arm (26.4%). Nearly three-fourths of patients had a 12-month duration of SVR35 in each arm (76.7% vs 76.9%, combination and control, respectively).

The rate of any grade adverse effect (AE) was common between arms, with more patients in the combination arm having a grade 3 or higher AE (85% vs 70%). The most common grade 3 or higher AEs in the combination vs control arms, respectively, were thrombocytopenia (51% vs 15%), anemia (46% vs 39%), and neutropenia (38% vs 4%). For all grade events, diarrhea was more commonly seen with the combination vs control (34% vs 14%). Serious AEs were less common with the combination at 26% compared with 32% for the control arm. AEs that led to dose reduction or dose interruption were twice as common in the combination arm.

“Importantly, dose reductions and interruptions were mostly due to the thrombocytopenia, but importantly none of those were due to clinical bleeding,” said Pemmaraju.

In 2022, AbbVie, the company developing navitoclax noted plans for a submission to the FDA in 2023, pending pivotal study results.2 At this time, the agent is not approved.

References

  1. Pemmaraju N, Mead AJ, Somervaille T, et al. Transform-1: a randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Blood. 2023;142(suppl 1):620.doi:10.1182/blood-2023-173509
  2. AbbVie presents positive investigational navitoclax combination data in phase 2 REFINE study suggesting anti-fibrosis activity for patients with myelofibrosis. News release. AbbVie. April 12, 2022. Accessed December 10, 2023. https://news.abbvie.com/2022-04-12-AbbVie-Presents-Positive-Investigational-Navitoclax-Combination-Data-in-Phase-2-REFINE-Study-Suggesting-Anti-Fibrosis-Activity-for-Patients-with-Myelofibrosis

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Study yields ‘encouraging’ preliminary data for navitoclax combination in myelofibrosis

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December 11, 2023

Key takeaways:

  • Navitoclax plus ruxolitinib led to improvement in spleen volume reduction in patients with untreated myelofibrosis.
  • Adverse events of thrombocytopenia and anemia appeared common but manageable.

SAN DIEGO — Navitoclax added to ruxolitinib led to a significant improvement in spleen volume reduction compared with placebo among patients with untreated myelofibrosis, study results presented at ASH Annual Meeting and Exposition showed.

Findings from the phase 3 TRANSFORM-1 study suggest the combination therapy has a manageable safety profile that appeared consistent with the use of both agents in previous studies, according to researchers.

“The is the first randomized trial in JAKi-naive [myelofibrosis] with a navitoclax and ruxolitinib combination, which led to a in spleen volume reduction 35% at week 24 twice as high as placebo plus ruxolitinib, with similar symptom response despite a lower average dose of ruxolitinib,” Naveen Pemmaraju, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, said during a presentation.

Background and methodology

The double-blind TRANSFORM-1 study assessed the efficacy and safety of navitoclax (AbbVie) — and investigational Bcl-2 inhibitor — plus the JAK2 inhibitor ruxolitinib (Jakafi, Incyte) compared with placebo plus ruxolitinib among adults with JAK2 inhibitor-naive myelofibrosis.

Inclusion criteria included adults with intermediate- or high-risk myelofibrosis with measurable splenomegaly, evidence of myelofibrosis-related symptoms, no prior JAK2 inhibitor treatment, and an ECOG performance score less than or equal to 2.

Researchers randomly assigned patients in a 1:1 ratio to ruxolitinib plus either navitoclax or placebo.

Spleen volume reduction 35% at week 24 served as the study’s primary efficacy endpoint. Secondary endpoints included change in total symptom score at week 24, spleen volume reduction 35% at any time, duration spleen volume reduction 35%, anemia response, reduction in marrow fibrosis, OS, leukemia-free survival, reduction in PROMIS Fatigue scale and improvement in EORTC QLQ-C30 physical functioning scale.

The study included 252 patients (125 received navitoclax and ruxolitinib, 127 received placebo plus ruxolitinib; median age, 69 years; 57% male) with a median follow-up of 14.9 months (0 – 29.5 months).

Results and next steps

Researchers reported that 79 patients (63.2%) in the investigative arm achieved spleen volume reduction 35% at week 24, compared with 40 patients (31.5%) in the control arm, thus meeting the study’s primary efficacy endpoint. Additionally, researchers noted that 96 patients (77%) in the investigative arm achieved spleen volume reduction 35% at any time, whereas 53 patients (42%) did so in the control arm.

Median duration of spleen volume reduction 35% had not been reached in the investigative arm compared with 19.4 months (95% CI, 16.8 months to not yet reached) in the control arm.

Researchers observed grade 3 or higher adverse events among 85% of patients in the navitoclax arm and for 70% of patients in the placebo arm. The most common adverse events among patients receiving navitoclax included thrombocytopenia, anemia, diarrhea, and neutropenia.

Additionally, 26% of patients in the navitoclax arm and 32% of patients in the placebo arm experienced serious adverse events, including anemia, thrombocytopenia and neutropenia.

With navitoclax treatment, adverse events led to a dose reduction of the agent in 101 patients (81%) and treatment interruption in 87 patients (70%).

Among enrolled patients, 83 (33%) discontinued study treatment. The most common reason for discontinuation included adverse events (n=32; 39% of discontinuations) and physician decision (n=14; 17% of discontinuations). Thirteen patient deaths occurred in each study arm.

“Adverse events of thrombocytopenia, anemia and neutropenia were common but manageable with dose modification without any clinically significant sequelae,” Pemmaraju said. “Preliminary data are encouraging and additional evaluations are ongoing to assess additional outcomes of overall survival and responses in subgroups.”

Source: 

Pemmaraju N, et al. Abstract 620. Presented at: ASH Annual Meeting and Exhibition; Dec. 5-9, 2023; San Diego.

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Megakaryocytes Derived PF4 a Key Driver of Myelofibrosis

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By Rob Dillard

December 12, 2023

Megakaryocytes (Mks) derived PF4 play an important role in the progression of myelofibrosis, according to a study that will be presented at the 65th ASH Annual Meeting & Exposition, which is taking place December 9-12 in San Diego, California.

“Previous research has shown that [Mks] play a role in myeloproliferative neoplasm (MPN) pathology by promoting inflammation and extracellular matrix deposition by activated stromal cells. However, the specific factors derived from Mks that contribute to the inflammatory milieu and myelofibrosis progression are not well defined,” the researchers wrote. In this study, they sought to determine which events drive bone marrow (BM) fibrosis via abnormal MK-stromal cross talk.

To conduct their analysis, Alessandro Malara and colleagues induced myelofibrosis in mice via injections of thrombopoietin-mimetic romiplostim (TPOhigh). Then, they isolated and assessed Mks, BM cells, and platelets from TPOhigh and control mice (injected with saline). They also analyzed protein extracts and cytokine levels in the plasma and BM cell-free fluids of treated mice.

To assess fibrosis-related markers, the investigators evaluated the expression of 2 myofibroblasts markers (a-SMA and vimentin), both in mouse embryonic fibroblasts (mEFs) and human BM mesenchymal stromal cells after stimulation with recombinant PF4 using Western blot.

The findings demonstrated that signaling pathways related to cytoskeletal reorganization, cell adhesion, and inflammation were commonly activated in the Mks, platelets, and BM cells of TPOhigh mice versus the saline-injected control mice. Among the differentially expressed proteins, chemokinePF4/Cxcl4 was upregulated exclusively in the proteasomes of the TPOhigh mice. Importantly, the investigators noted that the findings show these mechanisms were interconnected during Mk-mEF cross talk.

“Our findings identify a crucial role of Mk derived PF4 in the fibrosis progression of MPN, providing further support for the potential therapeutic strategy of neutralizing PF4,” the researchers concluded.

Reference

Malara A, Capitanio D, Calledda F, et al. Proteomic screening identifies megakaryocyte derived PF4/Cxcl4 as a critical driver of myelofibrosis. Abstract #1793. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

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Navitoclax with Ruxolitinib Improves Myelofibrosis with Manageable Safety

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By Patrick Daly

December 6, 2023

Ruxolitinib combined with navitoclax induced spleen volume reduction of ≥35% at week 24 (SVR­35W24) at a rate twice as high as with ruxolitinib and placebo in Janus kinase (JAK) inhibitor–naïve patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis (MF), according to authors of the ongoing phase III TRANSFORM-1 study.

The study, evaluated the doublet therapy to address “a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival” in patients with MF, according to lead author, Naveen Pemmaraju, MD, of the University of Texas MD Anderson Cancer Center in Houston. Findings were presented at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

The cohort included 252 patients with a median age of 69 (range, 37–87) and intermediate-2 or high-risk MF with splenomegaly, signs of MF-related symptoms, no prior JAK2 inhibitor therapy, and an Eastern Cooperative Oncology Group performance score of 2 or less.

The primary outcome was SVR­35W24, and secondary outcomes included change in Myelofibrosis Symptom Assessment Form total symptom score (TSS) at week 24, SVR­35 at any time, SVR­35 response duration, anemia response, reduction in marrow fibrosis, overall survival, leukemia-free survival, reduction in fatigue, and improvement in physical functioning at the data cutoff of April 13, 2023.

Investigators noted 79 of 125 (63.2%) patients in the navitoclax group achieved SVR­35W24 compared with 40 of 127 (31.5%) in the placebo group (P<0.0001). Furthermore, 96 (77%) patients on navitoclax achieved SVR­35 at any time compared with 53 (42%) patients on placebo.

The median time to SVR response was 12.3 weeks (range, 10.1–48.3) in the navitoclax group versus 12.4 weeks (range, 11.3–72.3) in the placebo group. Patients in the navitoclax group had a mean change from baseline in TSS of –9.7 (95% CI, –11.8 to –7.6) at week 24, whereas patients in the placebo group had a mean change of –11.1 (95%CI, –13.2 to –9.1; P=0.2852).

Adverse events (AEs) of grade 3 or higher occurred in 85% and 70% of navitoclax and placebo patients, respectively. The most common AEs in greater than 30% of patients on navitoclax were thrombocytopenia, anemia, diarrhea, and neutropenia.

Serious AEs occurred in 26% of patients in the navitoclax and 32% of patients in the placebo group, including anemia in two and one patients, respectively, as well as thrombocytopenia and neutropenia in two and one navitoclax patients. Overall, 39% of navitoclax or placebo discontinuations were due to AEs, and 17% were due to a physician’s decision.

Overall, “the responses were durable; AEs of thrombocytopenia and anemia were common but manageable with dose modification without any clinically significant sequalae,” the authors summarized.

Reference

Pemmaraju N, Mead AJ, Somervaille TCP, et al. A randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Abstract #620. Presented at the 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

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