Verstovsek Discusses Prognostic Models and Treatment for High-Risk Myelofibrosis

Publication
Article
Targeted Therapies in OncologyMay 2022
Volume 11
Issue 7
Pages: 81

During a Targeted Oncology case-based roundtable event, Srdan Verstovsek, MD, PhD, discussed prognostic models for myelofibrosis and the use of JAK inhibitors as therapy.

Srdan Verstovsek, MD, PhD

United Energy Resources, Inc, Professor of Medicine

Director, Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms

Chief, Section for Myeloproliferative Neoplasms

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Srdan Verstovsek, MD, PhD

United Energy Resources, Inc, Professor of Medicine

Director, Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms

Chief, Section for Myeloproliferative Neoplasms

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Targeted OncologyTM: What prognostic models for myelofibrosis are most commonly used?

VERSTOVEK: There are the IPSS [International Prognostic Scoring System], DIPSS [Dynamic IPSS], and DIPSS-Plus models.1-4 There are others that are much more complicated, like MIPSS70 [Mutation-Enhanced IPSS]. It does require a grade of bone marrow fibrosis and the high molecular risk category; [for example, ASXL1, EZH2, SRSF2, IDH1/2]. Next-generation sequencing is mandatory, and that is not readily done, so it’s complicated. There are versions of these prognostic scoring systems and the MIPSS70-Plus includes cryogenics, as well.5 That’s why you need to go online. There is a website where you can calculate it, but I have not tried this one because it takes time.

There is also the MYSEC-PM [Myelofibrosis Secondary to Polycythemia Vera (PV) and Essential Thrombocythemia (ET)-Prognostic Model], which was specifically developed for secondary myelofibrosis6—and that will be post-PV and post-ET myelofibrosis, of course. This one is not that complicated on purpose. It looks at age, hemoglobin, platelets, blasts, [calreticulin-unmutated genotype]— yes or no—and constitutional symptoms. Dr Francesco Passamonti from Italy made these up from his large database of secondary myelofibrosis.

I asked him, “Where are the other mutations and karyotypes?” He said, “That is too complicated. Nobody does it.” He’s leaning toward simplicity. Still, not too many people [use] the MYSEC-PM.

These are all listed in the guidelines.7 The guidelines do change quite a bit as Dr [Fariborz] Gorouhi said, “Well, we have a younger group of doctors in charge of the NCCN [National Comprehensive Cancer Network] guidelines, and they are up to speed and introduce changes quite often in the guidelines.” For high-risk myelofibrosis, the NCCN guidelines would say that you do look at the symptoms, with the help of MPN-10 [Myeloproliferative Neoplasms Symptom Assessment Form], if possible.7,8 Otherwise, it’s a judgment call about the seriousness of the symptoms.

The second [assessment] is the platelets.7 [The breakpoints for the] platelets are less than 50 × 109/L, 50 × 109/L, or more. If there are more than 50,000 platelets, the guidelines would say [to treat with] ruxolitinib [Jakafi] or fedratinib [Inrebic] and monitor for the resolution of the symptoms and signs. If the patient relapses, then perhaps you use one JAK inhibitor after the other. There are not too many other medications listed in the guidelines, because there are no others approved and there are no other good choices out there to be listed here for this purpose.

What are the most important data from clinical trials of ruxolitinib?

There were 2 studies—COMFORT-I [NCT00952289] and COMFORT-II [NCT00934544]—that studied ruxolitinib.9,10 They randomized ruxolitinib with either placebo or the best available therapy. In these studies, ruxolitinib was markedly superior to the placebo or best available therapy.

The [data were] suggestive of significant benefit in almost all the patients treated with ruxolitinib on the symptoms and spleen [volume], because hardly any patients are primary refractory. The real question is: Why don’t all patients have complete elimination in the spleen? We have a variety of responses. That’s the conundrum here, because [approximately] 97% of the patients have a degree of spleen reduction but to a different degree.9,10 There was a comparison [with] the best available therapy, which was mostly hydroxyurea, in COMFORT-II hydroxyurea [Hydrea] was the best available therapy choice10 and ruxolitinib was better. Usually, it works during the first 3 months. I usually say it happens right away, within 3 to 6 months. This is where you get the best [results] or you don’t, and where you get some adverse events.

The driving force for use of therapies is the presence of symptoms, then symptom improvements. Certainly, they improve on ruxolitinib.9,10 They all improve across the board, and the symptoms get to the maximum improvement within 4 to 8 weeks. It’s the distinction between the benefit of the symptoms vs the effect on the spleen.

Symptoms are controlled to the maximum usually within a month or 2 but the effect on the spleen takes longer— 3 to 6 months. There are other ways of looking at symptomatic improvement using different questionnaires. Certainly, all of them by and large would be showing a symptomatic benefit [with ruxolitinib]. That’s why physicians use ruxolitinib quite often. It’s been around for 10 years, and I use it with satisfaction across the board.

How much does the overall survival impact your decision to prescribe ruxolitinib?

This was a comparison between the patients in the COMFORT-I and COMFORT-II studies together compared with the control.11 The control was no treatment or the best available therapy, where [most] patients crossed over to ruxolitinib. And despite the crossover, you see a difference in overall survival [OS] of [approximately] a year and a half.

What matters most, in terms of getting that survival benefit, is the degree of a spleen response; this is what is tied to that survival benefit.12-14 What we have from the multicenter study in Italy is from everyday practice—no PET scans, MRIs, or ultrasounds, just the palpation. The OS of spleen response at 6 months with half the palpable spleen gone, you see the survival benefit. [To put it simply], it’s like debulking: making the tumor as small as possible and making a difference. The durability of the spleen response [also affects OS]; the smaller it gets, the longer it lasts, and that translates into a survival benefit.

I’m curious about this particular observation because it’s not in only 1 study, it’s at least in 6 or 7 studies so far. I should add that radiographically, COMFORT-I and COMFORT-II have shown the same point by volume.9,10 The smaller the spleen becomes, the better the durability and better OS, but in every practice nobody does this. The palpation data resonate more with what you do in every practice, saying, “Hey, I feel the spleen is smaller. It [may be] half than it was.” Maybe that’s good for the patients as it's going to last longer.

How do treatments with anti-inflammatory effects impact patients?

With early intervention with interferon alfa, when people are not so sick, there certainly is a potential to decrease the burden, perhaps even eliminate malignant clones as we see in PV or ET.

In more advanced cases, anti-inflammatory has more potential than JAK inhibitors [in decreasing the cytokines]. One can call that actual modification of the biology of the disease that leads to, perhaps, a little longer life of the patients—for a year and a half, and some say even longer.

How do JAK inhibitors interact with COVID-19?

It’s anti-inflammatory. There were studies with JAK inhibitors and COVID-19. On the other hand, just to make sure we also know that stopping ruxolitinib, fedratinib, or a JAK inhibitor in patients with MPNs, when they get COVID-19, will worsen their overall outcome. It’s a higher death rate if you suddenly stop the JAK inhibitors in MPNs [affected by COVID-19. It’s] good to know the other side of the coin.

How does the dosage of ruxolitinib affect symptoms and OS?

One issue here is the dose when we aim to, perhaps, do more than only control the symptoms. The total symptom score for 10 mg twice a day is equally effective for control of the symptoms as the higher doses.15 The most common dose used in the community setting in the United States is 10 mg twice a day. You learn from experience.

For the spleen, the higher the dose, the better the spleen response.15 Therefore, if we are to move to control the spleen as much as possible and perhaps give that survival benefit a little more, we would go with a higher dose, or escalate to a higher dose, to get that spleen under control. Certainly, do not go to the lower dose too often. Five mg twice a day is not going to work that well, [it is better to use] at least 10 mg, then higher, if possible.

What is most important to know about the safety profile of ruxolitinib?

We all know about the anemia and thrombocytopenia that happen. But to some degree, [AEs] also determine the dosing because we don’t want to cause worsening of anemia, which happens often if we start with the higher doses.9,10 This contributes to the overall underdosing to some degree.

If the patients have low platelets, there are studies to define which dose to use.16-18 In a case where a patient has a platelet count of 98 × 109/L, perhaps we should consider 5 mg twice a day as a starting point, then go up. That came from these kinds of studies, and this particular study was the EXPAND study [NCT01317875], which says you can start with 10 mg twice a day if you have platelets between 50 × 109/L and 100 × 109/L. Maybe not even 5 mg, but if you start with 5 mg, I hope you go from 5 mg twice a day to 10 mg twice a day and not use daily, because the half-life is very short.

In that study, there was still some thrombocytopenia and anemia, which will happen more than otherwise because you start with lower platelet numbers.16-18 But with the proper management, you can get a good result. Going from a low dose to high dose, you can have good control of the spleen symptoms. That’s happened quite often.

There are studies that show that the same approach is useful in anemic patients [who are] anemic at the very beginning of starting therapy with ruxolitinib. You start with 10 mg twice a day, then go to 15 mg, then 20 mg. It’s safer and you can get the same type of good response as you usually do by starting from the high to low [dose].

What is most important to know about fedratinib?

It was approved in 2019, and [the approval was] based on the JAKARTA study [NCT01437787].19 It randomized to 2 different doses of fedratinib compared with a placebo. This is a very old study, [with] no head-to-head comparison between fedratinib and ruxolitinib.

The results on the spleen response are similar to ruxolitinib; it was a 37% response rate.19 The placebo didn’t do much at all. It was equally effective without statistical numerical difference in patients with platelets below 100 × 109/L, which would be 50 × 109/L to 100 × 109/L. Ruxolitinib and fedratinib cannot be given to patients with platelets below 50 × 109/L. But [for patients with a platelet count of] 50 × 109/L to 100 × 109/L, it was a 36% response rate for the spleen and 49% for those who have a high platelet count, although the starting dose was equal for all patients on the trial—400 mg [daily] without dose adjustments for the low platelets.

However, there are some differences [between ruxolitinib and fedratinib] in toxicity. Diarrhea, nausea, and vomiting happened in two-thirds of the patients.19 We explained this by virtue of this agent also being an FLT3 inhibitor, and most FLT3 inhibitors cause some GI [gastrointestinal] upset, so maybe that’s why this drug causes diarrhea, nausea, and vomiting. Typically, that requires some prophylactic antidiarrhea or antinausea medications. Tell the patients to expect that to happen [and that it] improves over time and hardly any patients eventually stop it. It is something to know.

The degree of anemia and thrombocytopenia is about the same as it is with ruxolitinib.19 There is a black box warning for a very rare complication, which is Wernicke encephalopathy.20 It’s very rare, but it is a black box warning, which means you [must] check for thiamine deficiency, which may happen due to interference of thiamine uptake by fedratinib from the GI tract into the [patients’] body. It can lead to Wernicke encephalopathy, and the thiamine level [must] be checked and supplemented. It’s something that is not the case with any other JAK inhibitors.

REFERENCES

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13. Palandri F, Palumbo GA, Bonifacio M, et al. Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. Oncotarget. 2017;8(45):79073-79086. doi:10.18632/oncotarget.18674

14. Menghrajani K, Boonstra PS, Mercer JA, et al. Predictive models for splenic response to JAK-inhibitor therapy in patients with myelofibrosis. Leuk Lymphoma. 2019;60(4):1036-1042. doi:10.1080/10428194.2018.1509315

15. 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

16. 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

17. Guglielmelli P, Kiladjian JJ, Vannucchi AM, 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. Blood. 2020;136 (suppl 1):4-5. doi:10.1182/ blood-2020-137742

18. 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

19. Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643-651. doi:10.1001/jamaoncol.2015.1590

20. Inrebic. Prescribing information. Bristol Myers Squibb. Accessed May 2, 2022. https://bit.ly/3FbdIcv

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