Verstovsek Discusses JAK Inhibitor Choices for Patients With Myelofibrosis

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 Oncology^TM: How would you approach treatment for a patient with higher-risk myelofibrosis?

VERSTOVSEK: The NCCN [National Comprehensive Cancer Network] guidelines for the treatment of patients with high-risk myelofibrosis recommend assessing the symptoms and signs, determining the prognosis, and then referring patients to transplant.¹ If platelet levels are above 50 × 10⁹ /L [and the patient is not a candidate for transplant], then Janus kinase [JAK] inhibitors, ruxolitinib [Jakafi] or fedratinib [Inrebic], are recommended.

What is the evidence for the use of ruxolitinib in this setting?

There were 2 phase 3 trials that led to the approval of ruxolitinib. The first one, COMFORT-I [NCT00952289], was a randomized study between ruxolitinib and placebo.² The second one, COMFORT-II [NCT00934544], compared ruxolitinib with the best available therapy, with most of [those] patients receiving hydroxyurea.³

The results from both trials showed a favorable spleen response.^2,3 That’s why we use it. There was [an approximately] 42% response rate in the spleen in COMFORT-I [odds ratio, 134.4; 95% CI, 18.0-1004.9; P < .001], with the majority of patients experiencing some degree of improvement from baseline.² I believe the definition of response was artificial at a 35% volumetric reduction in the spleen, which is [approximately] half of the spleen gone by palpation, and I think any decrease from baseline should be considered a response. I’m happy that most [patients] responded.

Similar results were seen in COMFORT-II, [with 97% of patients on ruxolitinib having a decrease in spleen volume compared with 56% of those on the] best available therapy, where hydroxyurea was the No. 1 choice.³ That’s why we usually say that JAK inhibitors are our first choice at the first symptoms and signs of the disease. We still use hydroxyurea for patients with high white blood cell count or high platelets in earlier stage of myelofibrosis. However, if we have to control the spleen symptoms then JAK inhibitors are better.

Another benefit seen with ruxolitinib was symptom improvement, which closely follows the improvement in the spleen.^2,3 Symptom improvement happened rapidly; in a month or 2, there was maximum symptom benefit. The effect on the spleen, on the other hand, usually takes a few months.

An important aspect to take into consideration is the survival benefit. We may argue about changing the natural history of the disease through bone marrow fibrosis change or allele burden change, but ultimately what matters is how long [patients] live. With an additional 4 months of follow-up after the primary analysis, the median OS [overall survival] of the pooled data from both COMFORT studies, comparing the survival of the patients who were exposed to ruxolitinib from the beginning to those who were in the control arms and who switched to ruxolitinib after a few months, shows an extension of life of [approximately] a year and a half [5.3 years (4.7- not estimable) vs 3.8 years (3.2-4.6); HR, 0.70; 95% CI, 0.54-0.91; P = .0065].⁴

In 2014, the FDA added this to the label, saying that ruxolitinib possibly can improve the survival.⁵ [Although] this survival benefit is not indicative of a cure, ruxolitinib does seem to make [patients] feel good for a little longer and that’s a very good first step.

How do these trials relate to community and real-world use of ruxolitinib? What role does dosage play?

A study from Italy reported the experience of 284 patients in the community setting.⁶ No MRIs or CT scans were done to assess the response, just palpation. There was a significant benefit in the OS by spleen response, 50% of the spleen gone by palpation [P = .04]. This is similar to the results from the clinical studies, and there are… 6 or 7 papers that point to the same connection. The smaller the spleen becomes, the longer the [patients] live. Some patient characteristics that influence how well they do include [therapy delayed for a long time], advanced disease, huge spleen, very high white blood cell count, and the dose.^7,8 One that I’m very sensitive about is the dose.

Results from COMFORT-I also showed that there is a clear-cut connection between the spleen response and the ruxolitinib dose [5 mg to 12.5 mg twice daily].⁹ The higher the dose, the better the spleen response and the possibility to live longer. The high dose debulks the disease as much as possible. On the other hand, there was no connection in terms of quality-of-life improvements.⁹

If the goal is to control just the quality of life, 10 mg twice a day is the maximum needed. That is what I see in the community setting, the preferred starting dose for most of the doctors. However, for maximum reduction in spleen size, one should go up. A higher dose may cause more myelosuppression and [patients] don’t like that. There is a 50% chance to cause grade 3 or 4 anemia, and [approximately] a 15% chance of significant thrombocytopenia.^2,3 Anemia is a problem….My preferred strategy is to start with a cautionary approach at 10 mg twice a day and then perhaps build the dose up.

The same strategy should be followed with patients who have low platelets [as in the phase 1b EXPAND study (NCT01317875)],¹⁰ as recommended in the guidelines.¹ Perhaps we should borrow the experience of how we treat patients with low platelets, starting with a low dose and building it up. For example, start with 5 mg twice a day, then increase to 10 mg twice a day, and so on. Maybe we could also apply that to the patients with anemia. It is simpler and easier. There is a lot of emphasis on these patients who have lower platelets because if they are on a low dose and are not escalated, they don’t do well. The median duration of therapy for patients with platelets below 100 × 10⁹/L is usually less than a year. Platelet numbers are prognostically important, so the outcome for these patients is not satisfactory. There is evidence of a significant lowering of platelets, but the cautionary approach can still work.¹¹ There was approximately a 30% response rate in [both] the spleen and symptom improvement.¹⁰

What is the evidence for the use of fedratinib in patients with primary or secondary myelofibrosis? How does it differ from ruxolitinib?

Fedratinib was approved 2.5 years ago.¹² This approval was based on the results from the phase 3 JAKARTA trial [NCT01437787] that compared 2 different doses of fedratinib [400 mg and 500 mg] vs placebo.¹³ The approved dose is 400 mg daily with no dose escalations. There was a 37% response rate, which, without a head-to-head comparison, is [approximately] the same as with ruxolitinib.^13,14

However, there are differences between the 2 drugs in terms of adverse events. Fedratinib can cause anemia and thrombocytopenia to a similar degree as ruxolitinib. There is also a degree of gastrointestinal [GI] irritation, low-grade diarrhea, nausea, and vomiting,¹⁴ probably because it is an FLT3 inhibitor. Giving patients anti-nausea or anti-diarrheal medications controls those problems. But the difference between the 2 is in these nonhematological adverse events. The other difference is a black box warning for a very rare condition, Wernicke encephalopathy.¹⁵ This happens because fedratinib interferes with the uptake timing from the GI tract and time in deficiency may cause Wernicke encephalopathy.¹³ Therefore it is necessary to check the time and level before prescribing and occasionally during therapy with fedratinib to maintain it within normal limits.

The NCCN guidelines suggest that they are equally positioned in the frontline setting and they do allow for one to be used after the other.¹ I would say that for patients with a good bone marrow reserve, without too much anemia or thrombocytopenia, fedratinib may provide a very good benefit. Another possibility for frontline use of fedratinib is in patients with low platelets.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 1.2022. Accessed March 23, 2022. https://bit.ly/2Wcczfa}

_{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. 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}

_{4. 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}

_{5. Jakafi. Prescribing information. Incyte; 2011. Accessed March 22, 2022. https://bit.ly/3Ns5H71}

_{6. 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}

_{7. 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}

_{8. 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}

_{9. 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}

_{10. 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}

_{11. Guglielmelli P, Kiladjian J, 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. Presented at the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual.}

_{12. FDA approves fedratinib for myelofibrosis. News release. FDA. August 16, 2019. Accessed March 23, 2022. https://bit.ly/3dErcBr}

_{13. 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}

_{14. Pardanani A, Tefferi A, Masszi T, et al. Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Br J Haematol. 2021;195(2):244-248. doi:10.1111/ bjh.17727}

_{15. Inrebic. Prescribing information. Bristol Myers Squibb; 2019. Accessed March 22, 2022. https://bit.ly/3wxmgs7}