Rampal Reviews Data for First-line Therapy in Myelofibrosis With High Platelet Count

Case-Based Roundtable Meetings Spotlight, Case-Based Roundtable Meetings Spotlight: November 1, 2022,
Pages: 54

During a Targeted Oncology case-based roundtable event, Raajit K. Rampal, MD, PhD, discussed recommendations and data on the use of JAK inhibitors to treat patients with myelofibrosis.

Targeted OncologyTM: What nontransplant therapies do the National Comprehensive Care Network (NCCN) guidelines recommend for the management of higher-risk myelofibrosis (MF)?

RAMPAL: In the current NCCN guidelines, for patients with a platelet count of at least 50,000/μL, fedratinib [Inrebic], ruxolitinib [Jakafi], and [clinical trial are options].1 Ruxolitinib and fedratinib are supported by category 1 data, and I think a clinical trial is always a reasonable option. We’re fortunate these days because there are 3 phase 3 registration trials going on, where patients are randomly assigned to either ruxolitinib or ruxolitinib plus an investigational agent. The investigational agents are a BET inhibitor, a BCLX/BCL2 inhibitor, or a PI3K inhibitor. In this day and age, a clinical trial is absolutely a reasonable first-line consideration.

For patients with a platelet count of less than 50,000/μL, [the NCCN guidelines recommend a clinical trial or pacritinib [Vonjo] if the patient is not transplant eligible].1 The landscape changed with the approval of pacritinib,2 which has been studied as first-line and second-line [therapy] in MF, but has also been studied selectively in a patient population very different from those in the COMFORT-I [NCT00952289], COMFORT-II [NCT00934544], and JAKARTA [NCT01437787] studies, [whose data supported] the approvals of ruxolitinib and fedratinib, respectively.3,4

For patients [with a platelet count of 50,000/μL or greater] who get ruxolitinib or fedratinib as a first-line therapy [and then] lose response or have some degree of progression, you can switch to an alternative JAK inhibitor.1

What data support the management of MF with ruxolitinib?

Ruxolitinib was approved based on the COMFORT-I and COMFORT-II trials.3 These were randomized trials of ruxolitinib vs either placebo or best available therapy. Included in these trials were symptomatic patients with intermediate- or higher-risk disease and platelet counts of 100,000/μL or greater.

It’s important to remember the platelet count of these patients when [you consider the] data from these trials.5,6 The top-line data from the COMFORT-I and COMFORT-II studies were essentially similar, showing that [the rate of] spleen volume reduction by at least 35% was superior with ruxolitinib vs the comparator arm in each study with COMFORT-I: 41.9% vs 0.7%, respectively [odds ratio, 134.4; 95% CI, 18.0-1004.9; P < .001] and COMFORT-II: 28% vs 0%, respectively.

In both studies, almost all of the patients in the ruxolitinib arms experienced spleen volume reduction [COMFORT-II: 97% vs 56% in the experimental and control arms, respectively]. In the comparator arms, there was [more] spleen volume increase, although some patients in the COMFORT-I placebo arm, strangely enough, had a spleen volume reduction, which I still don’t understand.5,6 The [parameter of] spleen volume reduction by 35% is an FDA-mandated end point; there’s nothing particularly magical about 35%. But the degree of spleen size reduction does matter, and there are data that demonstrate that the amount of spleen volume [reduction] does influence a patient’s overall survival [OS].7

Is that because we are saving lives by shrinking spleens? I don’t think so. I think spleen volume reduction is a marker of disease responsiveness to the JAK inhibitor, but it is important to remember that the amount of spleen reduction does correlate with patient survival. These patients can be terribly symptomatic, as [we] know. In the COMFORT-I study, the symptom burden reduction [was measured by] the Total Symptom Score, a validated tool, and the majority of patients treated with ruxolitinib showed symptom improvement.

Night sweats, early satiety, itching, bone pain, inactivity, and abdominal discomfort all [improved] in the patients who received ruxolitinib and worsened in patients who received the placebo.5 The same pattern was observed in the COMFORT-II study, wherein symptom response was measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire.6

Survival was not an end point of the COMFORT studies. In the ad hoc analysis, there appeared to be a survival benefit in the COMFORT-I but not in the COMFORT-II study. This prompted a pooled analysis of the COMFORT-I and COMFORT-II data [that reflected] the patients in the intention-to-treat arm.

The data showed that there did seem to be a survival benefit. The median OS was 5.3 years vs 3.8 years in the ruxolitinib and control arms, respectively [HR, 0.70; 95% CI, 0.54-0.91; P < .0065].8,9 We have to take into account that this was a pooled analysis and this was not a primary end point of the studies. But these data suggest that there is improved survival [in treated patients].

The question is why: [Did the treatment] change the natural history of the disease or [did it] just change patients’ overall performance status? If a patient is terribly symptomatic and cachectic from their disease, are they living longer because they’re responding to treatment? I think there are 2 answers. There’s the real-world answer, which is that it [doesn’t] matter. If patients are living longer, they’re living longer. And then there’s the academic question as to why [we are seeing this survival benefit]. I don’t think we know the answer to that.

Of the patients who did die, death was most often caused by progression to acute myeloid leukemia [86 of 1054 patients]. [Other causes of death included] thrombosis, bleeding, infection, and portal hypertension, which can be a byproduct of the disease process itself.8,9 Infection is an important adverse event to remember. There are signals from other studies that ruxolitinib treatment may increase the risk of Herpes zoster infection or [tuberculosis] reactivation.

What data support the idea that spleen response correlates with OS among ruxolitinib-treated patients?

An important [analysis addressed this relationship,] treating spleen response as a binary variable of response vs no response at 6 months, with response defined as a 35% spleen volume reduction. Patients who had a spleen response also had a better OS outcome [P = .04].

The OS [also correlated with] the durability of the spleen response. In that analysis, the nonresponders had the worst OS. [Separate analyses were performed for] patients who had a stable response and for patients who had an unstable response, [and these groups] had overlapping OS curves [P = .04].10 Those data might suggest that patients’ quality of life is being improved and that’s why they’re living longer.

What factors are associated with a lower spleen response?

The factors associated with a lower spleen response include high-risk disease, spleen size of at least 20 cm, high white blood cell count, delay in starting ruxolitinib after diagnosis, and using a dosage of less than 10 mg twice daily.11,12 I think that [the influence of dosage and of spleen size are both] important concepts. Both the patient and the physician are often reluctant to start therapy if the patient is not symptomatic, but [I think] you have to keep this warning in mind.

If [the spleen] is getting progressively larger, you’re going to reach a point where even a high dose of ruxolitinib may not achieve the optimal response. That could affect the patient’s OS. [Another way to look at this is that] if the maximal effect of the drug is going to be to reduce the spleen by a certain percentage volume, the bigger the spleen gets [before you start treatment], the larger the residual spleen will be even if you get a maximal percentage reduction.

How does ruxolitinib efficacy correlate with dosage?

[Analysis revealed that] spleen volume reduction correlated with ruxolitinib dosing. Maximal efficacy was achieved at a dose of at least 10 mg twice daily. There was some [efficacy] difference between the 10- and 15-mg doses, but not much of a difference between the 20- and 25-mg doses. There was a clear efficacy difference between a dose of less than 10 mg and the higher doses.13 One needs to try to optimize the dosing of ruxolitinib to achieve the best spleen response. The symptom response [showed a similar trend].

[Patients achieved] some degree of response at a dose of less than 10 mg twice daily, but doses of 10 mg twice daily and higher [conferred maximal] symptom response. We always worry about the hematologic parameters. When we start a patient on therapy, their blood counts start to decrease and we have to begin transfusing them, [we have to decide whether to dose reduce].

Do we reduce to 5 mg twice daily because the blood counts are more stable [at that dosage]? Sometimes when you reduce to that dose, the patient instantly feels better. They’re not completely better, but they are relatively better. That can give us a false sense of security, and [we] have to be careful of that. I think it is useful to start at a low [dose] and titrate up. I always start at 5 mg twice daily and titrate the dose up to [the target dose], which is usually approximately 10 mg twice daily. If you start at 20 mg twice daily, often that patient’s hemoglobin level or platelet count crashes, and then you have to back off and you don’t end up with the optimal dose.

What data can guide the use of ruxolitinib, with respect to patients’ platelet counts?

The dose of ruxolitinib is based on the patient’s platelet count. Per the package insert, the starting dose for patients with platelet counts of 50,000/μL to 100,000/μL is 5 mg twice daily. For patients with higher platelet counts, you can [start with] 10 mg twice daily.14 The problem is that if you leave patients with low platelet counts at 5 mg twice daily, they’re going to have an inferior outcome. [Keep in mind that, according to the] Dynamic International Prognostic Scoring System [DIPSS] and the DIPSS-Plus, patients with platelet counts under 100,000/μL are already prone to inferior outcomes, [which can be exacerbated by suboptimal dosing]. There are data to support the idea that you can safely increase the dose of ruxolitinib if the platelet count is between 50,000/μL and 100,000/μL. In the EXPAND study [NCT01317875], patients were divided into 2 strata, defined by a platelet count of either 50,000/μL to 74,000/μL or 75,000/μL to 99,000/μL.

All patients were started at a dose of 5 mg twice daily, and the dose was [gradually increased to] 15 mg twice daily. The safe dose was determined to be 10 mg twice daily in both strata.15,16 That’s an important thing to remember, because leaving patients at 5 mg twice daily can lead to suboptimal outcomes. In the EXPAND study, grade 3 and 4 thrombocytopenia was observed in 40% of patients with a higher platelet count and in 78% of patients with a lower platelet count. Platelet count decrease occurred in 25% vs 6% of the patients in those respective groups, and anemia occurred in 25% vs 17%, respectively.16 Most of the patients [in both strata] had some degree of spleen volume decrease, and some achieved 35% spleen volume reduction. That is an important end point that correlates with survival, so pushing the dose can be beneficial. The symptom score [data exhibited a similar trend] in both strata.15


1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 3.2022. Accessed September 24, 2022. https://bit.ly/2E77tIB

2. FDA approves drug for adults with rare form of bone marrow disorder. News release. FDA. March 1, 2022. Accessed September 24, 2022. https://bit.ly/3RVeqPT

3. 2011 Notifications. FDA. February 13, 2018. Accessed September 24, 2022. https://bit.ly/3VoIQNq

4. FDA approves fedratinib for myelofibrosis. News release. FDA. August 16, 2019. Accessed September 24, 2022. https://bit.ly/3MwpD8k

5. 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

6. 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

7. Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al; COMFORT Investigators. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015;100(9):1139-1145. doi:10.3324/haematol.2014.119545

8. 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

9. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895-2901. doi:10.1182/blood-2008-07-170449

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

11. 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

12. 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

13. 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

14. Jakafi. Prescribing information. Incyte; 2021. Accessed September 25, 2022. https://bit.ly/3g9TOXa

15. 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

16. Guglielmelli P, Kiladjian J-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: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 1252. Accessed September 25, 2022. https://bit.ly/3RT8kzy