Managing Intermediate-Risk Myelofibrosis With Ruxolitinib

Publication
Article
Peers & Perspectives in OncologyDecember II, 2024
Pages: 33

During a Case-Based Roundtable® event, Andrew Kuykendall, MD, discussed treatment for a 68-year-old patient with intermediate-1 risk myelofibrosis and mild anemia.

Kuykendall

Andrew Kuykendall, MD

Assistant Member Department of Malignant Hematology

Moffitt Cancer Center

Tampa, FL

CASE SUMMARY


  • A 68-year-old woman presented to her physician with mild fatigue and splenomegaly, with the spleen palpable 6 to 7 cm below the left costal margin.
  • She had no significant comorbidities and was found to carry the JAK2 V617F mutation with a normal karyotype.
  • A bone marrow biopsy revealed megakaryocytic proliferation and atypia with reticulin fibrosis.
  • A peripheral blood smear showed leukoerythroblastosis, characterized by immature myeloid cells and nucleated red blood cells, which is a hallmark of myelofibrosis.
  • Prognostic scoring classified the patient as DIPSS intermediate-1 risk per the Dynamic International Prognostic Scoring System, or intermediate risk by the Mutation-Enhanced International Prognostic Score System-70.
  • Lab findings include mild anemia (hemoglobin: 9.7 g/dL), a slightly proliferative white blood cell count (23 × 10⁹/L), platelets at 450 × 10⁹/L, and peripheral blasts at less than 1%.
  • Based on these findings, a diagnosis of primary myelofibrosis was made.
poll

PEERS & PERSPECTIVES IN ONCOLOGY: Would you initiate ruxolitinib ( Jakafi) for this patient with intermediate-risk myelofibrosis?

KUYKENDALL: This patient has good platelet counts, white blood cells that are high, some mild anemia—but it is not overly concerning—and certainly splenomegaly. This is someone who could benefit from ruxolitinib, so I think that is a very reasonable choice. She is 68 years old with no comorbidities and intermediate-risk disease, so I think referral for transplant for an early evaluation may be reasonable. Does she need to go for a transplant right away? Maybe not, but it depends on the response to ruxolitinib, and [it is] certainly worth a discussion with intermediate-risk disease, as transplant does offer our only curative option.

If their hemoglobin level is now 7.8 g/dL, would this change your approach for this patient?

If this person is now at 7.8 g/dL, they either need a transfusion now or, if you start them on ruxolitinib, they may need one soon after that. That may change your thinking, whether that means you are going to go with a different agent or maybe a combination, but it certainly does take a different set of priorities into account.

poll 2

How do guidelines suggest managing patients with higher-risk myelofibrosis?

When we look at the NCCN guidelines right now,1 and when you take patients who have higher-risk myelofibrosis—so typically defined as intermediate-2 to high-risk patients, although this probably applies for some intermediate-1 risk patients as well— the first point is whether they have intact platelets. If they have intact platelets, we still want to consider them for a transplant if they are higher risk, but transplant is [often] not something that is going to happen tomorrow, so you still have to think about how you are going to best treat this patient.

In patients who have splenomegaly or constitutional symptoms, we have a lot of options for patients who have intact platelets. Ruxolitinib is certainly the most often used and the one we have the most comfort level with. [However, we also] have the ability to use fedratinib [Inrebic], and there are some weaker data for using momelotinib [Ojjaara] or pacritinib [Vonjo] in the frontline setting for these patients.

In patients who have less than 50,000/μL platelets, our options are a bit more limited. Certainly, transplant becomes an option, especially for high-risk patients with thrombocytopenia, and especially severe thrombocytopenia. We want to think about transplant, but if that is not immediately available, then pacritinib is the agent that is probably most associated with benefit in the markedly thrombocytopenic patient population. Momelotinib has data there, as well.

Can you provide an overview of the different Janus kinase ( JAK) inhibitors available?

Ruxolitinib was approved in 2011,2 and fedratinib was approved 8 years later.3 One can understand why we have a comfort level there with ruxolitinib because, for 8 years, it was the only agent that was approved. We have had the approval of pacritinib and momelotinib more recently.4,5 Indications are pretty similar for ruxolitinib and fedratinib, so higher-risk myelofibrosis. For pacritinib, this is now an accelerated approval for patients with platelets less than 50,000/μL, although the NCCN also allows for its use in the second-line setting, regardless of platelet count. Momelotinib is approved for patients with myelofibrosis and anemia.

When we talk about some unique concerns, abrupt discontinuation of ruxolitinib can lead to ruxolitinib discontinuation syndrome, which can invoke cytokine release syndrome. This is something to consider when patients are hospitalized. It is probably not advisable in most situations to abruptly stop ruxolitinib. Fedratinib has a black box warning for encephalopathy, including Wernicke encephalopathy, based on a small number of cases, so it is recommended to monitor thiamine levels during this.

Pacritinib has been associated with an increased risk of bleeding, [which is] something to [consider]; we saw 14% vs 7% had an incidence of major bleeding. Then momelotinib is overall well tolerated, but sometimes you can need dose adjustment in the setting of severe hepatic impairment.

Can you discuss the clinical trials and evidence supporting the approval of ruxolitinib for myelofibrosis?

Ruxolitinib was approved based on the COMFORT trials.6,7 COMFORT-I [NCT00952289] was a randomized phase 3 trial that compared ruxolitinib vs placebo, whereas COMFORT-II [NCT00934544] randomly assigned patients in a 2:1 ratio to ruxolitinib or best available therapy [BAT]. When reviewing the overall data, the interesting takeaway—beyond the improvements in spleen size and symptoms—is the survival benefit observed in patients treated with ruxolitinib. In COMFORT-I, patients who were initially randomly assigned to ruxolitinib demonstrated a survival benefit compared with placebo. This benefit was also observed in COMFORT-II when statistical adjustments accounted for patient crossover.

This finding has sparked some controversy in the field, as it raises the question of how an agent that does not eliminate the underlying disease provides a survival benefit. To put this in context, many of these patients present with massive splenomegaly and severe symptoms. By potently reducing spleen size and improving symptoms, ruxolitinib could enhance survival by improving nutritional status and overall physical condition.

What do the pooled analyses from the COMFORT trials reveal about the impact of ruxolitinib on outcomes in myelofibrosis?

The COMFORT-I and COMFORT-II pooled analysis further examined outcomes in myelofibrosis by disease duration. The data showed that patients starting ruxolitinib with a disease duration of less than 1 year performed better than all other groups. Even patients on placebo or BAT tended to do better if they started treatment earlier. However, there is a significant caveat here: Patients with longer disease durations inherently do worse due to lead time effects. There also could be a rationale for ruxolitinib having more impact earlier in the disease process when patients have fewer cytopenias, fewer additional mutations, and less complex disease. This suggests that patients might have a greater ability to benefit earlier in the disease course. When you look at the pooled analysis of responses in terms of spleen volume and symptoms, it is clear that ruxolitinib is potent in improving spleen volume and overall symptom scores, whether compared with placebo or BAT.

How does ruxolitinib’s impact on anemia and thrombocytopenia influence treatment strategies?

One of the caveats with ruxolitinib is its tendency to cause significant anemia and thrombocytopenia. This is something clinicians must consider when prescribing ruxolitinib, as it can push patients into requiring transfusions. The Spanish group conducted an interesting study addressing this issue by exploring an alternative dosing strategy. Traditionally, ruxolitinib dosing is based solely on platelet count: starting at 20 mg twice daily if platelets are above 200,000/µL, 15 mg twice daily for platelets between 100,000/µL and 200,000/µL, and 5 mg twice daily if platelets are below 100,000/µL. This approach does not take into account anemia. In real-world settings, patients with hemoglobin levels of 8 or 9 g/dL who start on 20 mg often experience further drops in hemoglobin, leading to transfusion dependence and subsequent dose reductions or even treatment discontinuation.

What evidence supports alternative dosing approaches for managing these adverse events (AEs)?

The Spanish group designed the REALISE trial [NCT02966353], which focused on patients with anemia and myelofibrosis.8 In this trial, anemic patients were started at 10 mg twice daily, with dose escalation after 3 months if platelet counts permitted. This strategy allowed 30% to 40% of patients to eventually reach higher doses, like 15 mg or 20 mg twice daily, which might not have been accessible otherwise. Many patients were kept on the 10 mg twice-daily dose without requiring reductions. The key takeaway is that alternative dosing strategies could enable patients to stay on treatment longer, thereby maximizing benefits.

What were the key findings from the REALISE trial regarding efficacy, transfusion requirements, and AEs?

Even with the lower starting dose, clinical responses remained strong. Spleen responses were observed in [more than] 50% of patients, and symptom improvements were seen in nearly 50%. This demonstrates that starting with a lower dose and escalating over time based on platelet counts did not compromise clinical efficacy. Additionally, transfusion requirements decreased over time. At baseline, the number of patients who were transfusion dependent was high, but this declined as the trial progressed, suggesting that this dosing strategy could reduce transfusion needs while maintaining potent spleen responses.

AE rates in the trial were also favorable. Rates of anemia and thrombocytopenia were lower than those reported in the COMFORT trials, where hematologic AEs occurred in 60% to 90% of patients. Other AEs were also minimal, which goes along with the fact that ruxolitinib [is generally well tolerated], aside from its hematologic toxicities.

REFERENCES

1. NCCN Guidelines for Patients: Myeloproliferative Neoplasms. NCCN; 2024. Accessed November 15, 2024. https://tinyurl.com/4jwy5fkj

2. Jakafi. Prescribing information. Incyte Corporation; 2011. Accessed November 15, 2024. https://tinyurl.com/pd2ktmhy

3. FDA approves fedratinib for myelofibrosis. FDA. August 16, 2019. Accessed November 15, 2024. https://tinyurl.com/42255mx6

4. Vonjo. Prescribing information. CTI BioPharma Corp; 2022. Accessed November 15, 2024. https://tinyurl.com/yfrx5pn7

5. Ojjaara. Prescribing information. GSK; 2023. Accessed November 15, 2024. https://tinyurl.com/47szrt2w

6. Mesa RA, Gotlib J, Gupta V, et al. Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2013;31(10):1285-1292. doi:10.1200/JCO.2012.44.4489

7. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701-1707. doi:10.1038/leu.2016.148

8. Cervantes F, Ross DM, Radinoff A, et al. Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study. Leukemia. 2021;35(12):3455-3465. doi:10.1038/s41375-021-01261-x

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