Tag Archives: Ruxolitinib

Ten years of experience with ruxolitinib since approval for polycythemia vera: A review of clinical efficacy and safety

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Lucia Masarova MD1 | John Mascarenhas MD, MS2 | Raajit Rampal MD, PhD3 | Wilson Hu MD4 | Robert A. Livingston MD, MPH4 | Naveen Pemmaraju MD1

Abstract
The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was approved by the US Food and Drug Administration in 2014 for the treatment of patients with polycythemia vera (PV) who have an inadequate response to or intolerance of hydroxyurea (HU). PV is a chronic myeloproliferative neoplasm defined by primary absolute erythrocytosis, bone marrow hypercellularity, and JAK mutations such as JAK2V617F. Patients with PV experience burdensome symptoms and are at risk of thromboembolic events, in particular those with resistance to or intolerance of initial treatments such as HU. Other risks for patients with PV include progression of disease to more aggressive forms with worse prognoses, such as myelofibrosis or blast‐phase myeloproliferative neoplasms. This review summarizes the efficacy and safety of ruxolitinib from key phase 2 and 3 trials (MAJIC‐PV, RESPONSE, RESPONSE‐2, RELIEF, and Ruxo‐BEAT), large real‐world studies, and a decade of postmarketing surveillance safety data. The authors focus on improved blood count control, rates of thromboembolic events, symptom improvement, and markers of disease modification such as reduction of JAK2V617F allele burden in patients treated with ruxolitinib. They also discuss the well‐characterized safety profile of ruxolitinib regarding hematologic and other adverse events of interest. In the 10 years since its approval, ruxolitinib remains a safe and effective standard‐of‐care treatment for PV. As the treatment landscape for PV continues to evolve in the coming years, the efficacy and safety profiles of ruxolitinib suggest it will remain a
preferred treatment as monotherapy and as a potential backbone of future combination regimens.

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Lower Pharmacy Costs Give Ruxolitinib Edge for Patients With MF and Anemia

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November 9, 2024

Author(s): Mary Caffrey

The clinical benefits and lower transfusion costs of momelotinib (Ojjaara) are not enough to offset its higher pharmacy costs compared with an older therapy for patients with myelofibrosis (MF) and anemia who rely on transfusions, according to a recent cost-effectiveness analysis.

The results were presented in a poster at the 16th International Congress on Myeloproliferative Neoplasms, held in Brooklyn, New York, October 24-25, 2024.1

Aaron T. Gerds, MD, MS | Image Credit: Cleveland Clinic

Led by Aaron T. Gerds, MD, MS, assistant professor of Medicine, Cleveland Clinic Taussig Cancer Institute, the authors presented data based on a predictive model that computed per-patient total cost of care for 6-month, 1-year, and 2-year periods, comparing the Janus kinase (JAK) inhibitors ruxolitinib (Jakafi), and momelotinib (Ojjaara). Both inhibit the JAK/STAT pathway, with momelotinib additionally targeting a pathway that can result in improved iron-restricted anemia.

As the poster authors stated, ruxolitinib is indicated for patients with intermediate- or high-risk MF, including those with primary MF, post-polycythemia vera MF, post–essential thrombocythemia MF. Momelotinib is indicated for patients with intermediate- or high-risk MF, including those with primary MF, post-polycythemia vera MF, and post–essential thrombocythemia MF in in adult patients with anemia.1

The SIMPLIFY-2 study showed that patients switching from ruxolitinib to momelotinib took less time to achieve transfusion in dependence.2

This analysis presented in Brooklyn was based on the SIMPLIFY-1 study, which compared ruxolitinib and momelotinib in patients who had not previously received a JAK inhibitor.3 The authors, many of whom worked SIMPLIFY-1, found that the difference in pharmacy costs is $11,095 per month, with momelotinib being more expensive. Although transfusion costs for ruxolitinib were projected to cost an additional $10,854 over a 6-month period, the total cost of care still favored ruxolitinib, Results were as follows:

  • At the 6-month mark, the total cost of care favored ruxolitinib by$46,388.
  • At the 1-year mark, the total cost of care favored ruxolitinib by $84,239.
  • At the 2-year mark, the total cost of care favored ruxolitinib by $144,539.

Assumptions in the model. Authors wrote that the model assumed patients remained on therapy for the entire duration of the study or until death. It was limited to pharmacy- and transfusion-related costs, “to isolate costs associated with reductions in transfusion; other costs of care were assumed similar between ruxolitinib and momelotinib.”

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Ruxolitinib Provides Better Efficacy Than Best Available Therapy in Polycythemia Vera

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Andrea S. Blevins Primeau, PhD, MBA
According to the results of a systematic review and meta-analysis published in the journal APMIS, patients with polycythemia vera (PV) achieved greater hematocrit control and improved symptoms with ruxolitinib compared with best available therapy (BAT). Ruxolitinib was also associated with higher rates of nonmelanoma skin cancer, anemia, and certain infections.

Researchers identified 6 studies, including 4 randomized controlled trials and 2 observational studies, comprising 1061 patients with PV during the systematic review of reports published through 2023. The meta-analyses used a risk ratio (RR) to estimate effect size.

All patients received treatment with ruxolitinib or BAT, which included hydroxyurea, interferon, pegylated interferon, pipobroman, or anagrelide. The primary outcomes were hematocrit control and complete hematologic response (CHR).

In the cohort, the median age was 66.4 years and 72.8% of patients were male. There were 41.6% of patients were treated with ruxolitinib, 34% were hydroxyurea resistant, and 60% were hydroxyurea intolerant.

Higher rates of hematocrit control were observed in the ruxolitinib group compared with the BAT group (RR, 1.907; 95% CI, 1.135-3.205; P =.015). Ruxolitinib was also associated CHR compared with BAT (RR, 1.965; 95% CI, 1.025-3.768; P =.042).

Among patients with hydroxyurea-resistant or intolerant PV, higher rates of CHR (RR, 2.28; 95% CI, 1.36-3.84; P <.01), at least a 50% reduction in the MPN-SAF score (RR, 3.19; 95% CI, 1.21-8.46; P =.02), and PGIC score (RR, 6.86; 95% CI, 3.45-13.63; P <.01).

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Ruxolitinib Plus Pegylated Interferon Alfa-2a Show Promise in Newly Diagnosed Polycythemia Vera

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November 1, 2024

Author(s): Alexandra Gerlach, Associate Editor

Ruxolitinib (Jakafi; Incyte Corp) in combination with pegylated interferon alfa-2a demonstrated efficacy and tolerability in patients with newly diagnosed polycythemia vera (PV). According to the 2-year end-of-study results from the phase 2 COMBI 2 clinical trial (EudraCT2018-004150-13), the treatment improved cell counts, bone marrow cellularity, and fibrosis in patients with PV.1

In the phase 2 COMBI 2 trial, researchers evaluated the safety and efficacy of ruxolitinib and low-dose peg-IFN-α2a in patients with newly diagnosed PV.

Image Credit: © MdBabul – stock.adobe.com

PV is a chronic, progressive myeloproliferative neoplasm characterized by the overproduction of red blood cells. The excess cells thicken the blood, slowing its flow and contributing to serious complications, such as blood clots. Almost all patients with PV have the JAK2V617F mutations, and the JAK2V617F variant allele frequency (VAF) is key for determining outcomes, including thrombosis and progression to myelofibrosis.2-4

Ruxolitinib is a Janus kinase inhibitor approved by the FDA in 2011 and is indicated for the treatment of patients with high-risk MF with reduced abnormal expression of PF4, which can lead to decreased fibrosis. It is additionally indicated as a second-line treatment of PV for patients who have an inadequate response to or cannot tolerate hydroxyurea. In the COMBI 2 trial, researchers assessed the efficacy of ruxolitinib in combination with pegylated interferon alfa-2a (peg-IFN-α2a) (Pegasys ProClick; Genentech), an injection commonly used to treat hepatitis B and C infections. According to data from prior studies, peg-IFN-α2a has been shown to induce durable hematologic and molecular remissions in patients with PV. However, approximately 20% to 40% of patients are intolerant or show limited response to peg-IFN-α2a.5-8

In the phase 2 COMBI 2 trial, researchers evaluated the safety and efficacy of ruxolitinib and low-dose peg-IFN-α2a in patients with newly diagnosed PV in an effort to counterbalance intolerance to peg-IFN-α2a. The primary end point was safety, with secondary end points including efficacy, based on hematologic parameters, quality-of-life measurements, and JAK2V617F variant allele frequency (VAF).8

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Update: Ruxolitinib Beats Best Available Therapy in Treating Polycythemia Vera

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October 14, 2024

Author(s): Mary Caffrey

An updated meta-analysis confirms that ruxolitinib, the Janus kinase (JAK) 1/JAK2 inhibitor sold as Jakafi, offers improvements in key measures of efficacy compared with best available therapy (BAT) for patients with polycythemia vera (PV),1 a rare, slow-progressing disorder that causes the blood to make too many red blood cells.

Caused by a genetic mutation, PV is not typically fatal on its own, but it can cause dangerous blood clots and damage to the spleen. In a small number of cases, it progresses to more aggressive forms of blood cancer.

The latest results were reported in the journal APMIS,1 formerly known as Acta Pathologica, Microbiologica, et Immunologica Scandinavica.

The analysis followed a 2020 meta-analysis involving 16 studies that appeared in Blood Advances.2 That analysis included evidence from 4 randomized controlled trials and included 663 patients; the authors estimated a thrombosis incidence of 3.09% per year for ruxolitinib vs 5.51% for BAT, but noted that globally, this did not reach significance (P = .098). “A clinical trial on selected patients at high risk of thrombosis would be warranted, but its feasibility is questionable,” the authors wrote.2

The current analysis examines ruxolitinib’s efficacy and safety compared BAT in 1061 patients with PV and in hydroxyurea-resistant and intolerant patients with PV across 6 studies, with a cutoff of November 2023. The patients included 620 on BAT and 441 on ruxolitinib. According to the investigators:

  • Those taking ruxolitinib showed higher hematocrit control (P = .015) and treatment response (P = .04) compared to BAT.
  • Patients taking ruxolitinib had significantly improved Myeloproliferative Neoplasms-Symptom Assessment Form scores (MPN-SAF), P < .01.

However, on the safety front, patients with PV treated with ruxolitinib had higher rates of nonmelanoma skin cancer (P < .01), as has been previously documented.

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High Rates of Polycythemia Vera Remission Seen With Ruxolitinib Plus Peg-IFN

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Andrea S. Blevins Primeau, PhD, MBA

Final results from the phase 2 COMBI II trial demonstrated high rates of remission of newly-diagnosed polycythemia vera (PV) after treatment with ruxolitinib plus pegylated-interferon-α2a (peg-IFN), according to a report published in Blood Advances.

The COMBI I trial previously demonstrated efficacy and safety of the combination of ruxolitinib with peg-IFN among patients who were refractory or intolerant to peg-IFN monotherapy and/or hydroxyurea.

“This study supports the previously described theory that combination therapy with ruxolitinib and peg-IFN may be one of the most promising treatment options in patients with myeloproliferative neoplasms,” the researchers wrote in their report.

In the investigator-initiated, single-center, phase 2 study, researchers treated 25 adult patients with newly-diagnosed PV with ruxolitinib and peg-IFN. All patients underwent pretreatment phlebotomies and patients who were high-risk, aged 60 or older, or who had a prior thrombosis also received hydroxyurea.

The primary endpoint was safety and secondary endpoints included complete remission (CR), peripheral blood count remission (PBCR), and bone marrow histologic remission (BMHR).

The median age of the patients was 70 years and 56% were male. The median number of phlebotomies from diagnosis to study entry was 3. There were 76% of patients who were considered high-risk, 20% had a prior thrombosis, and 12% had splenomegaly. The median hemoglobin was 13.8 g/dL and the median hematocrit was 0.44 IQR. The median variant allele fraction (VAF) of JAK2 V617F at baseline was 54 IQR.

Remission was achieved by 52% of patients by 12 months, with 12% of patients having achieved a CR. At 24 months, the overall remission rate was 56% and the CR rate remained at 12%.

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Ruxolitinib Could Be Useful in MF Care

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Leonardo Jaimes, MD

Ruxolitinib appears to produce durable responses and minimal adverse effects in patients with myelofibrosis (MF) in a real-world setting, according to a recently published study in Cancer.

Since its US Food and Drug Administration approval over a decade ago, the JAK1/JAK2 inhibitor ruxolitinib has become one of the most commonly used drugs for the management of MF-associated symptoms, the study team noted. Its approval is based on the results from the COMFORT study, which included only intermediate-2 and high-risk patients, they continued.

“However, intermediate-1 risk patients may carry a significant burden of disease and are increasingly treated with ruxolitinib in the real-life setting. Moreover, in some European countries (e.g., Germany) approval of ruxolitinib is not restricted to higher risk patients but rather to those with symptomatic disease (even when intermediate-1 or low risk),” the authors wrote.

Given the lack of studies investigating the effectiveness and safety of ruxolitinib in an intermediate-1 risk patient population and the small cohorts and short follow-up times used in previous studies, the research team aimed to assess the drug in a real-world clinical practice context.

The retrospective study included data from over 1000 patients with MF who had received ruxolitinib since 2013. Approximately 56% of the patients were intermediate risk-1.

The authors observed a 26% spleen response rate after six months of ruxolitinib in the intermediate risk-1 population and a 68% symptom response rate. Both rates were slightly inferior in patients with intermediate risk-2.

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Bose’s Guide to Ruxolitinib, Fedratinib, Pacritinib, and Momelotinib

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By Prithviraj Bose, MD

Prithviraj Bose, MD, professor in the Department of Leukemia at MD Anderson Cancer Center, provides an overview of the different JAK inhibitors currently available for patients with myeloproliferative neoplasms.

Transcription:

0:09 | We have 4 JAK inhibitors approved for the treatment of myelofibrosis in the US. Important to note, pacritinib [Vonjo] is not approved outside the US. There is obviously a lot to say on this topic, especially, ruxolitinib [Jakafi] was approved in 2011, fedratinib [Inrebic] in 2019 and then pacritinib and momelotinib [Ojjaara], more recently, 2022 and 2023. But I think I will just hit some high points.

0:36 | So for ruxolitinib, the first thing I would say about that is that it is the JAK inhibitor with the most clearly demonstrated survival benefit in myelofibrosis. Now, is that an effect just of ruxolitinib and not of the others? We do not know that. It could be a class effect, but the data are the data and the data are that ruxolitinib is the one that has a clearly shown survival benefit. I think that needs to be considered as we use it, and it is usually the most frequently used frontline drug. Now, where you can get into trouble with ruxolitinib is with cytopenias, low blood counts, and this is a drug that you need to be able to dose well in order to get the benefit that you are seeking. The dose can get compromised by cytopenias.

1:29 | That is where I will tie that into the entry of pacritinib and momelotinib. These are easier to use in the setting of cytopenias. In fact, pacritinib has a label for platelets than 50, and momelotinib is for patients with anemia in myelofibrosis. So right there, you can see that they sort of have their place more in that cytopenic population, which could be frontline, or, more commonly, second-line, after ruxolitinib. I think those are great additions in the sense that you can give them at good doses despite low blood counts, which becomes difficult with ruxolitinib, like I just said. [They are] certainly very welcome additions to the arsenal.

2:12 | I will just say 1 last thing about fedratinib, which was the second one approved. This is a good drug, perhaps as good as ruxolitinib from an efficacy stand point, but really with no clear advantage over ruxolitinib. So, I do not use it in the frontline. I do use it, however, in post-ruxolitinib settings, where the blood counts are good. In those proliferative scenarios, as opposed to the cytopenic scenarios, in second-line and beyond, I do find fedratinib to be a useful drug. It has some toxicities that one has to pay attention to. All patients should get thiamine supplementation, stuff like that, but overall, I would say those are the kind of very high level points about the 4 drugs.

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Ruxolitinib Stands Out Among JAK2 Inhibitors for Myelofibrosis

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By Targeted Oncology Staff

In this virtual tumor board discussion, experts review the case of a 68-year-old woman diagnosed with primary myelofibrosis. The discussion focuses on recent data and emerging insights to guide clinical decision-making and explore the latest advances in treatment strategies for this challenging disease.

Prithvira J. Bose, MD: What are the first steps you would take for this patient, and how do you view multidisciplinary collaboration?

Julie Huynh-Lu, PA-C: Specific to [The University of Texas] MD Anderson [Cancer Center], the role of the physician assistant or nurse practitioner in the leukemia department is to evaluate the patient. Aside from doing a review of systems, I go over the myeloproliferative neoplasms [MPN] questionnaire with the patients to review any changes in their score. Whether they have started therapy or not, [we determine whether they] need to be on therapy based on their answers.

I do a physical assessment of the patient checking their spleen. We don’t order ultrasounds or CT scans on patients unless we’re unable to palpate due to pain in that area. I’ll measure the spleen size every time the patient comes in with a tape measure.

Having a second set of eyes evaluating the patient [is key] because some questions that I may ask, someone else may not—or the physician may ask questions that I may not know [to ask]. Collaboration among nurses, physician assistants or nurse practitioners, and physicians in compiling patient information ensures the best care for the patient.

We are lucky to have the MPN10 form in the Epic system on our flow sheet, and patients can fill out this form before they check in for their appointment. If they were unable to fill it out, I can go into that flow sheet, ask those questions, and fill it out with them. Then, the score [generates] for each patient.

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Managing Ruxolitinib-Associated Liver Toxicity in Patients With Myelofibrosis Requires a Nuanced Approach

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September 4, 2024

William J. Hogan, MBBCh, MRCPI

Key Points:

  • Ruxolitinib plays an important role in the treatment of symptomatic myelofibrosis, but its associated toxicities and adverse withdrawal effects can pose a challenge.
  • Myelofibrosis is linked with hepatic dysfunction, and ruxolitinib—despite its associated risks of hepatic transaminitis—may limit inflammation and progressive fibrosis, with liver injury resolution reported after treatment.
  • Overall, management of liver injury related to ruxolitinib depends on the cause and severity.

 

Question: In patients with myelofibrosis, how do you manage liver toxicity from ruxolitinib use beside dose de-escalation?

Answer: Ruxolitinib is a small-molecule JAK1/2 inhibitor that has an established role in the treatment of patients with symptomatic myelofibrosis, hydroxyurea-resistant polycythemia vera, and acute and chronic graft-versus-host disease. It has a potent anti-inflammatory effect that can provide very useful palliation of constitutional symptoms and splenomegaly in patients with myelofibrosis via inhibition of the JAK 1 and 2 pathways, which are involved in the production of inflammatory cytokines and hematopoietic growth factors.1-3 Common toxicities include myelosuppression, hepatic transaminitis, diarrhea, fatigue, headache, and peripheral edema. In patients with advanced myelofibrosis or florid inflammatory states, sudden withdrawal can lead to a systemic inflammatory response syndrome that can precipitate cardiopulmonary decompensation in frail patients, especially those with tenuous cardiopulmonary function, and corticosteroid prophylaxis or treatment may be required.4

In a mouse model of liver injury using carbon tetrachloride, JAK1/2 expression was implicated in progression of liver fibrosis. Inhibition of JAK1/2 downregulates downstream signaling, reduces progression to fibrosis, and even accelerates fibrosis reversal by inhibiting proliferation, migration, and activation of hepatic stellate cells in vitro.5 Myelofibrosis is associated with hepatic dysfunction by several mechanisms, including infiltration by hematopoietic stem cells (ie, extramedullary hematopoiesis [EMH]), portal vein thrombosis, and obliterative portal venopathy. EMH may respond favorably to ruxolitinib, and liver injury resolution after ruxolitinib treatment has been reported in patients with severe liver compromise related to myelofibrosis.6 These findings suggest that the drug may be able to reduce the consequences of inflammation—limiting progressive fibrosis in some circumstances—and may be of durable benefit in selected patients. A retrospective review of patients with liver injury and underlying myeloproliferative disorders treated with ruxolitinib and evaluated by biopsy demonstrated a variety of etiologies7; however, it is not always easy to determine how much is related to the underlying disease versus drug effects based on the biopsy findings, and this distinction is predominantly a clinical decision.

Liver toxicity typically manifests as mild hepatic transaminitis and can be exacerbated by drug–drug interactions. The incidence of hepatic transaminitis has been reported to be between 25% and 50%. Typically, these elevations are mild and self-limited, with < 1.5% of patients having values > 5 times the upper limit of normal. The drug is metabolized in the liver predominantly via the CYP3A4 pathway, and liver injury may be the result of the production of a toxic intermediate. Drug–drug interactions, such as with azole antifungals, can increase the effective exposure and enhance the potential for toxicity. Because suppression of intracellular signaling impairs immune response, suppression of viral replication may be impaired, increasing the potential for reactivation of quiescent viruses. This has been reported with reactivation of hepatitis B, resulting in clinically meaningful liver injury in patients who are at risk. It appears that the risk of viral reactivation with transaminitis and hyperbilirubinemia is greater in patients with HBsAg positivity, but reactivation has also been reported in those with anti-HBc. Efficacy with entecavir has been reported in treating viral reactivation and prophylaxis, so a nucleoside analog such as entecavir or tenofovir should be considered in patients who are at high risk.8-10

Management of liver injury related to ruxolitinib depends on the cause and severity. Identifying contributing causes, such as drug–drug interactions and prior viral hepatitis exposure and excluding other hepatotoxins are the initial imperative. Prior viral exposure with reactivation should be treated or prophylaxed when applicable. For mild transaminase elevations without hyperbilirubinemia, monitoring or temporary dose reduction may be appropriate. In more significant liver injury, dose interruption may be necessary. Consideration of an alternative JAK inhibitor may occasionally be warranted, as there does not appear to be significant evidence to suggest cross-reactivity between ruxolitinib and other JAK inhibitors. Of note, a retrospective review of liver injury occurring in patients with myeloproliferative neoplasms receiving ruxolitinib suggested a variety of potential etiologies, including those unrelated to the drug itself (EMH), in addition to obstructive portal vein apathy and drug-induced liver injury.

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