Ruxolitinib a New Oral Option for the Treatment of Patients with Intermediate- or High-Risk Myelofibrosis Disorders

Rhonda Williams

December 2011, Vol 2, No 7 - Cancer Drugs


Myeloproliferative neoplasms (MPNs) are a group of closely related hematologic malignancies that arise from abnormal development and function of the body’s bone marrow cells. Primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) comprise the Philadel phia chromosome (Ph)-negative MPNs.1

Myelofibrosis (MF) can arise on its own, which is called PMF, or it can result from the progression of other MPNs, such as postpolycythemia vera MF (PPV-MF) and postessential throm – bocythemia MF (PET-MF).1

The Burden of Disease and Its Impact
MF is characterized by cytopenias, splenomegaly, poor quality of life, and shortened survival.1 Because chronic MPNs previously were not classified as hematologic malignancies, limited epidemiologic studies are available to estimate the incidence of MF. Multiple regional studies suggest that an estimated 6328 new cases of chronic myeloproliferative disorders (CMPDs as they were previously known) occurred in the US population in 2004.2 Of these patients, 45% had PV, 24% had ET, and 10% had PMF.2

The average annual age-adjusted incidence in the United States between 2001 and 2003 was 2.1 per 100,000 persons, with rates ranging among states from a low of 0.8 per 100,000 persons in Delaware to as high as 4.1 per 100,000 persons in Idaho.2 The incidence was significantly higher in males (2.6 per 100,000) than in females (1.8 per 100,000; P <.05).2 In addition, the incidence increased significantly with age, reaching 13.3 per 100,000 persons among individuals aged ≥80 years.2

Although appropriate treatment of patients with ET and PV is associated with prolonged survival, patients with symptomatic forms of PMF have a median survival of <5 years.1 The prognosis ofMF is quite variable; however, thosewho develop anemia generally have a poorer prognosis. Patients with a good prognosis can live for many years without experiencing major symptoms,whereas thosewith a poor prognosismay have a significantly shorter survival. Asmall percentage of patients with MF can transform to acute myeloid leukemia, which is often difficult to treat and can be fatal.

Few treatment options exist for patients with MF. Until recently, the choice of treatment was often dictated by a patient’s symptoms and specific circumstances. Some patients with MF may remain symptom-free for many years, without undergoing treatment; however, monitoring for any signs or symptoms that may suggest worsening of the disease is required. For patients who require symptomatic treatment, chemotherapeutic agents, immunomodulatory drugs, and biological response modifiers (eg, hydroxyurea, androgen therapies, cortico – steroids, thalidomide, lenalidomide, and interferon) are often used.

It is important to note that these therapies are not always directed to the biological processes that underlie the origin of disease or lead to progression of PMF. Therefore, these strategies are often primarily palliative in nature, and their effect on survival is uncertain. Finally, surgery or radiation therapy may also be used in those who fail to respond to other treatments. For many patients with MF, however, available treatments may be ineffective and allogeneic stem-cell transplantation may be the only potential known cure.

A decisive advance in our understanding of the underlying molecular mechanisms of MPNs has been the discovery of a somatic gain-of-function point mutation in the Janus kinase (JAK) 2 gene, which is a common clinical feature in patients with ET, PV, and PMF.3,4 We now know that approximately 50% of patients withMF have a gain-of-function mutation in the JAK2 gene.5,6 Discoveries in the molecular pathogenesis of PV, ET, and PMF enabled the genetic classification and molecular diagnosis of these neoplasms. The World Health Organization diagnostic criteria, which were based largely on clinical and pathologic descriptions, were subsequently revised for PV, ET, and PMF to include the incorporation of testing for JAK2 and other genetic mutations.7

In addition to modifying the criteria for diagnosing, monitoring, and assessing patients with ET, PV, and PMF, the discovery of JAK2 involvement in patients with MF also led to the development of small-molecule inhibitors that specifically target JAK2. Although JAK2 mutations are responsible for the majority of dysregulated signaling in Ph-negative MPNs, JAK1 and JAK2 may interact, resulting in their transactivation.8,9

Armed with this information and a greater understanding of the cellular and molecular events that lead to the development of PMF, the possibility of more targeted and effective therapies for this disorder has become a reality.

In November 2011, the US Food and Drug Administration (FDA) granted marketing approval of oral Jakafi (ruxolitinib) tablets for the treatment of patients with intermediate- or highrisk MF, including PMF, PPV-MF, and PET-MF.10

Clinical Pharmacology Mechanism of Action
Jakafi, a kinase inhibitor, inhibits the Janus-associated kinases JAK1 and JAK2, whichmediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus, leading to modulation of gene expression.10

MF is known to be associated with dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2V617Fpositive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutated cells in the spleen, and decreased circulating inflammatory cytokines (eg, tumor necrosis factor– alpha and interleukin-6).10

Pharmacodynamics. In healthy persons and in patients with MF, ruxolitinib inhibited cytokine-induced STAT3 phosphorylation in whole blood. The maximal inhibition of STAT3 phosphorylation occurred 2 hours after dosing, returning to nearbaseline levels by 10 hours in both groups of people.

Pharmacokinetics. Maximal plasma concentration (Cmax) of ruxolitinib occurred 1 to 2 hours after oral administration. Pharmacokinetic studies demonstrated no evident food effect on the absorption of ruxolitinib; when administered with a high-fat meal, the mean Cmax decreased moderately (24%) and the area under the curve remained nearly unchanged (ie, 4% increase). In early clinical trials, the volume of distribution at steady state was between 53 L and 65 L in patients with MF.10

Phase 3 Clinical Trials
Jakafi was approved by the FDA based on the results of 2 randomized, phase 3 trials (Study 1 and Study 2) conducted in patients with MF.10 These trials are described in detail in the product prescribing information, with key data highlighted in this article.

Trial Designs
Study 1 was a randomized, doubleblind trial that compared ruxolitinib with placebo in patients with MF who were refractory to or were not candidates for available therapy. The primary end point was the proportion of patients achieving a reduction in spleen volume of >35% from baseline at week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT). Secondary end points included the duration of >35% reduction in spleen volume from baseline and the proportion of patients with a >50% reduction in Total Symptom Score from baseline to week 24. The latter was measured using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary.10

Study 2 was a randomized, openlabel trial that compared ruxolitinib with the best available therapy in patients with MF. The study investigators selected the best available therapy on a patient-by-patient basis, with the most frequently used agents, including hydroxyurea (N = 47%) and glucocorticoids (N = 16%). The primary end point of this trial was similar to that in Study 1—the proportion of patients achieving a reduction in spleen volume of >35% from baseline, but at week 48 (as measured by MRI or CT). The secondary end point of Study 2 was the proportion of patients achieving a >35%reduction in spleen volume from baseline to week 24.10

In both trials, patients were required to have palpable splenomegaly >5 cm below the costal margin, as well as an MF risk category of intermediate-2- risk (2 prognostic factors) or high-risk (>3 prognostic factors).10

Dosing in these trials was based on platelet counts. The starting dose of ruxolitinib was 15 mg administered orally twice daily in patients with baseline platelet counts of 100 to 200 x 109/L and 20 mg administered orally twice daily in patients with baseline platelet counts >200 x 109/L. The doses of ruxolitinib were then adjusted during the course of therapy based on efficacy and tolerability. Maximum doses based on platelet counts were as follows10:

  • Platelet count 100 to ≤125 x 109/L: 20 mg twice daily
  • Platelet count 75 to ≤100 x 109/L: 10 mg twice daily
  • Platelet count 50 to ≤75 x 109/L: 5 mg twice daily.
Table 1
Baseline Characteristics of Patients in Study 1 and Study 2
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Patient Populations
Baseline characteristics of patients enrolled in Study 1 and Study 2 are shown in Table 1. The 2 patient populations were very similar in terms of demographics and the extent of disease before study treatment.10

Table 2
Percentage of Patients with ?35% Reduction in Baseline Spleen Volume
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Efficacy
The primary end point in both phase 3 trials was the proportion of patients achieving a reduction in spleen volume of ≥35% from baseline at week 24 in Study 1 and at week 48 in Study 2 (Table 2). A significantly greater percentage of ruxolitinib-treated patients achieved thismagnitude of reduction in baseline spleen volume compared with either placebo (41.9% vs 0.7%, respectively; P <.001) or best available therapy (28.5% vs 0%, respectively; P <.001).10

In Study 1, a secondary end point was improvement in symptoms, as measured by the MFSAF v2.0. This scale captures MF-related symptoms, including abdominal discomfort, pain under the left ribs, night sweats, itching, bone or muscle pain, and early satiety. A higher proportion of ruxolitinib- treated patients experienced a ≥50% reduction in Total Symptom Score compared with placebo (45.9% vs 5.3%, respectively; P <.001). The median time to symptom response was <4 weeks.10

Safety Profile
Because clinical trials are conducted underwidely varying conditions, rates of adverse reactions observed in the clinical trials of a particular drug cannot be compared directly with rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ruxolitinib was assessed in 617 patients in 6 clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with MF in 2 phase 3 studies. In these 2 studies, patients had a median duration of exposure to ruxolitinib of 9.5 months (range, 0.5-17 months), with 88.7% of patients treated for >6 months and 24.6% treated for >12 months. A total of 111 patients started treatment at 15 mg orally twice daily and 190 patients started at 20 mg orally twice daily.10

The most often reported adverse events were thrombocytopenia and anemia; themost frequent nonhematologic adverse events were bruising, dizziness, and headache.9 A total of 11.0% of patients receiving ruxolitinib and 10.6% of patients receiving placebo discontinued therapy because of adverse events.9

Table 3
Adverse Reactions and Laboratory Abnormalities Reported in Study 1: Ruxolitinib versus Placebo
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The rates of adverse reactions and laboratory abnormalities reported in Study 1 are summarized in Table 3. The median time to onset of grade 2 or higher anemia was approximately 6 weeks. Mean decreases in hemoglobin of 1.5 to 2 g/dL below baseline after 8 to 12 weeks of therapy were reported in ruxolitinib-treated patients, recovering gradually to reach a new steady state of approximately 1.0 g/dL below baseline.10 The median time to onset of grade 3 or 4 thrombocytopenia was approximately 8 weeks. Patients with baseline platelet counts of 100 to 200 x 109/L experienced a higher incidence of grade 3 or 4 thrombocytopenia than did those with baseline platelet counts >200 x 109/L.10

Dosing
Ruxolitinib is dosed orally and can be administered with or without food. If a dose is missed, the patient should not take an additional dose, but should take the next usual prescribed dose. When discontinuing ruxolitinib therapy for reasons other than thrombocytopenia, gradual tapering of the dose may be considered—for example, by 5 mg twice daily each week.10

In patients who are unable to ingest tablets, ruxolitinib can be administered through a nasogastric tube (8 French or greater) by suspending 1 tablet in approximately 40 mL of water and stirring for approximately 10 minutes. Within 6 hours after the tablet has dispersed, the suspension can be administered via a nasogastric tube using an appropriate syringe. After use, the tube should be rinsed with approximately 75 mL of water. The effect of tube-feeding preparations on ruxolitinib exposure during administration through a nasogastric tube has not been evaluated.10

Table 4
Proposed Ruxolitinib Starting Doses
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The recommended starting dose of ruxolitinib is based on platelet count (Table 4). A complete blood count (CBC) and platelet count must be performed prior to initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. Doses may be titrated based on safety and efficacy.10

Table 5
PMaximum Restarting Doses for Ruxolitinib after Safety Interruption
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Treatment with ruxolitinib should be interrupted in patients with platelet counts <50 x 109/L. Once the platelet count recovers to >50 x 109/L, dosing may be restarted or increased following recovery of platelet counts to acceptable levels. Table 5 shows the maximum allowable dose that may be used when restarting ruxolitinib therapy following a previous interruption.10

Patients who develop anemia may require blood transfusions. Dose modifications of ruxolitinib in patients who develop anemia may also be considered.10 Neutropenia (absolute neutrophil count [ANC] <0.5 x 109/L) was generally reversible and was managed by temporarily withholding ruxolitinib. CBCs should be monitored as clinically indicated, with dosing ad – justed as required.10

Dose Modification Based on Response
If efficacy is considered insufficient and platelet and neutrophil counts are adequate, doses may be increased in 5- mg twice-daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more often than every 2 weeks. Discontinue treatment after 6 months if no reduction in spleen size or symptom improvement is observed since initiation of ruxolitinib therapy.10

Based on limited clinical data, longterm maintenance with a 5-mg twicedaily dose has not demonstrated responses, and continued use of this dose should be limited to patients in whom the benefits outweigh the potential risks.10

Dose increasesmay be considered in patients who meet all of the following criteria10:

  • Failure to achieve a reduction from pretreatment baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume, as measured by CT or MRI
  • Platelet count >125 x 109/L at 4 weeks and platelet count never <100 x 109/L
  • ANC >0.75 x 109/L.

Dose Adjustment, Concomitant Strong CYP3A4 Inhibitors
On the basis of pharmacokinetic studies in healthy volunteers, when administering ruxolitinib along with strong cytochrome (CY)P3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose is 10 mg twice daily for patients with platelet counts <100 x 109/L.

Additional dose modifications should be made with careful monitoring of safety and efficacy. Concurrent administration of ruxolitinib with strong CYP3A4 inhibitors should be avoided in patients with platelet counts <100 x 109/L.10

Contraindications, General Warnings, and Precautions
There are no black box warnings or contraindications associated with the use of ruxolitinib. Warnings and precautions associated with use of the agent include such hematologic adverse reactions as thrombocytopenia, anemia, and neutropenia. As indicated earlier, a CBC and platelet count must be performed prior to initiating therapy with ruxolitinib.

In clinical trials, patients with platelet counts <200 x 109/L at the start of therapy were more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible, however, and was usually managed by modifying or interrupting the dose of ruxolitinib in clinical trials.

Table 6
Dosing Recommendations for Thrombocytopenia
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Patients may also require a platelet transfusion, if clinically indicated. Dose reductions should be considered if platelet counts decrease, with the goal being to avoid dose interruptions for thrombocytopenia (Table 6).10 Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal, and viral infections. Active serious infections should have resolved prior to initiating ruxolitinib therapy. Physicians should carefully observe patients receiving ruxolitinib for signs and symptoms of infection, and should initiate appropriate treatment promptly. Physicians should inform patients about early signs and symptoms of herpes zoster, and should advise patients to seek treatment as early as possible.

References

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  2. Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008;112:45-52.
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  4. Kralovics R, Passamonti F, Buser AS, et al. A gain-offunction mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790.
  5. Santos FPS, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2010;115:1131-1136.
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  7. 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; 113:2895-2901.
  8. Mertens C, Darnell JE Jr. SnapShot: JAK-STAT signaling. Cell. 2007;131:612.e1.
  9. Jatiani SS, Baker SJ, Silverman LR, Reddy EP. JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes Cancer. 2010;1:979-993.
  10. Jakafi [prescribing information]. Wilmington, DE: Incyte Corporation; 2011.