JAKAVI® (ruxolitinib) in polycythaemia vera

JAKAVI® is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis. JAKAVI® is also indicated for adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea.¹

For your patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea¹

PV is a life-threatening condition associated with increased mortality and reduced quality of life, caused by a high symptom burden detrimentally impacting patients.^2,3 

~1 in 4 patients with a myeloproliferative neoplasm report that their condition interferes with or limits their daily activities.³ In the global MPN Landmark Survey (N=699), symptom reduction was reported as the primary goal of treatment by 61% of patients with PV.*³

The British Society for Haematology guidelines recommend a variety of first-, second- and third-line treatments for patients with PV.⁶ Hydroxyurea (also known as hydroxycarbamide) is commonly used as a first-line cytoreductive treatment in high-risk PV patients.⁷

Despite this, up to 20.7% of patients with PV may become intolerant or resistant to hydroxyurea treatment, which may lead to increased mortality.^§8–10 Patients with PV who are HU resistant or intolerant are also at an increased risk of transformation to myelofibrosis or acute myeloid leukaemia.⁹

ELN guidelines recommend switching patients to an alternative cytoreductive therapy from HU if one of the following criteria are met:^11,12

In patients treated with HU who require a therapy change, either ruxolitinib or interferon alfa should be chosen on the basis of individual clinical features – in particular, age, spleen size, symptoms, history of skin cancers, and patient preferences.^‖12

*Data from patients with MPNs (ET, n=302; MF, n=174; PV, n=223) surveyed in the International MPN Landmark Survey (N=699).^3
†Data from patients with an MPN (N=286) surveyed in the UK MPN Landmark Survey.^4
‡Data from patients with PV (n=78) surveyed in the UK MPN Landmark Survey (N=286).^4
§HU resistance or intolerance was defined using the 2010 ELN criteria.^7,10 In a retrospective analysis of 106 patients with PV in Belgium, when using the original and modified ELN criteria, 20.7% and 39.6% of patients were resistant or intolerant to HU, respectively.^10,11
¶HU dosed at ≥1.5 g per day for at least 4 months and without reporting intolerance.^12
‖In particular, age, spleen size, symptoms, history of skin cancers and patient preferences.¹²

JAKAVI® (ruxolitinib) demonstrated superior haematocrit control and spleen size reduction (composite primary endpoint) vs BAT in the RESPONSE trial**^1,13

The RESPONSE trial is a Phase III, randomised, open-label, multicentred study to evaluate the safety and efficacy of JAKAVI® vs BAT in venesection-dependent patients with splenomegaly who have HU-resistant or intolerant PV.¹³ The composite primary endpoint was HCT control and ≥35% reduction in spleen volume at Week 32. 

RESPONSE-2 is a Phase IIIb, prospective, randomised, open-label, multicentred study assessing the safety and efficacy of JAKAVI® vs best available therapy in venesection-dependent patients without splenomegaly who are resistant to or intolerant of HU.¹⁴ The primary endpoint was the proportion of patients who achieved HCT control at Week 28. 

Study design^3,13–15

JAKAVI® was associated with observed relief of PV symptoms vs BAT^‡‡13

JAKAVI® has a well-characterised safety profile¹

The most commonly reported AEs with JAKAVI® in PV were:¹ 

Haematological AEs

Non-haematological AEs

The most frequently reported adverse drug reactions were anaemia and increased alanine aminotransferase.

Anaemia and thrombocytopenia CTCAE grade 3 or 4 were reported in 2.9% and 2.6% of the patients, respectively.

The three most frequent non-haematological laboratory abnormalities (any CTCAE grade) identified as adverse reactions were increased alanine aminotransferase (45.3%), increased aspartate aminotransferase (42.6%), and hypercholesterolaemia (34.7%). No CTCAE grade 4 increased alanine aminotransferase or hypercholesterolaemia, and one CTCAE grade 4 increased aspartate aminotransferase were observed.

Discontinuation due to adverse events, regardless of causality, was observed in 19.4% of patients.

Adapted from JAKAVI® Summary of Product Characteristics.¹

^aADR derived from post-marketing experience.^1
bFrequency is based on new or worsened laboratory abnormalities compared to baseline.^1
cCommon Terminology Criteria for Adverse Events (CTCAE) version 3.0; grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening.^1
dPancytopenia is defined as haemoglobin level <100 g/L, platelet count <100x10⁹/L, and neutrophil count <1.5x10⁹/L (or low white blood cell count of grade 2 if neutrophil count is missing), simultaneously in the same lab assessment.¹

Contraindications¹

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the SmPC

• Pregnancy and lactation

Special warnings and precautions¹

Myelosuppression
Treatment with JAKAVI® can cause haematological adverse drug reactions, including thrombocytopenia, anaemia and neutropenia. A complete blood count, including a white blood cell count differential, must be performed before initiating therapy with JAKAVI®. Treatment should be discontinued in patients with platelet count less than 50,000/mm³ or absolute neutrophil count less than 500/mm³ (see section 4.2 of the SmPC).
It has been observed that MF patients with low platelet counts (<200,000/mm³) at the start of therapy are more likely to develop thrombocytopenia during treatment.

Thrombocytopenia is generally reversible and is usually managed by reducing the dose or temporarily withholding JAKAVI®  (see sections 4.2 and 4.8 of the SmPC). However, platelet transfusions may be required as clinically indicated.

Patients developing anaemia may require blood transfusions. Dose modifications or interruption for patients developing anaemia may also need to be considered.

Patients with a haemoglobin level below 10.0 g/dl at the beginning of the treatment have a higher risk of developing a haemoglobin level below 8.0 g/dl during treatment compared to patients with a higher baseline haemoglobin level (79.3% versus 30.1%). More frequent monitoring of haematology parameters and of clinical signs and symptoms of JAKAVI®-related adverse drug reactions is recommended for patients with baseline haemoglobin below 10.0 g/dl.

Neutropenia (absolute neutrophil count <500) was generally reversible and was managed by temporarily withholding JAKAVI® (see sections 4.2 and 4.8 of the SmPC).

Complete blood counts should be monitored as clinically indicated and dose adjusted as required (see sections 4.2 and 4.8 of the SmPC).

Infections
Serious bacterial, mycobacterial, fungal, viral and other opportunistic infections have occurred in patients treated with JAKAVI®. Patients should be assessed for the risk of developing serious infections. Physicians should carefully observe patients receiving JAKAVI® for signs and symptoms of infections and initiate appropriate treatment promptly. Treatment with JAKAVI® should not be started until active serious infections have resolved.

Tuberculosis has been reported in patients receiving JAKAVI®. Before starting treatment, patients should be evaluated for active and inactive (‘latent’) tuberculosis, as per local recommendations. This can include medical history, possible previous contact with tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/or interferon-gamma release assay, as applicable. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.

Hepatitis B viral load (HBV-DNA titre) increases, with and without associated elevations in alanine aminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBV infections taking JAKAVI®. It is recommended to screen for HBV prior to commencing treatment with JAKAVI®. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines.

Herpes zoster
Physicians should educate patients about early signs and symptoms of herpes zoster, advising that treatment should be sought as early as possible.

Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) has been reported with JAKAVI® treatment. Physicians should be particularly alert to symptoms suggestive of PML that patients may not notice (e.g., cognitive, neurological or psychiatric symptoms or signs). Patients should be monitored for any of these new or worsening symptoms or signs, and if such symptoms/signs occur, referral to a neurologist and appropriate diagnostic measures for PML should be considered. If PML is suspected, further dosing must be suspended until PML has been excluded.

Non-melanoma skin cancer
Non-melanoma skin cancers (NMSCs), including basal cell, squamous cell, and Merkel cell carcinoma, have been reported in patients treated with ruxolitinib. Most of the MF and PV patients had histories of extended treatment with hydroxyurea and prior NMSC or pre-malignant skin lesions. A causal relationship to ruxolitinib has not been established. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Lipid abnormalities/elevations
Treatment with JAKAVI® has been associated with increases in lipid parameters including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. Lipid monitoring and treatment of dyslipidaemia according to clinical guidelines is recommended.

Special populations
Renal impairment
The starting dose of JAKAVI® should be reduced in patients with severe renal impairment. For patients with end-stage renal disease on haemodialysis the starting dose should be based on platelet counts for MF patients, while the recommended starting dose is a single dose of 10 mg for PV patients (see section 4.2 of the SmPC). Subsequent doses (single dose of 20 mg or two doses of 10 mg given 12 hours apart in MF patients; single dose of 10 mg or two doses of 5 mg given 12 hours apart in PV patients) should be administered only on haemodialysis days following each dialysis session. Additional dose modifications should be made with careful monitoring of safety and efficacy (see sections 4.2 and 5.2 of the SmPC).

Hepatic impairment
The starting dose of JAKAVI® should be reduced by approximately 50% in MF and PV patients with hepatic impairment. Further dose modifications should be based on the safety and efficacy of the medicinal product. In GvHD patients with hepatic impairment not related to GvHD, the starting dose of JAKAVI® should be reduced by approximately 50% (see sections 4.2 and 5.2 of the SmPC).

Interactions
If JAKAVI® is to be co-administered with strong CYP3A4 inhibitors in MF and PV patients or dual inhibitors of CYP3A4 and CYP2C9 enzymes (e.g. fluconazole) in MF, PV and GvHD patients, the unit dose of JAKAVI® should be reduced by approximately 50%, to be administered twice daily (for monitoring frequency see sections 4.2 and 4.5 of the SmPC).

The concomitant use of cytoreductive therapies with JAKAVI® was associated with manageable cytopenias (see section 4.2 of the SmPC for dose modifications during cytopenias).

Withdrawal effects
Following interruption or discontinuation of JAKAVI®, symptoms of MF may return over a period of approximately one week. There have been cases of patients discontinuing JAKAVI® who experienced severe adverse events, particularly in the presence of acute intercurrent illness. It has not been established whether abrupt discontinuation of JAKAVI® contributed to these events. Unless abrupt discontinuation is required, gradual tapering of the dose of JAKAVI® may be considered, although the utility of the tapering is unproven.

Excipients
JAKAVI® contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

JAKAVI® dosing in PV¹ 

JAKAVI® treatment should only be initiated by a physician experienced in the administration of anti-cancer medicinal products.

Initiation and dosing in polycythaemia vera patients differ from that in myelofibrosis:¹ 

If efficacy is considered insufficient and blood counts are adequate, doses may be increased by a maximum of 5 mg twice daily, up to the maximum dose of 25 mg twice daily.¹

The starting dose should not be increased within the first 4 weeks of treatment and thereafter no more frequently than at 2-week intervals.¹

In PV, treatment should also be interrupted when haemoglobin is below 8 g/dl. After recovery of blood counts above these levels, dosing may be restarted at 5 mg twice daily and gradually increased based on careful monitoring of CBC, including a WBC differential.¹

Special populations
Renal impairment
No specific dose adjustment is needed in patients with mild or moderate renal impairment.

The recommended starting dose for PV patients with severe renal impairment is 5 mg twice daily. Patients should be carefully monitored with regard to safety and efficacy during ruxolitinib treatment.

The recommended starting dose for PV patients with ESRD on haemodialysis is a single dose of 10 mg or two doses of 5 mg given 12 hours apart, to be administered post-dialysis and only on the day of haemodialysis. These dose recommendations are based on simulations and any dose modification in ESRD should be followed by careful monitoring of safety and efficacy in individual patients. No data is available for dosing patients who are undergoing peritoneal dialysis or continuous venovenous haemofiltration.

Hepatic impairment
The recommended starting dose is 5 mg twice daily for PV patients. Patients diagnosed with hepatic impairment while receiving ruxolitinib should have complete blood counts, including a white blood cell count differential, monitored at least every one to two weeks for the first 6 weeks after initiation of therapy with ruxolitinib and as clinically indicated thereafter once their liver function and blood counts have been stabilised. Ruxolitinib dose can be titrated to reduce the risk of cytopenia.

ADR, adverse drug reaction; AE, adverse event; BAT, best available therapy; BID, twice a day; BL, baseline; CBC, complete blood count; CTCAE, common terminology criteria for adverse events; ECOG, Eastern Cooperative Oncology Group; ELN, European LeukemiaNet; ET, essential thrombocythaemia; HCT, haematocrit; HU hydroxyurea; IFN, interferon; JAK Janus kinase; MACE, major adverse cardiac events; MF, myelofibrosis; MPN, myeloproliferative neoplasm; MPN-SAF TSS, symptom assessment form total symptom score; MRI, magnetic resonance imaging; OS, overall survival; PRO, patient-reported outcome; PV, polycythaemia vera; QoL, quality of life; ULN, upper limit normal; WBC, white blood count.

For further information please consult the Summary of Product Characteristics.

References

1. JAKAVI® (ruxolitinib) Summary of Product Characteristics.

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5. Novaritis Data on File. Patient Quotes in PV from Advisory Board [MPN_PV_2020_001]. November 2020.

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9. Alvarez-Larrán, et al. Br J Haemtol 2016;172:789–793.

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17. assamonti F, et al. Lancet Haematol 2022;9:e480–92.

18. Scottish Medicines Consortium. Ruxolitinib (Jakavi). Available at: https://www.scottishmedicines.org.uk/medicines-advice/ruxolitinib-jakavi-full-smc2213/. [Accessed November 2024]. 

19. Verstovsek S, et al. Haematologica 2016;101:821–829.

20. Mylan. Anagrelide summary of product characteristics. Available at: https://www.medicines.org.uk/emc/product/9255/smpc/print [Accessed November 2024].

UK | November 2024 | FA-11208788