Ruxolitinib effective in polycythemia vera patients with or without splenomegaly

In a pooled analysis of the RESPONSE and RESPONSE-2 trials, patients with polycythemia vera (PV) who were treated with ruxolitinib achieved durable haematocrit control, better symptom control and a consistent reduction in JAK2V617F allele burden, as compared to patients treated with best available therapy. These results provide further evidence of the benefit of ruxolitinib in patients with PV, with or without splenomegaly.

Polycythemia vera (PV) is a myeloproliferative neoplasm characterised by elevated haematocrit, excessive red blood cell production, and presence of Janus kinase 2 (JAK2) activating mutations. Patients with PV often experience burdensome symptoms, most commonly fatigue, concentration problems, itching, night sweats and splenomegaly-related symptoms. Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor approved for the treatment of PV in adults who have had an inadequate response to or are intolerant of hydroxyurea. In the RESPONSE and RESPONSE-2 trials, ruxolitinib was superior to best available therapy at providing haematocrit control and complete haematologic response, as well as in improved PV-related symptoms. At ASH 2023, Dr. Harrison presented the results of a pooled analysis of RESPONSE and RESPONSE-2.

Study design

RESPONSE and RESPONSE 2 were randomised, open-label, multicentre phase III trials that assessed efficacy and safety of ruxolitinib in adults with PV who had resistance or intolerance to hydroxyurea. Splenomegaly was required for enrolment into RESPONSE but not for RESPONSE 2. Patients in both studies were randomised (1:1) to ruxolitinib (starting dose, 10 mg twice daily) or best available therapy (BAT; most commonly hydroxyurea [59%, 49%] or interferon formulations [12%, 13%] in RESPONSE and RESPONSE 2, respectively). Patients in either trial who were randomised to BAT could cross over to ruxolitinib at the time of primary analysis (week 32 in RESPONSE and week 28 in RESPONSE 2) or later for efficacy or safety reasons. In this pooled analysis, haematocrit control was assessed in the pooled population at weeks 28 and 80 and was defined as haematocrit <45% that was maintained since week 16 with ≤1 phlebotomy occurring post-randomisation and before week 4. Symptom control (using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score [MPN-SAF TSS]) and changes over time in JAK2V617F allele burden were also assessed.

Results

In total, 371 patients were included in the trials and patient demographics and baseline characteristics were similar across trial and treatment groups. Among patients randomised to ruxolitinib, the mean JAK2V617F allele burden decreased from 66.1% to 41.4% at four years. Among patients in the ruxolitinib crossover group, the mean JAK2V617F allele burden decreased from 69.5% to 37.1% at four years. Analysis of the BAT group is limited by small patient numbers after week 32, as most patients crossed over to ruxolitinib. A partial molecular response was achieved by 38.9% of patients in the ruxolitinib groups, and in 35.3% of patients in the crossover groups. Furthermore, 20.7% in the ruxolitinib randomised group, 9.0% in the crossover group and 3.7% in the BAT group achieved a best JAK2V617F allele burden below 10%. Haematocrit control at week 28 was significantly higher with ruxolitinib than with BAT (62.0% vs. 18.2%, p< 0.0001). Durable haematocrit control was maintained to week 80 by 47.3% of patients that were randomised to ruxolitinib while nearly all patients in the BAT arm crossed over to ruxolitinib. Patients randomised to ruxolitinib also experienced greater improvements in symptom severity as compared to BAT. At week 16 and 30, a significantly greater percentage of patients in the ruxolitinib group achieved at least a 50% improvement in MPN-SAF TTS (both p< 0.0001). Similarly, mean improvements in MPN-SAF TTS at week 16 and 30 were significantly greater with ruxolitinib (both p< 0.0001).

Conclusion

Reductions in JAK2V617F allele burden were consistently observed through week 208 in patients treated with ruxolitinib, including those who crossed over from BAT. Furthermore, 39% of patients in de ruxolitinib group achieved a partial molecular response. Patients with PV treated with ruxolitinib achieved durable haematocrit control through week 80 and had better symptom control through week 30 compared with BAT.

Reference

Harrison C, et al. Ruxolitinib Treatment in Polycythemia Vera Results in Reduction in JAK2 Allele Burden in Addition to Improvement in Hematocrit Control and Symptom Burden. Presented at ASH 2023; Poster 4553.

Name: Jakavi 5/10/15/20 mg tablets Composition: Each tablet contains 5/10/15/20 mg ruxolitinib (as phosphate). Excipient with known effect: Each tablet contains 71.45/142.90/214.35/285.80 mg lactose monohydrate. For the full list of excipients, see full leaflet. Pharmaceutical form: Tablet. Therapeutic indications: Myelofibrosis (MF): 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. Polycythaemia vera (PV): Jakavi is indicated for the treatment of adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Graft versus host disease (GvHD): Jakavi is indicated for the treatment of patients aged 12 years and older with acute graft versus host disease or chronic graft versus host disease who have inadequate response to corticosteroids or other systemic therapies (see full leaflet). Posology: Jakavi treatment should only be initiated by a physician experienced in the administration of anti-cancer medicinal products. A complete blood cell count, including a white blood cell count differential, must be performed before initiating therapy with Jakavi. Complete blood count, including a white blood cell count differential, should be monitored every 2-4 weeks until Jakavi doses are stabilised, and then as clinically indicated (see full leaflet). Starting dose: The recommended starting dose of Jakavi in myelofibrosis (MF) is based on platelet counts: Greater than 200,000/mm3: 20 mg orally twice daily - 100,000 to 200,000/mm3: 15 mg orally twice daily - 75,000 to less than 100,000/mm3: 10 mg orally twice daily - 50,000 to less than 75,000/mm3: 5 mg orally twice daily. The recommended starting dose of Jakavi in polycythaemia vera (PV) is 10 mg given orally twice daily. The recommended starting dose of Jakavi in acute and chronic graft versus host disease (GvHD) is 10 mg given orally twice daily. Jakavi can be added to the continued use of corticosteroids and/or calcineurin inhibitors (CNIs). Dose modifications: Doses may be titrated based on efficacy and safety. Myelofibrosis and polycythaemia vera: 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. The starting dose should not be increased within the first four weeks of treatment and thereafter no more frequently than at 2-week intervals. Treatment should be discontinued for platelet counts less than 50,000/mm3 or absolute neutrophil counts less than 500/mm3. 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 re-started at 5 mg twice daily and gradually increased based on careful monitoring of complete blood cell count, including a white blood cell count differential. Dose reductions should be considered if the platelet count decreases during treatment as outlined in Table 2 (see full leaflet), with the goal of avoiding dose interruptions for thrombocytopenia. In PV, dose reductions should also be considered if haemoglobin decreases below 12 g/dl and is recommended if it decreases below 10 g/dl. Graft versus host disease: Dose reductions and temporary interruptions of treatment may be needed in GvHD-patients with thrombocytopenia, neutropenia, or elevated total bilirubin after standard supportive therapy including growth-factors, anti-infective therapies and transfusions. One dose level reduction step is recommended (10 mg twice daily to 5 mg twice daily or 5 mg twice daily to 5 mg once daily). In patients who are unable to tolerate Jakavi at a dose of 5 mg once daily, treatment should be interrupted. Detailed dosing recommendations are provided in Table 3 (see full leaflet). Dose adjustment with concomitant strong CYP3A4 inhibitors or dual CYP2C9/3A4 inhibitors: When ruxolitinib is administered with strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole) the unit dose of ruxolitinib should be reduced by approximately 50%, to be administered twice daily (see section 4.5). The concomitant use of ruxolitinib with fluconazole doses greater than 200 mg daily should be avoided. More frequent monitoring (e.g. twice a week) of haematology parameters and of clinical signs and symptoms of ruxolitinib-related adverse drug reactions is recommended while on strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes.Special populations: Renal impairment, Hepatic impairment, Elderly patients (≥65 years),Paediatric population: see full leaflet. Treatment discontinuation: Treatment of MF and PV may be continued as long as the benefit-risk remains positive. However the treatment should be discontinued after 6 months if there has been no reduction in spleen size or improvement in symptoms since initiation of therapy. It is recommended that, for patients who have demonstrated some degree of clinical improvement, ruxolitinib therapy be discontinued if they sustain an increase in their spleen length of 40% compared with baseline size (roughly equivalent to a 25% increase in spleen volume) and no longer have tangible improvement in disease-related symptoms. In GvHD, tapering of Jakavi may be considered in patients with a response and after having discontinued corticosteroids. A 50% dose reduction of Jakavi every two months is recommended. If signs or symptoms of GvHD reoccur during or after the taper of Jakavi, re-escalation of treatment should be considered. Contraindications: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the full leaflet. Pregnancy and lactation. Undesirable effects: Summary of the safety profile: Myelofibrosis: The most frequently reported adverse drug reactions were thrombocytopenia and anaemia. Haematological adverse drug reactions (any Common Terminology Criteria for Adverse Events [CTCAE] grade) included anaemia (83.8%), thrombocytopenia (80.5%) and neutropenia (20.8%). Anaemia, thrombocytopenia and neutropenia are dose-related effects. The three most frequent non-haematological adverse drug reactions were bruising (33.3%), other bleeding (including epistaxis, post-procedural haemorrhage and haematuria) (24.3%) and dizziness (21.9%). The three most frequent non-haematological laboratory abnormalities identified as adverse reactions were increased alanine aminotransferase (40.7%), increased aspartate aminotransferase (31.5%) and hypertriglyceridaemia (25.2%). In phase 3 clinical studies in MF, neither CTCAE grade 3 or 4 hypertriglyceridaemia or increased aspartate aminotransferase, nor CTCAE grade 4 increased alanine aminotransferase or hypercholesterolaemia were observed. Discontinuation due to adverse events, regardless of causality, was observed in 30.0% of patients. Polycythaemia vera: The most frequently reported adverse drug reactions were anaemia and increased alanine aminotransferase. Haematological adverse reactions (any CTCAE grade) included anaemia (61.8%), thrombocytopenia (25.0%) and neutropenia (5.3%). 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 adverse reactions were weight gain (20.3%), dizziness (19.4%) and headache (17.9%). 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. Acute GvHD: The most frequently reported overall adverse drug reactions were thrombocytopenia, anaemia and neutropenia. Haematological laboratory abnormalities identified as adverse drug reactions included thrombocytopenia (85.2%), anaemia (75.0%) and neutropenia (65.1%). Grade 3 anaemia was reported in 47.7% of patients (grade 4 not applicable per CTCAE v4.03). Grade 3 and 4 thrombocytopenia were reported in 31.3% and 47.7% of patients, respectively. The three most frequent non-haematological adverse drug reactions were cytomegalovirus (CMV) infection (32.3%), sepsis (25.4%) and urinary tract infections (17.9%). The three most frequent non-haematological laboratory abnormalities identified as adverse drug reactions were increased alanine aminotransferase (54.9%), increased aspartate aminotransferase (52.3%) and hypercholesterolaemia (49.2%). The majority were of grade 1 and 2. Discontinuation due to adverse events, regardless of causality, was observed in 29.4% of patients. Chronic GvHD: The most frequently reported overall adverse drug reactions were anaemia, hypercholesterolemia and increased aspartate aminotransferase. Haematological laboratory abnormalities identified as adverse drug reactions included anaemia (68.6%), thrombocytopenia (34.4%) and neutropenia (36.2%). Grade 3 anaemia was reported in 14.8% of patients (grade 4 not applicable per CTCAE v4.03). Grade 3 and 4 neutropenia were reported in 9.5% and 6.7% of patients, respectively. The three most frequent non-haematological adverse drug reactions were hypertension (15.0%), headache (10.2%) and urinary tract infections (9.3%). The three most frequent non-haematological laboratory abnormalities identified as adverse drug reactions were hypercholesterolaemia (52.3%), increased aspartate aminotransferase (52.2%) and increased alanine aminotransferase (43.1%). The majority were grade 1 and 2. Discontinuation due to adverse events, regardless of causality, was observed in 18.1% of patients. Tabulated list of adverse drug reactions from clinical studies and description of selected adverse drug reactions: see full leaflet. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. Marketing authorization holder and numbers: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. EU/1/12/773/004-0012, 014-016 Delivery: Medicinal product subject to prescription. Date of revision of the text: 29.04.2022. Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.e