In the management of myelofibrosis (MF), Dynamic International Prognostic Scoring System (DIPSS) and DIPSS-plus are commonly used prognostic scoring systems for stratifying the risks of patients and guiding treatment decisions.¹ However, these scoring systems do not fully reflect the totality of symptom burden of MF patients.¹ In reality, some MF patients with lower risk scores could be highly symptomatic, and treatments are needed to reduce the spleen length, alleviate their symptoms and improve their quality of life (QoL).¹ In an interview with Omnihealth Practice, Dr. Harry Gill discussed the unmet treatment needs in patients with symptomatic low- or intermediate-1 (INT-1)-risk MF (as per DIPSS and DIPSSplus) and shared 2 clinical cases to demonstrate the benefits of early treatment with ruxolitinib in symptomatic low- or INT-1-risk MF patients.

Beyond DIPSS/DIPSS-plus: Addressing the unmet needs among lower-risk MF patients

MF is a chronic Philadelphia chromosome (Ph)-negative myeloproliferative neoplasm (MPN) which may occur as a primary or secondary MF (following polycythemia vera [PV] or essential thrombocythemia [ET)].¹ The pathogenesis of MF is characterized by mutations such as Janus kinase 2 (JAK2), calreticulin gene (CALR) or myeloproliferative leukemia (MPL), resulting in dysregulation of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling.¹ In general, the main clinical MF manifestations include splenomegaly and constitutional symptoms of fatigue, fever or anemia.^1,2 Other complications include symptomatic portal hypertension that might lead to variceal bleeding or ascites.²

DIPSS is one of the commonly used prognostic scoring systems in MF which includes age, hemoglobin (Hb) level, leukocyte count, circulating blast, and the presence of constitutional symptoms; while DIPSS-plus is recognized as a more accurate system, which considers platelet count, the need for red blood cell (RBC) transfusion and unfavorable karyotype, on top of the 5 criteria of the DIPSS.³ Although DIPSS and DIPSS-plus are informative for the prognostic prediction of MF patients, neither of them could reflect the severity of the symptom burden of MF patients.¹ Since MF-associated symptom burden could be debilitating to these patients,  it would also be clinically meaningful to take patients’ symptomatic improvements into account when making treatment decisions.¹

Ruxolitinib in the management of lower-risk myelofibrosis

Ruxolitinib is the first-in-class JAK1/JAK2 inhibitor currently approved for the treatment of MF-related splenomegaly and/or symptoms.⁴ The approval was based on the positive results of the pivotal phase 3 COMFORT-I and COMFORT-II studies.⁵ In the COMFORT I trial, 41.9% of INT-2- or high-risk MF patients treated with ruxolitinib reached the primary endpoint (i.e. ≥35% reduction in spleen volume at 24 weeks) vs. 0.7% in the placebo group (p<0.001); while in the COMFORT II trial, ruxolitinib treatment reduced the spleen volume by ≥35% in 28% of INT-2- or high-risk MF patients at 48 weeks vs. 0% among patients treated with best available therapy.^5,6 In other studies such as JUMP, a large phase 3b expanded-access trial, ruxolitinib also achieved clinically meaningful improvements in spleen length and symptoms, as well as high treatment tolerability, among low- and/or INT-1-risk MF patients.^7,8 In local clinical practice, Dr. Gill had experiences in treating low- or INT-1-risk MF patients with ruxolitinib and shared 2 clinical cases to show the real-world benefits of early ruxolitinib treatment.

Case 1: A 30-year-old female patient with INT-1 risk MF and high-risk JAK2V617F mutation

A 30-year-old female complained of prolonged abdominal distension for over 6 months and was subsequently diagnosed with overt MF of high-risk JAK2V617F mutation, also involving inactivating mutations in histone methyltransferase of enhancer of zeste homolog 2 (EZH2).  Recording a low Hb level of 7.9g/dL with presenting symptoms, the patient was classified as INT-1-risk MF by DIPSS. Her spleen length was 25cm by palpation measured from the left costal margin and extended below umbilicus. The patient also had portal hypertension due to pressure from the enlarged spleen. In consideration of her high symptom burden, the patient was treated with ruxolitinib for improving symptoms and preventing complications associated with splenomegaly. .

During the first month of ruxolitinib treatment, the patient’s palpable spleen length was reduced remarkably to 17.5cm with a manageable Hb level of 7.1g/dL (figure 1). In the following 2 months, her condition continued to improve, and her palpable spleen length was further reduced to 10cm, and her Hb level was increased to 8.0g/dL. In the seventh month, thalidomide was added to the regimen for improving her anemia. Her Hb level was then further increased to 9-10g/dL. As of June 2022, the patient had been on ruxolitinib for 9 months with an overall reduction in palpable spleen length of 80% (i.e., down from 25cm to 5.0cm). During the whole course of ruxolitinib treatment, the patient did not experience any serious adverse events (AEs) that required dose interruption or modification.

Case 2: A 42-year-old male patient with low-risk MF

A 42-year-old man was hospitalized for abdominal discomfort. A complete blood count (CBC) incidentally showed elevated levels of white blood cell count (i.e., 14 x 10⁹/L) and platelet count (i.e., 950 x 10⁹/L), as well as a slightly reduced Hb level (i.e., 12.5g/dL). The peripheral blood film indicated the presence of tear-drop poikilocytes with no evidence of circulating blasts. Physical examination revealed the presence of splenomegaly, which was 8cm below the left costal margin. A computed tomography (CT) scan of the abdomen showed splenomegaly and changes, which were indicative of portal hypertension. The bone marrow aspirate was aparticulate, and the trephine biopsy confirmed the diagnosis of overt primary MF. Cytogenetic study showed a normal karyotype, while the next-generation sequencing confirmed the presence of type 1 calreticulin (CALR) mutation and tet methylcytosine dioxygenase 2 (TET2) mutation. He did not complain of weight loss, loss of appetite or night sweats

The patient was deemed low risk by the DIPSS and was initially treated with pegylated interferon alfa-2a. Two months later, he complained of progressive epigastric discomfort. His spleen was palpable 10cm below the left costal margin, and an upper endoscopy showed the presence of oesophageal and gastric varices. There was no evidence of liver cirrhosis, as the patient was not a hepatitis B or C carrier. The overall findings suggested worsened portal hypertension secondary to splenomegaly.

Subsequently, the patient switched to ruxolitinib 15mg twice daily (BID). After 3 months of the ruxolitinib treatment, his spleen was no longer palpable, and a reassessment of upper endoscopy showed that his oesophageal, and gastric varices had also resolved.

Discussion

Remarkable improvement in response in spleen volumn  and symptom burden with ruxolitinib in clinical trial

JUMP is a single-arm, open-label, phase 3b expanded-access trial for assessing the safety and efficacy of ruxolitinib among MF patients, including those with low- and INT-1 risks who were not included in the COMFORT trials.^7,9 A total of 2,233 patients aged ≥18 years with a diagnosis of primary or secondary MF by the World Health Organization (WHO) and the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria were enrolled in this trial and were stratified by the DIPSS as high (n=194), INT-2 (n=755), INT-1 (n=835), or low-risks (n=60).⁹

Overall, ruxolitinib provided clinically meaningful reductions in spleen length and symptoms for MF patients across all the risk subgroups and was generally well tolerated.⁷ At week 48, 64.3% of low-risk MF patients and 63.6% of INT-1-risk MF patients achieved ≥50% reduction in spleen length; and by week 72, the proportion increased to 78.3% and 67.6%, respectively (figure 2).⁹ Furthermore, the median time to first 50% reduction in spleen length was 4.6 weeks for INT-1-risk MF patients vs. 7.1 weeks and 8.1 weeks for the INT-2 and high-risk groups, respectively.⁹ With ruxolitinib, 13.3% of INT-1-risk MF patients achieved a complete resolution of splenomegaly.⁹ Clinically meaningful improvements in symptoms as per the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) total score (TS) and the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale were observed in 45%-50% of the overall JUMP population.⁷ Among the INT-1-risk MF patients, symptomatic improvements were observed as early as 4 weeks since the treatment initiation.⁷

Optimizing treatment response with ruxolitinib by effective AE management

Dr. Gill emphasized that it is crucial to consider baseline patient characteristics for obtaining optimal treatment response from ruxolitinib. Specifically, CBC is recommended before treatment initiation, and the initial dose of ruxolitinib ought to be based on the baseline platelet counts.³ During the course of ruxolitinib treatment, Dr. Gill reminded that physicians should be aware of the possible occurrence of cytopenias.^3,10 In the JUMP study, anemia and thrombocytopenia were the most commonly reported hematological AEs. ⁹ For low or INT-1-risk patients treated with ruxolitinib, the median Hb level decreased from baseline (106g/L) to a nadir from week 4 to 24 (94-99g/L), but after week 24, it rebounded gradually to near baseline level (figure 3).⁹ Dose adjustment and RBC transfusion are effective approaches to manage more serious anemia and to reduce the likelihood of temporary or permanent treatment discontinuation. However, it should be noted that the dose of ruxolitinib should not be lowered to ≤5mg BID since studies have shown that such a low dose of ruxolitinib was associated with reduced efficacy of ruxolitinib.¹⁰ To retain clinically meaningful reductions in spleen volume and symptomatic improvements by ruxolitinib, the final titrated doses are suggested to maintain at ≥10mg BID (figure 4).¹⁰

Beyond observation: Consider 3 “S” and improve outcomes in low-/INT-1-risk patients with high symptom burden

As a matter of fact, some low- or INT-1-risk MF patients have high symptom burden and complications such as splenomegaly, severely impairing their quality of life. “In the management of MF, we need to consider 3 “S”, namely spleen size, symptom, in addition to survival. In other words, low-risk or INT-1 risk MF does not mean just observation,” Dr. Gill stated, “it is imperative to assess the symptom burden of patients with lower risks early so as to allow timely intervention. As recommended by the latest National Comprehensive Cancer Network (NCCN) guidelines, the MPN-10 questionnaires should be integrated into routine clinical practice to identify the subtle symptoms with MF early since only by regular monitoring of symptoms can optimal treatment be offered to patients in a timely fashion.”  Supported by the published clinical data, guidelines recommend initial treatment with ruxolitinib in symptomatic MF patients with lower risks, including low- and INT-1-risk, for alleviating symptom burden and reducing spleen size.³ “When clinical benefits with ruxolitinib in these patients are observed, the treatment has to go on to control their symptoms and maintain their quality of life,” Dr. Gill stressed, “regular reassessment of symptoms using MPN-10 questionnaires should be continued during the course of therapy so that treatment could be adjusted accordingly to achieve optimal patient outcomes.”

Key takeaways

• Low-risk or INT-1-risk MF does not necessarily mean observation because some lower-risk patients by current scoring systems may have high symptom burden which could impair their QoL
• The median time to the first 50% reduction in spleen length was 4.6 weeks for INT-1-risk MF patients vs. 7.1 weeks and 8.1 weeks for the INT-2 and high-risk groups in JUMP study
• Dr. Gill recommended considering 3 “S”, namely spleen size, symptom, and survival, for making treatment decisions in MF management
• JAK inhibitors which demonstrated remarkable efficacy in clinical studies and local practice, should be considered for low-/INT-1-risk patients with high symptom burden and complications such as splenomegaly
• Effective AE management is crucial for obtaining optimal treatment response with ruxolitinib in low-/INT-1-risk patients. When clinical benefits with ruxolitinib in these patients are observed, the treatment should continue to control the symptoms and maintain their QoL
• Regular assessment of patients’ symptom burden using the MPN-10 questionnaires is recommended and can allow for timely ruxolitinib treatmentt

_{JAKAVI^®
Important note: Before prescribing, consult full prescribing information.
Presentation: Tablets containing 5 mg, 10 mg, 15 mg, and 20 mg ruxolitinib.
Indications: • 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. • Treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea. • Treatment of patients aged 12 years and older with acute or chronic graft-versus-host disease who have inadequate response to corticosteroids or other systemic therapies. Dosage and administration: • Complete blood cell counts must be performed before initiating Jakavi^®. Complete blood counts should be monitored every 2 to 4 weeks until optimal dose is reached. •Administration twice daily at the same time every day, with or without food. • Recommended starting dose for adults in MF: 20 mg (platelet count >200,000/mm³), 15 mg (platelet count between 100,000 and 200,000/mm³) and 10 mg (platelet count between 75,000 and 100,000/mm³), 5mg (platelet count between 50,000 and 75,000/mm³), orally twice daily. •Recommended starting dose for adults in PV and for pediatrics aged 12 years and older and adults in GvHD: 10 mg twice daily. •Dose adjustments and temporary interruptions are recommended in MF-patients with thrombocytopenia and in GvHD-patients with thrombocytopenia, neutropenia, and hyperbilirubinemia (see full prescribing information). •Treatment should be interrupted if platelet counts <50,000/mm³ or ANC <500/mm³ (MF and PV patients) or Hb <8g/dL (in PV patients).•In PV, dose reduction to be considered if Hb <12 g/dL and recommended if Hb <10 g/dL.•Dose adjustment may be required due to thrombocytopenia or when used with strong CYP3A4 inhibitors or dual moderate inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole; avoid concomitant use of fluconazole >200 mg daily). • The starting dose should not be increased within the first 4 weeks of treatment and thereafter no more frequently than at 2-week intervals. •Maximum dose is 25 mg twice daily. •Treatment to be continued as long as the benefits outweigh the risks for the patient. Tapering in GvHD-patients may be considered in responders who have discontinued corticosteroids. 50% dose reduction every 2 months recommended. If signs or symptoms reoccur during or after the taper, consider treatment re-escalation. •Recommend to reduce the starting dose by approximately 50% in MF, PV and GvHD patients with severe renal impairment (Clcr <30 mL/min), and with hepatic impairment. Patients diagnosed with renal or hepatic impairment should be monitored and the dose should be reduced as appropriate. •No additional dosage adjustment required for elderly patients. • The safety and efficacy of Jakavi in children and adolescents aged up to 18 years with MF and PV have not been established. The Jakavi dose in paediatric patients with GvHD aged 12 years and older is the same as in adults. The safety and efficacy of Jakavi have not been established in patients less than 12 years of age. Contraindications: Hypersensitivity to ruxolitinib or to any of the excipients. Pregnancy and lactation. Warnings and precautions: •Decrease in blood cell count: hematologic adverse drug reactions, including thrombocytopenia, anaemia and neutropenia, have been reported with Jakavi treatment. Complete blood counts must be performed. Dose reduction or interruption may be required in patients developing thrombocytopenia, anaemia and neutropenia. • 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. Jakavi therapy should not be started until active serious infections have resolved. Tuberculosis cases have been reported. Before starting treatment patients should be evaluated for active and inactive (“latent”) tuberculosis, as per local recommendations. Hepatitis B viral load (HBV-DNA titre) increases have been reported in patients with chronic HBV infections. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines. •Herpes zoster: Physician to educate patients about early signs and symptoms of herpes zoster, advising that treatment should be sought as early possible . •Progressive multifocal leukoencephalopathy (PML) has been reported. Physicians should be alert for symptoms suggestive of PML (e.g., cognitive, neurological or psychiatric symptoms or signs). If PML suspected suspend treatment until PML is excluded. •Non-Melanoma Skin Cancer (NMSC): NMSC, including basal cell, squamous cell, and Merkel cell carcinoma, have been reported in Jakavi treated patients. Periodic skin examination recommended. •Lipid Abnormalities/Elevations: Increases in lipid parameters, including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides have been associated with Jakavi. Monitoring and treatment of dyslipidaemia is recommended. •Hepatic and severe renal impairment: Due to increased Jakavi exposure, dose reduction is required.  Pregnancy, lactation, females and males of reproductive potential Pregnancy: Use in pregnancy is contraindicated. Breast-feeding: Women taking Jakavi must not breast-feed. Contraception: Sexually active females should use effective contraception during treatment. In case pregnancy should occur during treatment, a risk/benefit evaluation must be carried out with careful counselling regarding potential risks to the foetus Adverse drug reactions: Myelofibrosis Very common (>10%): Urinary tract infections, herpes zoster, pneumonia, anaemia, thrombocytopenia, neutropenia, gastrointestinal bleeding, other bleeding, hypercholesterolaemia, hypertriglyceridaemia, dizziness, headache, elevated lipase, constipation, ALT increased, AST increased, hypertension, bruising, weight gain. Common (1 to 10%): Sepsis, pancytopenia, intracranial bleeding, flatulence. Uncommon (0.1 to 1%): Tuberculosis. Polycythemia vera Very common (>10%): Urinary tract infections, herpes zoster, anaemia, thrombocytopenia, bruising, other bleeding, hypercholesterolaemia, hypertriglyceridaemia, weight gain, dizziness, headache, elevated lipase, constipation, ALT increased, AST increased, hypertension. Common (1 to 10%): Pneumonia, neutropenia, pancytopenia, gastrointestinal bleeding, flatulence. Not known (frequency cannot be estimated): Tuberculosis. Acute Graft versus host disease Very common (>10%): CMV infections, sepsis, UTI, thrombocytopenia, anaemia, neutropenia, pancytopenia, hypercholesterolemia, hypertension, nausea, increased ALT and AST.  Common (1 to 10%): headache. Chronic Graft versus host disease  Very common (>10%): Thrombocytopenia, anaemia, neutropenia, hypercholesterolemia, headache, hypertension, increased lipase, increased amylase, increased ALT and AST, increased blood CPK, increased blood creatinine Common (1 to 10%): CMV infections, UTI, BK virus infections, constipation Interactions:  Dose of Jakavi should be reduced by approx. 50%, to be administered twice daily, when co-administered with strong CYP3A4 inhibitors or dual inhibitors of CYP3A4 and CYP2C9 enzymes. Avoid fluconazole daily doses >200 mg.  
Packs and prices: 56’s pack Legal classification: P1S1S3
Reference: EMA Mar 2022 (included Canada Jun 2021 PI on VTE, 2018-PSB/GLC-0930-s, 2020-PSB/GLC-1108-s and 2020- PSB/GLC-1155-s)}

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