A haematologist’s experience of ruxolitinib in Intermediate-1 myelofibrosis patients

Blood cancers


14 Sep 2016

The selective Janus kinase (JAK) 1 and JAK2 inhibitor ruxolitinib was approved by the PBS in February for use in patients with myelofibrosis1 Dr Lynette Chee, a consultant haematologist at the Royal Melbourne Hospital, describes its use in a 43-year-old woman with Intermediate-1 risk myelofibrosis. She also outlines the evidence around the drug and gives some advice to treating haematologists on antiviral prophylaxis.

Indications for use

Ruxolitinib, a selective Janus kinase (JAK) 1 and JAK2 inhibitor, has been approved by the Pharmaceutical Benefits Scheme in Australia since 1 February 2016 for use in patients with primary myelofibrosis or post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis with the disease severity of high risk or Intermediate-2 risk or Intermediate-1 risk with severe disease-related symptoms which are resistant, refractory or intolerant to available therapy.1,2

Measuring disease severity

The disease severity is calculated from the Dynamic International Prognostic Scoring System (DIPSS) which is based on age >65 years, Hb <100g/L, white cell count >25×109/L, peripheral blood blasts ≥1% and presence of constitutional symptoms.3 The age-adjusted DIPSS can be applied to younger patients <65 years using similar variables excluding age.3 DIPSS-Plus includes all the above variables and in addition, transfusion dependence, platelets <100×109/L and unfavourable cytogenetics.4

The evidence

The Phase III COMFORT-I (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I) study conducted in the United States, Canada and Australia, demonstrated the efficacy of ruxolitinib in comparison to best available treatment (BAT) in reducing the spleen size, reducing the often significant myelofibrosis-related constitutional symptoms and improving overall survival in higher-risk (Intermediate-2 and High) patients with myelofibrosis.5

The most common adverse event was that of worsening anaemia and thrombocytopenia in the first 3 months of commencing treatment with gradual improvement thereafter in responders.5 The COMFORT-II trial conducted in Europe demonstrated similar efficacy in improvement in splenomegaly and constitutional symptoms.6 In the three-year and five-year follow-up analysis, there was a survival benefit demonstrated in the ruxolitinib arm with a reduction in the risk of death by 52% (p=0.009) and 33% (p=0.06, not significant) respectively, with crossover from the BAT to ruxolitinib arm confounding results.7,8

However, the safety and efficacy of ruxolinitib in lower-risk myelofibrosis were not studied in these trials and as splenomegaly, constitutional symptoms and reduced quality of life can similarly affect this lower-risk group of patients, whether the benefits of ruxolitinib extend to this patient cohort is of interest.5,6

The case study

Here we present a case of a 43-year-old female patient who presented with bone pain and mild lymphadenopathy in whom subsequent blood tests revealed a normocytic anaemia and thrombocytosis.

Haemoglobin was 105g/L, white cell count 6.3 and platelets 572×109/L. The blood film showed marked red cell anisopoikilocytosis with occasional teardrop cells, hypersegmented neutrophils and moderate platelet anisocytosis suggestive of a myeloproliferative disorder.

There were no blasts seen on the peripheral blood smear. A bone marrow biopsy confirmed the diagnosis of myelofibrosis (MF-3 reticulin stain) likely transformed from essential thrombocythaemia based on megakaryocyte morphology. Cytogenetics was normal and molecular mutations were negative for JAK2 and positive for calreticulin (CALR). Based on these findings, her DIPSS score was 1 for constitutional symptoms which placed her in the Intermediate-1risk category with an expected median overall survival of 14.2 years.3

Using the revised DIPSS-Plus score, her score was also 1 placing her in the Intermediate-1 risk category with a estimated median survival of 80 months.4 Due to her relatively young age, she was referred for consideration of an allogeneic stem cell transplantation should her disease progress to a higher-risk category.

Over the course of the next 2–4 months, her constitutional symptoms worsened with night sweats, fatigue and increasing bone pain. She had no palpable splenomegaly. Her full blood examination abnormalities remained stable with no signs of progression. She was commenced on ruxolitinib 20mg twice daily which she tolerated well.

As expected, her haemoglobin dropped to a nadir of 82g/L on commencement of ruxolitinib and her platelet count normalised. Her bone pain, night sweats and fatigue completely resolved following 2 months of treatment and she remains red cell transfusion-independent with a haemoglobin ranging between 85–90g/L after 6 months of treatment.

Managing myelofibrosis patients in the Intermediate-1 risk category

In the UK ROBUST Phase II trial (Mead et al, BJH, 2015) which assessed the efficacy of ruxolitinib in Intermediate-1 (n=14), Intermediate-2 (n=13) and high-risk (n=21) myelofibrosis, the primary endpoint was a reduction in splenomegaly by ≥50% by palpation and/or a ≥50% decrease in Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF TSS) at 48 weeks.9

This is in contrast to the COMFORT studies which assessed reduction in spleen volume of ≥35% by magnetic resonance imaging (equivalent to approximately 50% reduction by palpation).5,6

All Intermediate-1 risk category patients had palpable splenomegaly ≥5cm from the costal margin.9 Across all risk groups, the overall response rate was 50% (57% in the Intermediate-1 group with no significant differences between risk groups).9

A ≥50% reduction in splenomegaly at week 48 was achieved in 39.6% of patients (50% in Intermediate-1, 15.4% in Intermediate-2, 47.6% in high) with a median duration of response of 32.3 weeks (16.1 weeks for Intermediate-1, 23.9 weeks for Intermediate-2 and 32.7 weeks for high).9 With regard to the symptomatic improvement as assessed by the MF-SAF TSS, a ≥50% reduction at week 48 was achieved in 20.8% of patients (Intermediate-1 21.4%, Intermediate-2 23.1%, high 19%).9 Progression-free survival was estimated at 87% and overall survival at 89% at 48 weeks.9

A larger Phase IIIB JUMP (JAK Inhibitior RUxolitinib in Myelofibrosis Patients) study reported on the safety and efficacy of ruxolinitib in patients with myelofibrosis on a single-arm expanded access programme off-trial across 26 countries (Europe 76%, Latin America 9%, Others 15%). This study included the largest cohort to date of 163 patients with lower risk Intermediate-1 myelofibrosis who had palpable splenomegaly (≥5cm from the costal margin).10

The primary endpoint was adverse events and secondary endpoints were >50% reduction in splenomegaly, patient-reported outcomes and progression-free, leukaemia-free and overall survival.10 The adverse event profile was consistent with that previously reported in the COMFORT studies, with only a 0.6% and 1.8% discontinuation rate for anaemia and thrombocytopenia respectively.10 The rates of infection were low, and infections were primarily grade 1/2 with a herpes zoster infection rate of 8%.10

The efficacy of reduction in splenomegaly at 24 weeks was 64% and at 48 weeks was 61% with a median time to first ≥50% reduction of 4.7 weeks.10 Approximately 30-40% of patients reported an improvement in the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and FACIT-Fatigue score at Weeks 4, 12, 24 and 48 of treatment.10 After a median follow-up period of 59 weeks, progression-free survival was estimated at 95% at 48 weeks with 5 disease progression and 2 deaths.10 Overall survival after a median follow-up of 60 months was 98% at 48 weeks with 3 deaths.10

The overall results from these two studies indicate the effectiveness of ruxolitinib in managing myelofibrosis patients in the Intermediate-1 risk category with benefits seen in reduction of splenomegaly and/or improvement in disease-related constitutional symptoms.9,10

The expected toxicity profile is similar to that seen in the higher-risk patients studied in the COMFORT-I and II trials with haematological toxicities manageable through judicious dose adjustments.9,10

The bottom line

Treating haematologists should, however, be cautious about infection risk due to the immunosuppressive effects of ruxolitinib and antiviral prophylaxis is recommended,11 particularly in at-risk populations.2 The survival benefit demonstrated in the higher-risk myelofibrosis patients, however, still needs to be proven through randomised studies in the Intermediate-1 group and may be difficult to demonstrate due to their relatively long expected median survival of 14.2 years compared with 1.5-4 years for the higher-risk groups (groups according to Passamonti and colleagues).3,9

As such, the long-term effects of prolonged ruxolinitib administration is unknown currently and whether commencement at an earlier stage of disease is beneficial in eradicating the abnormal clones thereby inducing durable remissions or whether it promotes resistance remains to be determined.


Please review approved Product Information before prescribing. Approved Product Information available on request from Novartis or at www.novartis.com.au/products/healthcare-professionals

1. Pharmaceutical Benefits Scheme. Available at: www.pbs.gov.au. Accessed June 2016. 2. JAKAVI Product Information. Available at: www.novartis.com.au/products/healthcare-professionals.shtml. Accessed July 2016. 3. Passamonti F et al. Blood 2010;115:1703–8. 4. Gangat N et al. J Clin Oncol 2011;29:392–7. 5. Verstovsek S et al. N Engl J Med 2012;366:799–807. 6. Harrison C et al. N Engl J Med 2012;366:787–98. 7. Cervantes F et al. Blood 2013;122:4047–53. 8. Harrison CN et al. Long-Term Efficacy and Safety in COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy for the Treatment of Myelofibrosis: 5-Year Final Study Results. Poster Presentation at the 57th Annual American Society of Hematology Meeting; December 5–8, 2015; Orlando, FL, USA; P59. 9. Mead AJ et al. Br J Haematol 2015;170:29–39. 10. Giraldo P et al. Safety And Efficacy Of Ruxolitinib In Patients With Intermediate-1–Risk Myelofibrosis From an Open-Label, Multicenter, Single-Arm Expanded-Access Study. Poster Presentation at the 20th Annual European Haematology Association Congress; June 11–14, 2015; Vienna, Austria; P675. 11. Ho J et al. Int Med J 2015:45:1221–30.

Novartis Pharmaceuticals Pty Limited. 54 Waterloo Road, Macquarie Park NSW 2113. ABN 18 004 244 160 Ph. (02) 9805 3555. For medical enquiries please contact 1800 671 203 (phone) or medinfo.phauno@novartis.com (email). ® Registered Trademark. JAK0192 NOV3314. Prepared September 2016.

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