Ruxolitinib in myelofibrosis: Evidence and experience

Practical insights into the role of ruxolitinib (JAKAVI®) in patients with myelofibrosis are continuing to accumulate, including data from a phase 3b expanded-access trial1 and a recent report identifying predictors of response.2

In this in-depth feature we explore the latest evidence, and speak to some key experts about its use in clinical practice.

Myelofibrosis prognosis

Myelofibrosis is characterised by bone marrow fibrosis, cytopenias, extramedullary hematopoiesis and dysregulation of the Janus kinase (JAK) pathway.3 Varying degrees of splenomegaly are often accompanied by constitutional symptoms (fever, weight loss and night sweats) and other symptoms including fatigue, pruritus and abdominal pain. Patients with high and intermediate-2 risk disease have a median life expectancy of about 1.5 to 4 years.

Allogeneic hematopoietic stem cell transplantation is the sole curative option.4 Most patients are ineligible for transplantation because of age or comorbidities, so treatment for the majority is focussed on symptom control and prolonging survival.

Ruxolitinib is indicated in Australia for the treatment of disease-related splenomegaly or symptoms in patients with primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis.5 It is available on the PBS for patients with high risk, intermediate-2 risk and intermediate-1 risk disease.

Efficacy of ruxolitinib

Ruxolitinib, a potent and selective JAK1/JAK2 inhibitor, was assessed in the phase 3 COMFORT-1 and COMFORT-2 studies.6,7

COMFORT-1 randomised 309 patients with intermediate-2 or high-risk myelofibrosis, including a number recruited at Australian centres, to twice-daily oral ruxolitinib (15 mg or 20 mg according to platelet count) or placebo.6

The primary end point, defined as the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, was reached by 41.9% of patients in the ruxolitinib group compared to 0.7% in the placebo group (P<0.001). Among responders, a reduction in spleen volume was maintained at 48 weeks.

The total symptom score at 24 weeks improved by 50% or more in 45.9% of ruxolitinib-treated patients compared to 5.3% of those randomised to placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group compared with 24 in the placebo group (hazard ratio 0.50, P=0.04).

The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Anaemia and thrombocytopenia were the most common adverse events in patients who received ruxolitinib, but they led to discontinuation of the drug in only one patient for each event.

The COMFORT-II study randomised 219 patients with intermediate-2 or high risk high myelofibrosis to ruxolitinib or best available therapy.7 A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48 (the primary endpoint) compared to none in the group receiving the best available therapy (P<0.001). The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at 12 months.

Patients treated with ruxolitinib had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anaemia, which were managed with a dose reduction, interruption of treatment, or transfusion.

Both COMFORT studies have reported long-term follow-up data, including patients who crossed from control groups to ruxolitinib treatment at the conclusion of the randomised phase. In the final 5-year analysis of COMFORT-1, patients randomised to ruxolitinib had a median spleen response duration of 168.3 weeks.8 The median overall survival in that group had not been reached, compared to 200 weeks in the placebo group (HR 0.69, 95% CI 0.50-0.96, P = 0.025) despite the crossover to ruxolitinib.

“The final COMFORT-I results continue to support ruxolitinib as an effective treatment for patients with intermediate-2/high-risk myelofibrosis,” the study team concluded.

For patients in COMFORT-II who achieved a reduction in spleen volume of at least 35% at any point during initial ruxolitinib treatment, the probability of maintaining response was 0.48 at 5 years (median 3.2 years).3 Median overall survival was not reached in the ruxolitinib arm and was 4.1 years in the control arm. There was a 33% reduction in risk of death with ruxolitinib compared with best available therapy, increasing to 56% when corrected for cross-over.

An exploratory analysis of 5-year data pooled from both COMFORT trials found the risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS 5.3 vs 3.8 years, respectively; HR 0.70, P=0.0065).9

Real-world outcomes

The JAK Inhibitor Ruxolitinib in Myelofibrosis Patients (JUMP) study, a phase 3b expanded-access trial, has enrolled 2,233 patients at more than 200 study sites in 26 countries. A 2016 analysis included 1,144 patients with intermediate- or high-risk myelofibrosis who had been treated with ruxolitinib for at least a year.1

As expected, the most common haematologic adverse events were anaemia and thrombocytopenia, but they led to treatment discontinuation in only a few cases. The most common non-haematologic adverse events were primarily grade 1/2 and included diarrhoea, pyrexia, fatigue and asthenia. The majority of patients (62.3% at week 48) achieved a ≥50% reduction from baseline in palpable spleen length.

“Improvements in symptoms were rapid, with approximately half of all patients experiencing clinically significant improvements,” the researchers said.
The JUMP trial1 also included 163 patients classified as intermediate-1-risk, a group that was not included in the COMFORT studies.

Similar to the higher-risk patients, the majority of these patients experienced clinically meaningful reductions in spleen size and improvements in disease-related symptoms.

At week 48, 60.5% of intermediate-1-risk patients achieved a ≥50% reduction from baseline in palpable spleen length.

The adverse event profile of ruxolitinib in intermediate-1-risk patients was consistent with that previously reported in higher-risk patients.

Predictors of response

The response to ruxolitinib in patients with myelofibrosis can be unpredictable at the start of treatment. A review of 408 Italian patients identified 34.9% as achieving a spleen response.2

Pre-treatment factors predicting a lack of response were high or intermediate-2 risk, large splenomegaly, transfusion dependency, platelet count <200×109/L, and a delay or more than 2 years in commencing ruxolitinib after the diagnosis of myelofibrosis. Patients treated with higher average ruxolitinib doses in the first 12 weeks (10 mg bd or more) achieved a higher response rate.

Ruxolitinib in practice

Speaking to the limbic Associate Professor Robert Bird, Director of Laboratory Haematology and a Clinical Haematologist at Princess Alexandra Hospital, said that constitutional symptoms were a major concern for most patients with more advanced stages of myelofibrosis.

“These include lethargy, anorexia, weight loss and aches and pains. The controlled clinical trials of ruxolitinib showed marked improvement in these symptoms, and subsequent clinical experience reflects this. It is very gratifying to see patients 2 to 4 weeks after starting ruxolitinib: their whole demeanour has changed.

He says the trial data on reduced spleen size is also borne out in clinical experience, with a surprisingly rapid reduction in splenomegaly and associated reduction in spleen-related symptoms.

“Perhaps the most exciting observation to emerge subsequent to the initial clinical trial data is improved survival for ruxolitinib-treated patients,” Professor Bird said. “Improving survival along with quality of life is one of the key goals in medicine.”

According to Professor Bird it was very fortunate that the PBS criteria essentially allowed ruxolitinib treatment for all patients with symptomatic myelofibrosis, whether intermediate-1, intermediate-2 or high risk, and regardless of whether it is primary or secondary to essential thrombocythaemia or polycythaemia vera.

“The unanswered question is whether patients with low risk myelofibrosis will benefit from treatment with ruxolitinib in terms of slowing disease progression and improved survival,” he says.

“This question is currently being addressed in clinical trials, but because of the relatively good prognosis for untreated patients in this group, any significant improvement in survival will take years to demonstrate.”

Some practical tips

Professor Bird provided some practical tips on managing ruxolitinib therapy:

  • Anaemia: “Characteristically worsens after initiation of ruxolitinib, but paradoxically I have seen previously transfusion-dependent patients become transfusion-independent due to improved symptom control,” he says. “Anaemia will improve over a few weeks so occasionally transfusion may be needed in the early stages of treatment, but this does not necessarily mean an ongoing transfusion requirement.”
  • Minimum dose: “The minimum dose of ruxolitinib which appears to confer survival benefit is 10 mg bd,” he says. “I try not to drop below this dose, although this is occasionally required due to cytopenias.”
  • Abrupt withdrawal: “Never abruptly withhold ruxolitinib or rebound constitutional symptoms will rapidly recur. The early description of a systemic inflammatory-like syndrome on abrupt ruxolitinib withdrawal, however, is very rarely encountered.”

Managing cytopenia key to maximising therapeutic benefit

Professor Joy Ho, from Royal Prince Alfred Hospital in Sydney, and colleagues have provided further practical guidance on the use of ruxolitinib.4,10 “Consistent with the physiological role of JAK signalling, the major toxicity of ruxolitinib is cytopenia,” they wrote. “Managing cytopenia is key to maximising the therapeutic benefit.”

Professor Ho and colleagues said efficacy should be assessed clinically by palpation of the spleen and liver, and by the patient’s report of symptoms. MRI, ultrasound imaging, bone marrow morphology and JAK2 allele burden do not assist in evaluating the response. Safety is monitored primarily by blood counts, which should be checked every 1-2 weeks initially.

The Product Information for Jakavi provides clear advice on dosing in relation to the initial platelet count. “Dose titration is the key to managing adverse events,” Professor Ho and colleagues said.

“Dose interruptions should be avoided where possible to prevent sudden rebound of symptoms. Improvements in splenomegaly and symptom burden are greatest in patients on doses of at least 10 mg bd.”

Their papers provide detailed advice on managing side effects, the duration of treatment, and protocols for ceasing the medication.



  1. Al-Ali HK et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica 2016; 101: 1065-1073.
  2. Palandri F et al. Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. Oncotarget 2017; 8: 79073-79086.
  3. Harrison CN et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia 2016; 30: 1701-7.
  4. Ho PJ et al. Practical management of myelofibrosis with ruxolitinib. Intern Med J 2015; 45: 1221-30.
  5. JAKAVI Approved Product Information.
  6. Verstovsek S et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366: 799-807.
  7. Harrison C et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012; 366: 787-98.
  8. Verstovsek S et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol 2017; 10: 55.
  9. Verstovsek S et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol 2017; 10: 156.
  10. Ho PJ et al. A case-based discussion of clinical problems in the management of patients treated with ruxolitinib for myelofibrosis. Intern Med J 2017; 47: 262-268.

AU3939 – October 2019

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