Diagnosis and Treatment of Myelofibrosis - Episode 3

Myelofibrosis: Long-Term Survival Data and Ruxolitinib Use

July 16, 2018

Jamile Shammo, MD:I consider ruxolitinib for patients who have myelofibrosis when I feel that their constitutional symptoms and their splenomegaly are compromising their quality of life. And, frankly, ruxolitinib is the only drug that we have available for the treatment of myelofibrosis. Sometimes patients who present with anemia as a sole cytopenia in myelofibrosis and tend to not have large spleen or constitutional symptoms, they will be treated accordingly, in essence, with agents that might improve their hemoglobin. So, I may not necessarily consider ruxolitinib in that instance. But someone who has significant constitutional symptoms, splenomegaly would be a person that I think would benefit greatly. And, of course, we have to stay within the FDA indication because the drug is approved for people who have intermediate-2 and high-risk disease. So, if I have a patient who fits that profile and has high-risk disease, they will be treated accordingly.

Patients who are started on ruxolitinib for the indication of myelofibrosis usually utilize a dose that’s based on the platelet count. So, if the platelet count is between 100,000 and 200,000, then you start with 15 mg twice a day. For patients who have a platelet count greater than 200,000, then you start with 20 mg twice a day. And then, of course, you need to monitor them for cytopenias moving forward and then adjust the dose accordingly. I think it’s very important to also recognize that kidney dysfunction and liver dysfunction may also figure into the dosing of this agent. I think all clinicians who prescribe this agent need to look at the kidney function and the GFR (glomerular filtration rate) and figure out the dose accordingly.

There have been multiple analyses that have tackled the issue of survival when it comes to the utilization of ruxolitinib in patients who have myelofibrosis, and these were particularly addressed in the COMFORT-I and COMFORT-II trials that have resulted in the approval of ruxolitinib in the United States as well as in Europe. So, if you looked at the COMFORT-II study, which was the trial that took place in Europe, there has been a recent publication with Dr. Harrison, and there they noted that patients who had been on ruxolitinib did have a survival advantage. And the drug actually resulted in 30% reduction in risk of death.

Now, the problem with the interpretation of the survival data when it comes to the COMFORT-II trial, as well as the COMFORT-I as well, is that those trials allowed for crossover. So, any time you end up crossing over from one arm to the next, survival analysis becomes somewhat compromised. But I think using certain statistical analysis sensors and perhaps the time of crossover is what resulted in the realization that actually survival advantage does exist, despite the fact that those patients did cross over.

Now, there’s also a pooled analysis that was done of both trials, COMFORT-I and COMFORT-II, and also published, I want to say, last year in September by Dr. Verstovsek. And what he did is that he followed the patients who had been on both trials and, at the 5-year mark, reported on the survival of the patients who had been assigned on an intent-to-treat essentially, whether or not they received ruxolitinib or placebo and whether or not they crossed over. And, again, in this trial, it was demonstrated—very similar to Claire Harrison’s evaluation or analysis of the COMFORT-II—that there was a reduction in hazard ratio for that. And they also utilized a specific statistical methodology. I think they called it rank-preserving structural failure time, and this statistical tool is supposed to sort of eliminate the bias that results from the crossover of the patient population who were randomized from the get-go. And, again, as in COMFORT-II, there seems to be a survival advantage. Now, granted, it would be obviously important to demonstrate this survival advantage moving forward, but I’m not sure that those trials will be done, to be perfectly honest. It may not actually be ethical to do.

Transcript edited for clarity.


June 2016

  • A 72-year old male presents to his primary care physician with fatigue, abdominal pain lasting 3 months, and night sweats
  • PMH includes depression and gout
  • Physical Exam: BP, 155/85; spleen palpable 6 cm below costal margin
  • Laboratory values:
    • Hb= 9.8 g/L
    • HCT= 38%
    • WBC= 22.3 x109/L
    • Platelets= 255 x109/L
  • Bone marrow biopsy:
    • Megakaryocytic proliferation and atypia with evidence of reticulin fibrosis
  • Blood smear showed leukoerythroblastosis
  • Genetic testing showsJAK2 V617Fmutation
  • Diagnosis: Primary myelofibrosis