The Clinical Management of Primary Myelofibrosis - Episode 4

COMFORT Trials: Initiating Therapy for Myelofibrosis

July 16, 2018

Harry Erba, MD, PhD:This patient is clearly symptomatic from her disease and the question is not whether or not you’re going to treat her, but with what? What is the best option for her? And I think we have data from the COMFORT-II study that can help us in that decision. The COMFORT-I study, just to remind you, was a study of ruxolitinib, the JAK1/JAK2 inhibitor, versus placebo. Well, I’m not going to dwell on that study because in that study, some patients didn’t receive anything. And a patient who has constitutional symptoms, symptomatic from their splenomegaly, I think most of us would want to treat that patient.

In COMFORT-II, which was a study that was done in Israel and Europe, patients with intermediate 2 and high-risk myelofibrosis, either primary myelofibrosis or following prior polycythemia vera or ET, were randomized to get ruxolitinib at a dose of 20 mg twice daily if their platelets were above 200,000, or 15 mg twice daily if their platelets were between 100,000 and 200,000. They were excluded from the study if their platelets were below 100,000.

Patient were twice as likely to get that than the control arm, which was best available therapy. Patients who received best available therapy, most of them received hydroxyurea. Some received modulatory agents like lenalidomide or thalidomide. Steroids have been used, and interferon as well, if I didn’t mention that already.

And so, there was a crossover in this study. The primary endpoint was at 48 weeks control of the splenic volume. So, a reduction of splenic volume as measured by MRI of more than 35% reduction in that volume. The primary endpoint was met. None of the patients in the best available therapy arm actually achieved that endpoint. And it was 28% of patients at 48 weeks who actually had a 35% or more reduction in the splenic volume with ruxolitinib. A key secondary endpoint was control of symptoms, which is important to consider in this patient who is symptomatic with night sweats, weight loss, and the abdominal fullness.

In that study, approximately 45% to 50% of patients had a 50% or more reduction in a total symptom score that had been validated previously in patients with myeloproliferative neoplasms such as myelofibrosis. Even when you consider each of the individual symptoms and the total symptom score—night sweats, pruritus related to cytokines, weight loss related to cytokines, but also symptoms related to the spleen like early abdominal fullness, pain under the ribs—patients had the same type of benefit from ruxolitinib in all of those individual symptoms.

So, I think in a patient like this who is symptomatic, I would start with ruxolitinib. Her platelet count is 189,000. The label dose is 15 mg twice daily. Quite frankly, I often start lower, but remember to escalate the dose as tolerated every 4 weeks.

Now there was another benefit that was seen in that study, another key secondary endpoint was survival. One of the problems with evaluating survival in this study, and as well the COMFORT-I study, was a crossover design. And if patients had a progression of splenomegaly or an increase in their requirement for opiate analgesics for control of painful spleen, they could actually cross over. And in fact, in the COMFORT-I study at a median of 9 months, patients crossed over from placebo to ruxolitinib. In the COMFORT-II trial, at a median of 15 months, they crossed over. Most of them crossed over from best available therapy to ruxolitinib.

However, when you evaluate survival at 3 years and now at 5 years on that study, even though there’s a crossover, there was a trend for an improvement in survival. ThePvalue at 5 years was 0.06, but there was a trend for an improvement in survival with about a 35% reduction in the risk of death of that 5-year follow-up of the COMFORT-II study. And so, in a patient like this, you’re not only trying to control symptoms, you’re not only trying to control the spleen, which you can do with ruxolitinib, but you are also trying to extend survival.

Well, let’s not forget that ruxolitinib so far has not been clearly shown to change the natural history of the disease. We have not been able to show, because of the crossover honestly in these studies, that there’s a decrease in fibrosis, it complicated that analysis. Although you could see some decrease in the allele burden of theJAK2missense mutation, it has not been dramatic. And so, it’s not clear that ruxolitinib really changed the natural history of the disease.

And so, in a patient with high-risk disease, she only has hypertension, if her spleen is controlled, she gains weight, and she has improved performance status, this is somebody who I would definitely still consider for allogeneic stem cell transplant, which is the only potentially curative option. So, that’s something we shouldn’t forget about in our patients with intermediate 2 and high-risk disease, that a potentially curative option that can actually reverse the fibrosis is allogeneic transplant.

Transcript edited for clarity.

March 2017

  • A 67-year old woman presents to her primary care physician with complaints of fatigue, abdominal fullness, night sweats, and 17-lb weight loss over the past 6 months.
  • PMH includes hypertension, controlled on enalapril 10 mg
  • Abdominal examination reveals spleen palpable 7 cm below the costal margin
  • Lab values:
    • HGB: 9.2 gm/dl
    • Platelets: 189 x 109/L
    • WBC: 19 x 109/L
  • Bone Marrow Biopsy:
    • MF-3
    • CD34+/CD117+ immunostaining demonstrated 1.2% blasts
    • JAK-V617F mutation
  • Diagnosis: Primary myelofibrosis