Treatment Options for a Patient With Myelofibrosis

Rami S. Komrokji, MD:This patient has several risk factors. He’s anemic, has leukocytosis, there is presence of circulating blasts, and he has a trisomy 8 that’s considered to be an unfavorable karyotype. Again, in the newer cytogenetic risk groups there is a very high-risk karyotype that is unfavorable. This patient fits the unfavorable cytogenetic risk group. He will come into a higher-risk group. We don’t know information about other somatic mutations, but just based on those variables he will be a patient who fits in the intermediate- to higher-risk group.

I want to emphasize, first, that we spend time making sure that we have the right diagnosis. We risk-stratify the patients, and based on that, we then develop our plan for therapy. For those patients who are higher risk, we consider an allogeneic stem cell transplant because it remains the only curative option for this disease.

In general, the cure rates are around 40% to 50%, but the procedure is associated with around a 20% transplant-related mortality and 1 to 2 years of quality of life may be affected. So we weigh the benefits and the risks. In patients who are intermediate or higher risk, I think the benefits outweigh the risks, particularly if patients are functional and don’t have major comorbidities. Unfortunately, the majority of patients may not be candidates for allogeneic stem cell transplant given the age of those patients or presence of other comorbidities. In general, probably only 10% to 20% of patients will get the transplant.

So unfortunately, most patients will not be candidates for allogeneic stem cell transplant, either given their age or presence of comorbidities. Roughly only 10% to 20% of patients will proceed to allogeneic stem cell transplant. For the rest of the patients, we tailor the treatment based on symptoms. We can divide patients into 3 groups: 1), where there is a major symptom or driver for treatment with constitutional symptoms and splenomegaly. Those usually go hand in hand. In the other group, the main indication for treatment is cytopenias, and namely anemia. And probably the most challenging group is when we have a combination of constitutional symptoms, splenomegaly, and anemia.

For patients with constitutional symptoms and splenomegaly, those typically are the ones who we think of JAK2 inhibitors for, like ruxolitinib. The treatment has been approved by the FDA for many years now. A couple of major studies that were randomized showed benefit for ruxolitinib for the treatment of patients with myelofibrosis.

There were 2 major studies: One called the COMFORT-I, which was done in the United States, and the COMFORT-II, which was carried in Europe. They were similar in design. COMFORT-I compared ruxolitinib to placebo, versus COMFORT-II, to best available therapy. One looked at the 24-week mark and the other looked at the 48-week mark, but now we have longer follow-up on those 2 studies.

The studies have shown that ruxolitinib was effective in reducing spleen and improving symptoms roughly in around 40% of the patients meeting the primary endpoint, which looked at a spleen reduction by MRI [magnetic resonance imaging] of more than 35%, which typically correlates to 50% reduction in the spleen by physical exam.

However, most patients actually derive more of a benefit than that, in terms that they all get some spleen reduction. It may not be to the point of the 50% reduction, but that still translates to a clinical benefit for the patient. And also, they get symptom improvement with the treatment.

Transcript edited for clarity.

Case: 66-Year-Old Man Diagnosed With Primary Myelofibrosis

January 2019

• A 66-year old man presents to primary care physician with complaints of fatigue, headache, and abdominal discomfort when taking deep breaths
• PMH: depression
• PE: Splenomegaly ~7 cm below left costal margin
• Lab values:
  • HGB: 9.2 g/dL
  • Platelets: 242 x 10⁹/L
  • WBC: 26.2 x 10⁹/L
  • Serum LDH: 1400 U/L
  • Serum EPO: 10.9 mU/mL
• Bone Marrow Biopsy:
  • MF-3
  • Circulating blasts, 1.1%
  • JAK V617Fmutation; trisomy 8
• Peripheral Blood Smear: leukoerythroblastosis
• Diagnosis: Primary myelofibrosis