Primary Myelofibrosis Therapeutic Response Assessment


Daniel DeAngelo, MD, PhD:For the appropriate patient—that is, a patient with intermediate-1 disease and symptomatic splenomegaly—or for a patient with higher-risk disease, such as intermediate 2 or high risk, I will typically initiate ruxolitinib. It’s important to look at the platelet count. For patients with severe thrombocytopenia, this can be a problem. But there are dosing guidelines dependent upon the patient’s baseline platelet count in terms of initiating ruxolitinib, and then titrating the dose appropriately. So, that needs to be thought of very accurately before the initiation of ruxolitinib.

What I expect when I initiate ruxolitinib in an appropriate patient is reduction of the size of the spleen, and I will use that as an assessment of response. But more importantly, how is the patient feeling? If a patient’s having night sweats, these should be abrogated. If a patient’s having fevers or pruritus, I would expect these to be improved. Sometimes patients want to please the physician and may overestimate their responses. And again, this goes back to the total symptom score, where you can objectify the patient’s baseline symptoms and follow them with time to see, objectively, how the patient is feeling.

Myelofibrosis is a chronic disorder, and patients can succumb to the disease through a multitude of avenues, unfortunately. If left untreated, continued constitutional symptoms leading to weight loss and deconditioning are often a mode of exit. Patients can develop thrombosis. This is typically reserved for patients with preserved platelet counts or even thrombocytosis, who are a subset of patients with primary myelofibrosis. Complications of splenomegaly, splenic sequestration, early satiety—many of these symptoms can be ameliorated with ruxolitinib, but not all. There is a small role for splenectomy in patients who have refractory disease and are surgical candidates. And unfortunately, about 15% to 20% of patients may have their disease transform into acute myeloid leukemia.

Unfortunately, even currently, we don’t have good stratification and good disease modifications for patients who have transformation to acute myeloid leukemia. For suitable patients who have a good performance status, who are of a young age, the treatment strategy is often induction chemotherapy with transplant. But unfortunately, myelofibrosis is a disease of the elderly, and many patients can’t tolerate induction chemotherapy and transplant. So, a lot of these issues are age-based.

There are a lot of new therapies that are being explored for patients with myelofibrosis. There are other JAK inhibitors that are being tested against ruxolitinib. These have been reported and presented at ASH 2016 and again at ASCO 2017, trying to compare their efficacies with ruxolitinib. Ruxolitinib is a higher-than-expected bar. Ruxolitinib is a drug that has mild disease modifications in terms of improving outcome, but it turns out to be a high bar to overcome. There are other strategies in terms of anti-fibrinolysis. PRM-151 is being developed. Imetelstat is being tested in a subset of patients who have splicing factor mutations. So, there’s a wide range of therapies directed against the disease that are being explored. Then there’s another set of therapies that are trying to augment and improve the anemia that’s often associated with this disorder. There are a lot of venues that are being pursued.

Most importantly, the biggest development over the last year or 2 is understanding the biology—hitting at the genetic makeup. What are the disease-initiating events? And by better understanding that, we’re going to have better therapies in the future.

Transcript edited for clarity.

  • A 53-year-old woman complains of increasing abdominal discomfort, early satiety, and 15-lb weight loss over the past 5 months
  • Abdominal examination reveals splenomegaly, palpable 8 cm. below the costal margin without hepatomegaly
  • CT scans of the chest, abdomen, and pelvis reveal moderate mediastinal lymphadenopathy and splenomegaly
  • Laboratory values:
    • WBC: 1.9 x 103cells/mm3
    • ANC: 1.4 x 103cells/mm3
    • Hb: 9.1 gm/dl
    • Platelets: 77,000 cells/mm3
  • Bone marrow biopsy:
    • MF-3
    • CD34+/CD117+ immunostaining demonstrated 1.2% blasts
    • JAK2-V617Fmutation
  • Diagnosis: primary myelofibrosis
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