Stepping Forward: Future Treatment of Myelofibrosis

Rami S. Komrokji, MD:There are still several areas of unmet need in the treatment of patients with myelofibrosis. We are starting to deal with the era of ruxolitinib failure. So many of those patients, after response or if there is a lack of initial response, will need subsequent treatment.

Our group recently looked at the real-life experience of patients after ruxolitinib failure, and the group from [The University of Texas] MD Anderson [Cancer Center] looked at the patients who were on clinical trials with ruxolitinib to see what happens after ruxolitinib failure. The median survival for those patients is estimated at 18 months, with not many options available for those patients.

There are other JAK2 inhibitors still undergoing clinical trials or under review to be approved. Fedratinib is one of those agents that actually has been tested in patients after ruxolitinib resistance or intolerance and has some meaningful clinical responses. So hopefully that will be an agent that, if approved, can be used as a second-line option. Pacritinib is another JAK2 inhibitor that particularly seems to be less myelosuppressive. So for patients with low platelets, that may be an option.

There are several trials trying to look at strategies of combination therapies with ruxolitinib in patients who have suboptimal response or lose their response. Those are still in clinical trials and there are several of them.

Imetelstat is a telomerase inhibitor that has been tested in patients after ruxolitinib failure and has demonstrated some clinical activity. Interestingly, there was a signal of possible survival improvement, so that’s being pursued further. It is associated with thrombocytopenia and myelosuppression as well.

Interferon is used in a small subset of patients with myelofibrosis. Small studies suggest that interferon treatment may alter the natural history for the disease. However, the toxicity is substantial, and more than half of the patients have to come off treatment because of adverse effects. So newer formulations of interferon have been tested, such as pegylated interferon. A newer pegylated form called ropeginterferon is in clinical trials, originally essential in thrombocythemia and PV [polycythemia vera], but also in myelofibrosis.

In practice, we may consider the use of interferon in younger patients with early disease, not extensive fibrosis, in an attempt to alter the natural history of the disease.

In terms of treatment of cytopenia, as I mentioned, it’s challenging. There are some agents being tested, namely TGF-beta inhibitors. There are 2 drugs, one called sotatercept and one called luspatercept, that were originally tested in MDS [myelodysplastic syndromes] and now have been tested in myelofibrosis. Those are fusion trap proteins that bind ligands before binding their receptor. That is important in terminal erythroid differentiation. In a pilot study with sotatercept, in patients with myelofibrosis, meaningful anemia improvement was observed. There is an ongoing study with luspatercept in patients with myelofibrosis as well.

In summary, we’ve made progress in understanding myeloproliferative diseases. In the last few years, with the discovery of all of the somatic mutations, molecular abnormalities, we have a much better understanding of the disease and its risk assessment. Hopefully this is translating now to better treatment options for patients. I think we do have several options. Presence of ruxolitinib established a new era for patients with myelofibrosis, and hopefully newer treatments will add to that backbone. This will hopefully improve also with our transplant procedure, for example, for curing patients. So I’m very optimistic.

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