Try Ruxolitinib Again When Effectiveness Wanes in Myelofibrosis

“If at first you don’t succeed, try, try again.” That old proverb is the newfound wisdom surrounding ruxolitinib use in patients with myelofibrosis (MF).

A recent study in Clinical Lymphoma, Myeloma & Leukemia demonstrates that resuming use of the JAK2 inhibitor ruxolitinib, after ceasing use when it lost effectiveness, can reactivate a response, reducing both splenomegaly (enlarged spleen) and constitutional symptoms.

This is encouraging because these complications of MF can be severe and negatively impact a patient’s quality of life. Splenomegaly can cause abdominal, chest or back pain; early satiety and bloating. Constitutional symptoms can include weight loss, fever and night sweats.

“COMFORT-I and COMFORT-II were landmark trials that showed ruxolitinib’s clinical benefits in reducing spleen size and improving constitutional symptoms,” says the new study’s first author Aaron T. Gerds, MD, MS, of Cleveland Clinic’s Department of Hematology and Medical Oncology. “But those trials didn’t establish a treatment for when patients progress on ruxolitinib.”

Progression is marked by a 25 percent or greater increase in spleen volume or leukemic transformation.

“To date there is only one FDA-approved medication, and still no approved treatment for patients whose disease progresses or who stop using ruxolitinib due to toxicities,” says Dr. Gerds. “But anecdotally in clinic — and backed up by preclinical models — we’ve seen that patients may derive benefit after a rechallenge.”

That’s what inspired Dr. Gerds and fellow researchers at Cleveland Clinic and the University of Southern California to conduct a retrospective study.

Up for a rechallenge

Researchers reviewed the cases of 13 patients (median age 71) with MF who were retreated with ruxolitinib at least once between 2012 and 2017. All patients had received 5-25 mg of the drug twice daily for a median of 62 weeks.

During the patients’ first course of ruxolitinib, they had shown initial improvement in constitutional symptoms and reduced spleen size. But then improvements waned or toxicity became intolerable, and they stopped taking the drug.

After one week or longer, patients were re-exposed to ruxolitinib (at any dosage) for at least two weeks.

Based on electronic medical record data, researchers recorded each patient’s:

• Duration of therapy.
• Dosage at initiation and cessation.
• Spleen length at initiation and cessation.
• Reason for discontinuation — including loss of response or inadequate response, change to alternate therapy, and intolerable toxicity.

They found that after retreatment with ruxolitinib:

• Spleen size reduced significantly — a mean of 7.1 cm — in nine of the 13 patients (69 percent). Compare that to the initial treatment, when spleen size reduced a mean of 10.9 cm.
• Constitutional symptoms improved in 12 of the 13 patients (92 percent).

Four patients that stopped taking ruxolitinib a second time due to diminishing response began taking it a third time. All four again reported improvement in spleen size and symptoms.

When the study was published in June 2018, six of the 13 patients were continuing to have a favorable response from their second or third course of ruxolitinib.

What this means to clinicians

“Other case series have found similar results — that retreatment with ruxolitinib can successfully reduce spleen size and other symptoms when it didn’t the first or even second time,” says Dr. Gerds.

Yes, this recent study was retrospective, the sample size small, and the cause of resensitization uncertain, but it can happen, he says. In some cases, the response to intermittent treatment is durable.

More research is needed to confirm these findings, but results suggest that retreatment with ruxolitinib is safe and potentially effective for MF patients without other standard therapy options.