乌鸦传媒

NEW YORK -- Physicians treating myelofibrosis patients with ruxolitinib (Jakafi) must pay careful attention to dosing during the first 3 months, given the risk of anemia and thrombocytopenia, according to leading experts on the medication speaking at a recent symposium here.

But after that initial period, few new side effects will arise, and many patients have now been doing well on the drug for 3 years or longer. And while ruxolitinib cannot cure myelofibrosis, it has .

As myelofibrosis advances, patients develop extremely swollen spleens and suffer constitutional symptoms including night sweats, aches and pains in the bones, low grade fever, and itching. Most commonly patients die from transformation to acute leukemia, according to , of The University of Texas MD Anderson Cancer Center in Houston, but many also die from body wasting, enlargement of the spleen or liver, or heart failure.

Verstovsek participated in the , and estimates he has treated more than 500 myelofibrosis patients with the drug.

Until recently, bone marrow transplants were the only treatment that could address these symptoms, and few myelofibrosis patients were young or healthy enough to be suitable transplant candidates, according to , of the Mayo Clinic Cancer Center in Scottsdale, Arizona, who also participated in the COMFORT trials. But ruxolitinib, approved by the US Food and Drug Administration in November 2011, can dramatically improve spleen enlargement and constitutional symptoms in myelofibrosis patients.

Ruxolitinib belongs to a class of drugs called Janus kinase (JAK) inhibitors, which work by interfering with the JAK-STAT signaling pathway. It targets JAK2, which plays a key role in the myeloproliferative disorders (MPDs). Sanofi , fedratinib, in November 2013 after some patients developed Wernicke's encephalopathy. Two other JAK inhibitors, , and , are currently in phase 3 trials.

There is a misconception that JAK inhibitors are only helpful to patients who carry the JAK2 V617F mutation, noted , of Stanford Cancer Institute in Stanford, California, who also participated in the COMFORT trials. However, he added, patients without the mutation can also respond well to treatment with JAK inhibitors.

At a recent patient symposium on the MPDs in New York City sponsored by the nonprofit , Verstovsek showed slides of myelofibrosis patients before and after treatment with ruxolitinib. In the "before" photos, patients were bedridden and wasted with hugely enlarged spleens; in the "after" shots, they were on their feet, looking fit, healthy and happy.

"The quality of life of patients is dramatically improved, and that's not just true of ruxolitinib, but of the other JAK inhibitors as well," he said. "There's never been a medication that can mitigate symptoms, improve quality of life like the JAK inhibitors."

While some patients' red blood cell or platelet counts will drop early in treatment, Verstovsek told the audience, the treating physician should not stop the drug, but should instead .

"What I try always to tell people is to adjust the dose instead of stopping and waiting for recovery and then starting at a lower dose, because patients lose any benefit," he said in an interview with 乌鸦传媒. "It's always better to proactively adjust the dose."

It's also critical, he added, that the medication be given twice, rather than once a day, given its 4-hour half-life.

In the initial studies of the drug, patients were started at 15 mg bid or 20 mg bid, Mesa noted in an interview with 乌鸦传媒.

"What we see now as we look back at the 3-year long-term follow-up of that experience is many patients needed to be slightly modified, most ended up with doses of 15 twice a day or even 10 twice a day," Mesa added. "In my practice most patients are treated initially at 10 twice a day and I increase the dose typically at about the 3-month mark if need be to further extend the benefits.

Starting at the lower dose range, and dose-escalating as tolerated, rather than starting at the higher dose range and reducing the dose in the setting of high-grade hematologic toxicity, is one approach to consider for patients who already have anemia, Gotlib noted.

From the standpoint of its nonhematologic side effect profile, ruxolitinib is generally well tolerated with headache, dizziness and bruising being the most common adverse events, Gotlib said. But given that myelofibrosis itself can suppress the immune system, and that the family of JAK proteins plays an important role in immune function, "patients and doctors need to be vigilant about the potential risk of developing unusual infections with ruxolitinib and other JAK inhibitors," he added. (There has been one case of progressive multifocal leukoencephalopathy reported in a patent taking Jakafi, but clinicians could not determine definitively whether it was due to the drug.)

"Assessing patients for signs or symptoms of mycobacterial, viral, or fungal infections before and during treatment is an integral part of the care of these individuals," Gotlib said.