JAK Inhibition for the Management of Primary Myelofibrosis - Episode 4

Treating With a JAK Inhibitor for Myelofibrosis

Rami S. Komrokji, MD:In addition to spleen reduction, obviously patients experience improvement in their symptoms. Fatigue is a hallmark adverse event in patients with myelofibrosis, where more than 80%, 90% of patients will have major fatigue that interferes with daily activities. Bone pain, weight loss. Patients derive a significant clinical benefit from treatment with ruxolitinib, which actually can be seen earlier than even spleen reduction. Typically, patients will start feeling better within a week to 2 weeks on treatment, in terms of symptom improvement, while spleen response may take 3 to 4 months to get the maximum benefit from treatment.

So those patients with splenomegaly or constitutional symptoms benefit from ruxolitinib treatment, which really has become the standard of care. The treatment is associated with myelosuppression, namely anemia, particularly at the beginning of the treatment where the nadir of the count is typically by the second month of treatment. Sometimes we need to do dose adjustments. Or, if the counts were borderline, we start with a lower dose. Sometimes we have those discussions with the patients to decide which is the major important symptom. Some patients with a large spleen or constitutional symptoms could tolerate a transfusion at the beginning while their symptoms are improving. But if the main presentation or indication for treatment is cytopenia, then ruxolitinib is not the treatment of choice for those patients.

Another point: There’s always a misbelief that the patients have to beJAK2-positive to respond to ruxolitinib. In reality, the JAK/STAT pathway is overactivated in patients with myelofibrosis in the presence or absence of theJAK2mutation, given other mutations that activate the pathway, or just by the cytokine release. So patients will benefit from ruxolitinib treatment regardless of theJAK2status.

We’ve had longer experience with those treatments now. The 2 studies have demonstrated survival benefits for patients who were treated with ruxolitinib, although the studies were not designed to look at survival advantage and the design allowed a crossover that makes it more difficult. But patients who were treated with ruxolitinib did have a better overall survival.

When I discuss that with patients, an indication for the treatment would be symptoms. We don’t treat patients to try to alter the natural history or improve survival. But those patients who are symptomatic with splenomegaly or constitutional symptoms will derive a survival advantage from the treatment.

So in general, ruxolitinib is well tolerated. Myelosuppression can be observed, and particularly anemia and thrombocytopenia. The nadir count usually is around the second month, week 8. So when we start patients on treatment, we check their counts either every week or every other week, and we adjust the dose accordingly. If the counts are borderline, we may start with a lower dose and quickly escalate to the appropriate dose based on the counts.

Other than myelosuppression, sometimes we do see nonspecific symptoms such as headache, dizziness. There is an increased incidence of urinary tract infection and herpes zoster reactivation. We don’t typically do prophylaxis, but we observe for those.

Ruxolitinib does have some immunosuppressive effect on the T cells. That’s why it’s actually approved for patients with graft-versus-host disease. However, long term, there have been very rare cases of infections such as TB [tuberculosis] reactivation or PML [progressive multifocal leukoencephalopathy]. But those are very rare. I’ve not seen them in my experience.

In general, patients do feel better with treatment. My experience has been positive with the treatment. I think one has to be aware of the right patient selection for the treatment, adjusting the dose and monitoring for adverse effects.

One other important point is that some of those patients sometimes get admitted for other reasons such as infection, other procedures, complications. One should not stop the treatment immediately. If a treatment is stopped immediately, the patient’s symptoms return quickly within a week or they could get more sick. So we really try to tell the patients to continue on treatment. If for some reason they are not able to take the treatment, sometimes we use steroids because the patients could get sick in the short term if they stop the treatment immediately.

For a subset of patients with cytopenia, namely anemia, treatment is more challenging. There are not many options available for those patients. Sometimes we may use erythropoietin-stimulating agents, where responses are low. Immune modulators such as thalidomide and lenalidomide are used for cytopenia. However, again, the responses rates are low. Danazol or anabolic steroids are used for those patients. Unfortunately, many of those patients with cytopenias will become transfusion-dependent.

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