Starting Therapy for Intermediate-Risk Myelofibrosis Based on Hemoglobin

Mark J. Fesler, MD

Hematologic Malignancy Specialist

Director of Bispecific Immunotherapy

St. Luke’s Center for Cancer Care

Chesterfield, MO

CASE SUMMARY

• A 68-year-old woman presented to her physician with symptoms of mild fatigue.
• Spleen was palpable 6 to 7 cm below the left costal margin
• Past medical history: no known comorbidities
• Next-generation sequencing testing: JAK2 V617F mutation
• Karyotype: 46,XX
• Bone marrow biopsy: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
• Blood smear: leukoerythroblastosis
• Diagnosis: primary myelofibrosis
• Risk
  • Dynamic International Prognostic Scoring System: intermediate-2
  • Mutation-Enhanced International Prognostic Scoring System for Transplantation-Age Patients: intermediate risk
• Laboratory values
  • Red blood cells: 3.40 x 10¹²/L
  • Hemoglobin: 9.7 g/dL​
  • Hematocrit: 32.3%​
  • Mean corpuscular volume​: 94 fL
  • White blood cells: 23.0 x 10⁹/L
  • Platelets​: 450 x 10⁹/L​
  • Peripheral blood blasts​: < 1% ​

Mark J. Fesler, MD: We know this patient's profile; we know they have intermediate-2 risk. We know that they have moderate anemia with a hemoglobin level of 9.7 g/dL. If I read this correctly, observation is not selected because we have a symptomatic patient who has an enlarged spleen with intermediate-2 risk disease. There may be various barriers for patients to go on clinical trials that you see every day in your practice. [So] we would start treatment on this patient and not just refer them for stem cell transplant. The outcome could be improved if we help this patient from a spleen size perspective.

If we alter it just slightly, still a patient with intermediate-2 risk but the patient has a hemoglobin level of 7.8 g/dL, would this alternate scenario change your approach to this patient?

Nicole Jacobi, MD: I chose momelotinib [Ojjaara] twice [for both polls], but I was on the fence before. I always think if I get the chance to get ruxolitinib [Jakafi] in, as long as the platelets are still OK, I should use it. I would [likely] use ruxolitinib with the other scenario and momelotinib now.

Fesler: That's essentially what I chose; ruxolitinib and then momelotinib. Ultimately, the way things are perceived by each one of you is going to be colored by your experience.

Rupa Chennamaneni, MD: I picked ruxolitinib because of the familiarity and the survival benefit. [In the scenario of] severe anemia, I changed to momelotinib.

DISCUSSION QUESTIONS

• How do you monitor and manage anemia in patients with primary myelofibrosis prior to starting JAK (Janus kinase) inhibitor therapy?​
• While receiving a JAK inhibitor therapy?

Fesler: Other than selection of JAK inhibitor, are there other things that you would do for either of these patients in terms of supporting erythropoiesis?

Pallavi Jasti, MD: I would consider erythropoietin-stimulating agents [ESAs]. Especially if the EPO [serum erythropoietin] level is low up front, I would consider adding an ESA to the JAK inhibitors.

Mark Fesler, MD: What cutoff do you use for the EPO level?

Jasti: [Below] 500 U/L.

Chennamaneni: I have also used luspatercept [Reblozyl].

Karim Anwar, MD: I have heard about anabolic steroids like danazol. I have not used it so I can't really comment.

Fesler: Danazol is a medication that's listed in the supportive care for anemia with this disease. I've used it a limited amount. Generally, it's been hard for me to tell if I was able to improve a patient's erythropoiesis. Several patients I've used it on remain transfusion dependent in spite of danazol therapy. It was tough to realize the exact benefit.

DISCUSSION QUESTION

• When do you typically intervene with ruxolitinib for intermediate- or high-risk patients?

Anwar: If the patient has minimal or no symptoms or intermediate grade, I might hold. I don't know if [such a patient] will qualify for intermediate grade, but if there are no cytopenias, I might just watch and initiate it once I see some symptoms or spleen enlargement.

Fesler: I think it's a great point, Dr Anwar. Intermediate risk is nonspecific. Intermediate risk can be intermediate-1 or intermediate-2. As the risk profile increases for the patient, the symptoms increase, so it is rare to encounter an intermediate-2 or high-risk patient who's completely asymptomatic. At intermediate-1, we more often see patients who are asymptomatic. The struggle is, do you start JAK inhibitors for those patients, or do you wait? Most of us start regardless, and I think that there's some credence in either approach. In a completely asymptomatic patient, careful monitoring of spleen and symptoms to see where the natural history of the disease is going is a legitimate way of handling this. But one could make an argument [we should] treat that patient right off the bat. As we get to intermediate-2 or higher-risk patients, we have [a lower] comfort level for watching and actively surveying the disease.

Labayog: We have patients with some adherence issues who have asthenia and fatigue, and sometimes they don't take [ruxolitinib] twice a day. Do you think you get the same benefit if it was [taken] daily?

Fesler: That’s a hard one to answer. I rarely get down to dose reductions that would require me to use it once daily with myelofibrosis. The pharmacokinetics of the drug would suggest that even if you're getting down to low dosages, 5 to 10 mg on a daily basis, the drug is designed to be given twice daily, so those patients may not be experiencing the full benefit. The other thing that I would wonder about is, is there potentially some risk during of reducing ruxolitinib levels so much in those patients that they get a rebound cytokine release. If they take it at 9 AM, then by 9 PM or in the middle of the night, [they might] start to experience some adverse symptoms that could be somewhat related to ruxolitinib withdrawal.

Jasti: Before momelotinib was approved, even if a patient's hemoglobin level was less than 7 g/dL, I would use ruxolitinib, because that was the only option to try and get a response while doing supportive care with transfusions, ESA, or whatever is needed. It changes now with the availability of momelotinib. I might prefer that more than ruxolitinib based on the comparative data for hemoglobin improvement.

DISCLOSURES: There were no known relevant disclosures by the participants.