Julie Huynh-Lu, PA-C
Lindsey E. Kalhagen, PA-C
At the 2024 JADPRO Live event, which is held annually for advanced practitioners in oncology, high-risk myelofibrosis was a featured topic. “The treatment landscape has developed so much that JADPRO asked us to present our talks on the main stage this year,” said Julie Huynh-Lu, PA-C, Supervisor of Advanced Practitioners in the Leukemia Department at MD Anderson Cancer Center. Ms. Huynh-Lu was joined by Lindsey E. Kalhagen, PA-C, of Northwestern Medicine in Chicago, who focused her talk on disease assessment.
Identifying Risk Category
It is critical to risk-stratify patients upon diagnosis, and several myelofibrosis risk-stratification models have evolved, Ms. Kalhagen noted. First, symptoms can be assessed with the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) and Brief Fatigue Inventory. Second, prognostic assessments can be done using the MIPSS70 and MIPSS70+. These tests take into account age, blood cell counts, circulating blasts, bone marrow fibrosis grade, constitutional symptoms, and genetic abnormalities. The points tallied from these factors put patients into low-, intermediate-, or high-risk groups. “The more information you have up front, the more it helps with prognosis,” Ms. Kalhagen said.
The patient’s risk category is prognostic for overall survival, which can range from about 1 year to 2 decades or more. “There are profound differences between low-, intermediate-, and high-risk myelofibrosis in terms of overall survival,” she said. “Low risk vs high risk determines the next steps in -treatment.”
Higher-risk patients should first be evaluated for autologous stem cell transplant (the only cure for myelofibrosis) or eligibility in a clinical trial. Factors to consider include mutational profile, age, performance status, major comorbidities, psychosocial status, and availability of a caretaker. The potential for complications is also a factor in decision-making. And, as always, a patient’s goals and preferences should be considered and honored.
Approach to Treating High-Risk Patients
As Ms. Huynh-Lu pointed out, there are two main reasons to initiate treatment of myelofibrosis: presence of splenomegaly and presence of disease-related symptoms. Selection of treatment should be informed by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®), which emphasize platelet counts, ≥ 50 × 109/L or ≤ 50 × 109/L, as the first consideration when transplant is not an option.
The preferred treatment is a JAK inhibitor, four of which are approved for intermediate/high-risk myelofibrosis: ruxolitinib, fedratinib, pacritinib, and momelotinib. “It’s a common misconception that a patient without a JAK2 mutation is not a candidate for a JAK inhibitor. The JAK inhibitors are not targeting a JAK2 mutation but the JAK/STAT pathway itself,” she noted. These agents, therefore, can be broadly prescribed.
Fedratinib is used in JAK inhibitor-naive or ruxolitinib-resistant patients. Pacritinib is approved for patients with platelet counts < 50 × 109/L as a first-line therapy, and for second-line therapy when platelets are > 50 × 109/L. Momelotinib is approved for patients with anemia. Both fedratinib and pacritinib are FLT3 inhibitors as well, making gastrointestinal toxicity a concern for some patients.
Pacritinib and momelotinib are also ACVR1 inhibitors, so their mechanism involves the hepcidin pathway. Hepcidin is a hormone produced by the liver that is involved with iron storage. Inhibition of hepcidin releases iron, which aids in the production of red blood cells and therefore may improve anemia.
Efficacy Shown With JAK Inhibitors
The efficacy of JAK inhibitors hinges on the reduction of spleen volume (SVR), which has been shown to improve survival, and improvement of symptoms. SVR35, reflecting a 35% reduction in spleen volume, is usually a clinical trial endpoint.
“Imagine a patient with a 20-cm spleen that can be reduced at least 35%, so that it becomes 13 cm. This can make a huge impact on the patient’s abdominal discomfort and ability to eat,” Ms. Huynh-Lu pointed out.
In the phase III COMFORT-11 and COMFORT-II2 trials, SVR35 was achieved in 42% and 28% of patients, respectively. Ruxolitinib is considered the first-line therapy for patients with symptoms, with or without splenomegaly, and platelet counts ≥ 50 × 109/L. “We do expect some initial hematologic toxicity, so in the first 8 to 12 weeks, you’ll probably see a drop in counts that ideally should stabilize,” she noted.
Other potential adverse events include infections (shingles), lipid abnormalities (regular monitoring may be warranted), skin cancers, mouth ulcers, and weight gain. If platelet counts drop too low and ruxolitinib needs to be discontinued, the drug should be tapered and not stopped abruptly. This approach avoids withdrawal syndrome, which can include fever, respiratory distress, disseminated intravascular coagulation, multiorgan failure, and even septic shock.
The phase III JAKARTA trial led to the approval of fedratinib at 400 mg/d as a first-line treatment in symptomatic patients with platelet counts ≥ 50 × 109/L with or without splenomegaly.3 This approach achieved SVR35 in 36% of patients and a 50% reduction in total symptoms score (TSS50) in 36% of patients as well. Wernicke’s encephalopathy was reported in four patients receiving a higher dose; thus, thiamine levels should be monitored, and supplementation should be started on initiation of fedratinib. Other possible side effects include worsening cytopenias as well as gastrointestinal, hepatic, and pancreatic toxicities.
Pacritinib was evaluated in the phase III PERSIST-2 trial of patients with intermediate-risk or high-risk myelofibrosis with platelet counts ≤ 100 × 109/L.4 In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib was more effective than best available therapy, including ruxolitinib, demonstrating an SVR35 in 18% vs 3% (P = .001), respectively, and a favorable trend toward improvement in symptoms, as noted by TSS50 in 25% vs 14%, respectively (P = .08).
Additionally, in patients with platelet counts < 50 × 109/L, SVR35 was 29% vs 3%, respectively. Increases in hemoglobin and reduction in transfusion burden were enhanced when pacritinib was given twice daily. Common adverse events with pacritinib may include worsening cytopenias, gastrointestinal toxicity, infection, hemorrhage, and QTc prolongation; thus, this drug may not be the best choice in patients with a history of bleeding or cardiac issues.
“Pacritinib answers the need for an effective drug in patients with low platelets, as ruxolitinib and fedratinib are not particularly effective there,” Ms. Huynh-Lu added. It is a first-line therapy for patients with symptoms, with or without splenomegaly and with platelet counts < 50 × 109/L, and as second-line therapy for patients with platelet counts ≥ 50 × 109/L.
Momelotinib was approved based on the phase III noninferiority SIMPLIFY-15 trial and the superiority trial SIMPLIFY-2,6 becoming a second-line option for patients with symptoms with or without splenomegaly, regardless of platelet count. SIMPLIFY-1 trial evaluated patients with platelet counts ≥ 50 × 109/L receiving momelotinib at 200 mg/d or ruxolitinib at 20 mg twice daily. SVR35 was 27% and 20%, and TSS50 was 28% and 42%, respectively. Although spleen reduction was similar, momelotinib was inferior in symptom reduction; it was, however, better than ruxolitinib in reducing transfusion requirements, with transfusion independence at 24 weeks achieved by 67%, vs 49% with ruxolitinib. Momelotinib could fill a need “in an area without many treatments other than add-on therapies,” she pointed out.
SIMPLIFY-2 compared momelotinib with best available therapy or ruxolitinib in patients with intermediate- or high-risk disease and suboptimal response to (or hematologic toxicity on) prior ruxolitinib. SVR35 was similar, at 7% and 6%, respectively, but TSS50 was better, at 26% and 6%, as was transfusion independence, 43% vs 21%, respectively. “These data are compelling for patients with myelofibrosis and anemia. They could potentially become transfusion-independent at week 24—especially those getting transfused once or twice a week,” Ms. Huynh-Lu commented.
Managing Common Side Effects of JAK Inhibitors
Four side effects are commonly encountered by patients taking JAK inhibitors that may be managed by providers: diarrhea, anemia, thrombocytopenia, and infections. Diarrhea is common across the board and can sometimes be ameliorated with loperamide (as needed); ondansetron may help with nausea. Anemia is usually treated with transfusions, dose adjustments, and add-on therapy; a change in the JAK inhibitor may be warranted if the current one has lost efficacy. Vaccination before treatment initiation and use of prophylactic antivirals may help to prevent infections.
It is important to consider that these and other conditions may not be side effects of the drugs but something unrelated. “There obviously are other reasons for patients to develop anemia besides progression of their myelofibrosis or their medications,” Ms. Huynh-Lu said, citing nutritional deficiencies, blood loss, and inflammation from unrelated comorbidities.
Treatment of Myelofibrosis-Related Anemia
As Ms. Huynh-Lu noted, certain medications can be added to JAK inhibitors for the treatment of anemia: erythropoiesis-stimulating agents if erythropoietin levels are < 500 mU/mL; steroids/androgens (ie, prednisone, danazol), though efficacy can be delayed, their long-term use of prednisone is unwise, and prostate cancer is a contraindication for danazol use; immunomodulatory drugs for del(5q) (lenalidomide); luspatercept, though it is approved for myelodysplastic syndrome and not myelofibrosis; and momelotinib or pacritinib, which have a category 2B recommendation in the NCCN Guidelines. Clinical trials are obviously an option.
Emerging Therapies for Myelofibrosis
For more than 10 years, treatment of myelofibrosis has focused on JAK inhibition, but different pathways are now being explored for new approaches. Some of these are:
- Transforming growth factor-ß ligand blocking agents (eg, luspatercept)
- BET protein inhibitors (eg, pelabresib)
- Antifibrotics (eg, PRM-151)
- B-cell lymphoma protein inhibitors (eg, navitoclax, an experimental BCL2 inhibitor)
- Telomerase inhibitors (eg, imetelstat)
- XPO1 inhibitors (eg, selinexor).
Clinical Take-Aways
Ms. Huynh-Lu and Ms. Kalhagen summed up their key points and take-aways as follows:
- High-risk myelofibrosis can be difficult to treat, largely due to the cytopenias that are hallmarks of this cancer.
- The use of risk-assessment tools can guide treatment discussions and decisions, especially the MIPSS70.
- Next-generation sequencing panels and cytogenetics tests can also help to guide therapy and optimize decision-making.
- The current treatment landscape is expanding far beyond JAK inhibitors.
- During treatment, patients need to be monitored frequently for adverse events, with dose adjustments as needed.
- Providers should be attuned to other potential cases of abnormal blood cell counts.
- Providers should regularly assess and document symptom burden and quality of life as well as note any trends.
DISCLOSURE: Ms. Huynh-Lu serves on the speakers bureau for GSK and Incyte. Ms. Kalhagen has served on the speakers bureau for Curio and Incyte.
REFERENCES
1. Verstovsek S, Mesa RA, Gotlib J, et al: A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366:799-807, 2012.
2. Harrison C, Kiladjian JJ, Al-Ali HK, et al: JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366:787-798, 2012.
3. Pardanani A, Tefferi A, Masszi T, et al: Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Br J Haematol 195:244-248, 2021.
4. Mascarenhas J, Hoffman R, Talpaz M, et al: Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: A randomized clinical trial. JAMA Oncol 4:652-659, 2018.
5. Mesa RA, Kiladjian JJ, Catalano JV, et al: SIMPLIFY-1: A phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor–naive patients with myelofibrosis. J Clin Oncol 35:3844-3850, 2017.
6. Harrison CN, Vannucchi AM, Platzbecker U, et al: Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): A randomised, open-label, phase 3 trial. Lancet Haematol 5:e73-e81, 2018.
