Ruben Mesa, MD
With the JAK 1/2 inhibitor ruxolitinib (Jakafi) firmly established as the targeted therapy standard for myelofibrosis, researchers are exploring novel agents and combinations to enrich this therapeutic backbone.
In a presentation at the 2016 NCCN Annual Congress on Hematologic Malignancies, Ruben Mesa, MD, chair, Hematology, Mayo Clinic, discussed the latest NCCN treatment guidelines for myelofibrosis and emerging treatments in the field.
Mesa summarized the NCCN Guidelines for Myeloproliferative Neoplasms (version 1.2017),1
which include treatment algorithms for myelofibrosis care. The algorithms are based on several scoring systems for evaluating patient risk, including the International Prognostic Scoring System (IPSS), the Dynamic International Prognostic Scoring System (DIPSS), and the DIPSS-Plus.
The IPSS is used to assign a prognosis based on risk factors at diagnosis. Patients are categorized based on the number of these myelofibrosis risk factors present at diagnosis: age >65, constitutional symptoms, hemoglobin <10 g/dL, white blood cell count >25 x 109/L, and blood blasts ≥1%.
The DIPSS is used to evaluate a patient’s prognosis as their condition evolves. This system incorporates the same risk factors as IPSS, but employs a different weight system. DIPSS-Plus includes additional risk factors than the standard DIPSS, such as karyotype, transfusion dependency, and platelet count.
Symptom burden for the NCCN guideline algorithms is assessed using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). This assessment involves patient rankings of the severity of 10 potential symptoms.
The NCCN guidelines for patients with low-risk myelofibrosis (IPSS, DIPSS, and DIPSS-Plus scores all = 0) who are asymptomatic recommend observation or a clinical trial.
The initial treatment for symptomatic low-risk patients should be ruxolitinib, interferons (Interferon alfa-2b, pegylated interferon alpha-2a, and pegylated interferon alpha-2b), or a clinical trial.
Patients with intermediate-risk 1 myelofibrosis (IPSS = 1; DIPSS = 1 or 2; DIPSS-Plus = 1), should initially be assigned to observation, ruxolitinib if symptomatic, a clinical trial, or allogeneic hematopoietic cell transplantation (HCT).
Among patients who are intermediate-risk 2 (IPSS = 2; DIPSS = 3 or 4; DIPSS-Plus = 2 or 3) or high-risk (IPSS = 3; DIPSS = 5 or 6; DIPSS-Plus = 4 or 6), transplant candidates should receive allogeneic HCT.
Transplant-ineligible patients with a platelet count ≤50,000 should consider a clinical trial and those with platelet levels >50,000 should receive ruxolitinib or consider a clinical trial.
Patients who are not eligible for a transplant and whose only symptom is anemia should receive treatment according to the NCCN Guidelines for management of myelofibrosis-associated anemia.
Evidence for Ruxolitinib
“As the only FDA-approved therapy in myelofibrosis, ruxolitinib certainly plays a very important part in the treatment guidelines,” said Mesa.
The FDA approved ruxolitinib in November 2011 for the treatment of patients with myelofibrosis based on two parallel phase III studies, COMFORT-I2
The double-blind COMFORT I trial included over 300 patients with intermediate-2 or high-risk myelofibrosis who were randomized to oral ruxolitinib twice daily (n = 155) or placebo (n = 154). The primary endpoint of a reduction in spleen volume of ≥35% at 24 weeks was reached in 41.9% of the ruxolitinib cohort versus 0.7% in the placebo group (P <.001). Crossover was allowed in the trial design.
The COMFORT II trial randomized 219 patients with intermediate-2 or high-risk primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis in a 2:1 ratio to oral ruxolitinib (n = 146) or best available therapy (n = 73). At week 24, 32% of patients in the ruxolitinib group and 0 patients in the best available therapy group had a ≥35% reduction in spleen volume (P
<.001). The rates were 28% and 0, respectively, at 48 weeks (P
5-year follow-up data from COMFORT-1 presented at the 2016 ASCO Annual Meeting showed that in both the primary ruxolitinib and crossover arms, the reductions in spleen volume from baseline were rapid and durable.4
The median follow-up was 268.4 weeks for the ruxolitinib group and 269 weeks for the placebo arm. The median overall survival was not yet reached for patients receiving ruxolitinib compared with 200 weeks for the control group.
All-grade adverse events for patients receiving ruxolitinib at the initial randomization included fatigue (n = 79 patients), diarrhea (62), ecchymosis (47), constipation (47), peripheral edema (46), dyspnea (45), cough (44), nausea (44), dizziness (40), headache (40), pyrexia (40), pain in extremity (38).