Investigators conducted post hoc analyses of the phase 3 JUMP clinical trial to determine how clinical characteristics correlate with response to therapy in patients with myelofibrosis.
Sparse options are available for the treatment of patients with primary myelofibrosis (MF), which is categorized among the rare myeloproliferative neoplasms. Even with the promise of autologous stem cell transplant (ASCT), the need for targeted therapy for this disease remains due to the guidelines around ASCT eligibility.
JAK inhibition with ruxolitinib (Jakafi) was explored as a new option in the phase 3 JUMP study (NCT01493414).1 A total of 223 patients were enrolled, making JUMP the largest study of ruxolitinib in MF. The goal of the study was to investigate the efficacy and safety of ruxolitinib in this patient population. The previously published data from JUMP were positive showing a ≥ 50% reduction in spleen size in 23.3% of the population and 25% to 50% reductions in 18.9% of the population. Most notably splenomegaly was resolved in 23.7% of patients in the study. Safety in the JUMP study was consisted with previous studies in that the most common adverse events (AEs) were anemia and thrombocytopenia, which did not lead to treatment discontinuation for most patients.2
Outside from the JUMP study results, investigators led by Vikas Gupta conducted post hoc analyses to determine how clinical characteristics correlate with response to therapy in patients with MF. This correlation was assessed through patient and disease characteristics collected in the JUMP study, as well as data on spleen response, and symptom improvement.
The evaluated patient population included 2223 individuals treated at 279 different clinical sites in Europe, Latin America, North American, and other regions. The median age of the patientsanalyzed was 67 years (range, 18-89). More than half of the study population (59.7%) was male. The MF subtype for patients enrolled was primary for 59.4%, and secondary for 40.6%. The subtype information was missing for 1 patient. The International Prognostic Scoring System (IPSS) risk was low or intermediate for 16.3% of patients, intermediate or high for 34.6%, with data missing for the remaining 49.1%. Dynamic IPSS (DIPSS) risk was low or intermediate-1 for 40.1% of patients, intermediate-2 for 33.8%, and high for 8.7%. DIPSS risk was missing for 17.4% of patients.
Laboratory values were assessed including hemoglobin level, platelet count, and white blood cell (WBC) count. The mean hemoglobin was <10 g/dL for 38.5% of patients and ≥10 g/dL for 61.5% of patients. The mean platelet count was <100 × 109/L for 6.2% of patient and ≥100 × 109/L for 93.8% of patients. Finally, the mean WBC count was ≤25 × 109/L for 81./2% of patients and >25 × 109/L 17.8% of patients. Data on platelet count and WBC count were missing for 0.4% of patients, each.
In terms of treatment history, 40.7% of patients were treatment-naïve, 59.3% were previously treatment, and 25.9% of patients had prior transfusions. In addition, transfusion dependency was observed in 7.1% of patients, while the remaining 92.9% were transfusion-independent. Spleen length at baseline was ≥10 cm for 65.9% of the study population and <10 cm for 34.1%.
Characteristics Impact Response to Ruxolitinib
With the majority of patients in the JUMP study having responded to treatment with ruxolitinib, the mean change in spleen size from baseline was a 68.3% decrease with a median decrease of 75.0% (range −100.0%-133.3%). At week 24, spleen responses were observed in 34.3% of patients. Investigators determined that some baseline factors were associated with spleen responses.
DIPSS demonstrated predictive value toward response to ruxolitinib, but, it was limited to patients having prior treatment (37.3%) versus no prior treatment (26.8%). The adjusted odd ratio (aOR) was 0.62 (95% CI, 0.45–0.84).
The association between spleen response and IPSS low or intermediate-1 risk, ruxolitinib as first-line treatment, and ruxolitinib dose >20 mg/day at week 12 were all deemed significant. Another significant predictor of spleen response observed in this study was ruxolitinib as first-line treatment, which appeared to be irrespective of DIPSS risk status. The percentages were 45.2% versus 38.0% (aOR, 0.59; 95% CI 0.37–0.93) for low or intermediate-1 risk and 37.3% versus 26.8% (aOR,0.46;95% CI 0.27–0.79) intermediate-2 or high risk.
In terms of treatment dosing, univariate multivariate analyses showed that >20 mg/day at Week 12 correlated with higher response rate with a percentage of41.3% versus 30.4% for those who received a lower dose (aOR, 0.47; 95% CI 0.33–0.68). The benefit of >20 mg ruxolitinib daily was seen across all risk group.
Baseline Characteristics Correlate With HRQoL and Symptoms
Another univariate analysis of the JUMP study observed symptom response in patients based on the Functional Assessment of Cancer Therapy Lymphoma Subscale (FACT-Lym) and theFunctional Assessment of Cancer Therapy Lymphoma Illness Therapy (FACIT) scale. Specially, a titrated total daily dose of ruxolitinib at >20 mg/day at week 12 of therapy was found to be associated with symptom response was 48.2% in patients who received ≤ 20 mg/day and 56.7% for those given >20 mg/day (OR, 0.71; 95% CI, 0.57-0.88). On the FACIT scale, the difference between patients who received ≤ 20 mg/day and >20 mg/day was 44.9% versus 51.5% (OR, 0.77; 95% CI, 0.62-0.96).
Providing further explanation of the findings from the post hoc analyses, Gupta et al wrote: “Although clinically meaningful improvements in symptoms were seen as early as 4 weeks after starting ruxolitinib in the JUMP study, symptom improvement (as assessed using the FACT-Lym total score and the FACIT-F scale) was not associated with any of the clinical or demographic factors assessed in the multivariate analyses. These results are in line with the main findings of the JUMP study, showing that symptom response rates were not affected by the ruxolitinib starting dose, and were similar when evaluated according to MF subtype.”
These findings support the use of ruxolitinib as a front-line therapy for patients with MF and at a daily dose level of 20 mg or higher.
1. Gupta V, Griesshammer M, Martino B, et al. Analysis of predictors of response to ruxolitinib in patients with myelofibrosis in the phase 3b expanded-access JUMP study [Published online November 19, 2020]. Leukemia & Lymphoma. doi: 10.1080/10428194.2020.1845334
2. Foltz L, Palumbo GA, Martino B, et al. safety and efficacy of ruxolitinib for the final enrollment of jump: an open-label, multicenter, single-arm, expanded-access study in patients with myelofibrosis (n = 2233). Blood. 2016; 128 (22): 3107. doi: 10.1182/blood.V128.22.3107.3107