Patients aged ≥18 years who met the WHO recommended criteria for the diagnosis of primary MF and MF secondary to essential thrombocythemia (ET) and polycythemia vera (PV) were eligible for the current study.16 Eligible patients had intermediate-2- or high-risk MF by the International Prognostic Scoring System (IPSS) criteria, with or without splenomegaly, or IPSS intermediate-1-risk MF with a palpable spleen (≥5cm from the costal margin) (information collected after protocol amendment 2). The IPSS risk status stratification was included per protocol amendment. Patients were included if they had a baseline platelet (PLT) count of ≥50×109/L; patients with PLT counts of 50–100×109/L were enrolled per amendments. Informed consent was obtained from all the patients.

JUMP is a single-arm, open-label, phase IIIb, expanded-access study. The starting doses of ruxolitinib were based on the PLT counts: 5mg twice daily (bid; 50–<100×109/L), 15mg bid (100–200×109/L), or 20mg bid (>200×109/L). Dose titration was allowed (per protocol) during treatment for safety and efficacy reasons, so that each patient was titrated to their most appropriate doses (5-mg-bid increments, up to a maximum of 25mg bid). Patients were followed for 28 days after the end-of-treatment visit (no data were collected for patients beyond the follow-up visit, including for those who transitioned to receive commercial ruxolitinib).

The primary endpoint was to evaluate the safety and tolerability of ruxolitinib, which included the frequency, duration, and severity of adverse events (AEs). Additional endpoints included the proportion of patients with ≥50% reduction in palpable spleen length (assessed by the International Working Group-Myeloproliferative Neoplasms Research and Treatment [IWG-MRT] criteria; Supplementary data), patient-reported outcomes (Functional Assessment of Cancer Therapy–Lymphoma [FACT-Lym] total score [TS] and Functional Assessment of Chronic Illness Therapy [FACIT]–Fatigue scores), progression-free survival (PFS), survival without transformation to leukemia (leukemia-free survival [LFS]), and overall survival (OS). Statistical analysis is discussed under Supplementary data.

A total of 2233 patients were enrolled at 279 clinical sites across 26 countries in the JUMP study (the last patient's last visit was on January 26, 2017). This subgroup analysis was conducted on 104 patients in the overall JUMP study cohort who were enrolled in Brazil. The trial was conducted in agreement with appropriate local regulations and the principles of the Declaration of Helsinki, and approved by the institutional review board at each participating institution. Written informed consent was collected from all the patients. All patients who received ruxolitinib were included in this analysis.

Baseline characteristics are presented in Table 1. The median age was 66 years (range, 41–87 years); 53.8% of the patients were ≥65 years. The median time from the initial diagnosis was 47.2 months (range, 1.1–204 months). Overall, 59.6% of patients were male, and 87.5% had primary MF.

All of the 104 Brazilian patients received treatment. Overall, 43.3% of the patients completed the treatment duration as per protocol. The most common reasons for discontinuation included death (17.3%), AEs (16.3%), and disease progression (12.5%) (Table 1, Supplementary data).

Median duration of exposure was 35.8 months (range, 0.6–59.7 months). Mean daily dose was 31.3mg for the Brazilian cohort (Figure 1, Supplementary data). The majority of the patients (69.2%) had at least one dose reduction/interruption, and the most common reason was AEs (54.8%).

The most common (in ≥5% of patients) hematologic AEs (Table 2) were anemia (all grades, 57.7%; grades 3/4, 48.1%), thrombocytopenia (all grades, 38.5%; grades 3/4, 12.5%), neutropenia (all grades, 11.5%; grades 3/4, 10.6%), and leukopenia (all grades, 9.6%; grades 3/4, 6.7%), and these results were consistent with the findings in the COMFORT studies.8–10 Of note, anemia (2.9%) was the only hematologic AE (in >1% of the patients) that led to study drug discontinuation (regardless of study drug relationship) in the Brazilian patient pool; no patient discontinued due to thrombocytopenia.

The hemoglobin level declined during the first 12 weeks of treatment, but increased to near-baseline levels after week 12 (Figure 1A). A similar trend was observed for PLT counts, wherein the values decreased during the first 4 weeks and then remained stable over time (Figure 1B).

Figure 1.

(A) Hemoglobin levels over time; (B) platelet count over time.

(0.32MB).

The most common non-hematologic AEs (in ≥5% of the patients) were primarily grades 1/2 (Table 2), except pneumonia (19.2%, grades 3/4) and sepsis (7.7%, grades 3/4); no discontinuation was reported for these two non-hematologic AEs. Rates were low (<5%) for the other non-hematologic AEs. The rate of infections in all grades was 76.9%. Herpes zoster infection was reported in 9.6% of the patients (n=10; grade 3/4, 1% [n=1]), but no treatment discontinuation was reported for any of these patients. Tuberculosis was reported in one patient (1%) and this led to treatment discontinuation.

Second malignancies that occurred in 19.2% of patients (n=20) in all grades included squamous cell carcinoma (5.8% [n=6]), basal cell carcinoma (3.9% [n=4]), skin neoplasm (2.9% [n=3]), prostate cancer (1.9% [n=2]), and squamous cell carcinoma of the skin (1.9% [n=2]). Other second malignancies occurred in 1% of patients; there was one case each of acute leukemia, leukemia, B-cell lymphoma, benign parathyroid tumor, and skin papilloma. Acute myeloid leukemia (disease progression) occurred in two (1.9%) patients.

Serious AEs were reported in 62.5% of patients (n=65). Serious AEs occurring in >2% of patients in all grades included pneumonia (21.2%), sepsis (7.7%), urinary tract infection (4.8%), anemia (4.8%), septic shock (3.9%), squamous cell carcinoma (3.9%), respiratory failure (3.9%), ascites (3.9%), bronchospasm (2.9%), skin infection (2.9%), cardiogenic shock (2.9%), abdominal pain (2.9%), fatigue (2.9%), renal failure (2.9%), and dyspnea (2.9%) (Table 2, Supplementary data).

The proportion of patients with ≥50% reduction from baseline in palpable spleen length at weeks 24 and 48 was 62.7% and 69.2%, respectively, while 10.7% of patients at week 24 and 13.8% at week 48 showed 25% to <50% reductions (Figure 2).

Figure 2.

Evaluable patients with a decrease from baseline in palpable spleen length.

(0.17MB).

The median time to first ≥50% reduction in palpable spleen length was 4.3 weeks (range, 2.9–160.3 weeks). Overall, 78.3% of the patients showed ≥50% reduction in spleen length at any point in time in the study (Figure 3). The Kaplan–Meier estimate for duration of first response (≥50% reduction in spleen length from baseline) at 24 weeks and 48 weeks was 89% (95% confidence interval [CI], 78%–94%) and 86% (95% CI, 74%–92%), respectively.

Figure 3.

Best percent change from baseline in palpable spleen length at any time by week 48.

(0.14MB).

Clinically meaningful improvements in symptoms were seen as early as 4 weeks after the treatment initiation and were maintained over time, as evaluated by the FACT-Lym TS (mean change from baseline was 10.8 [15.6%] at week 4, 12.6 [14.1%] at week 24, and 12.2 [14.3%] at week 48) and the FACIT-Fatigue scale (the mean change from baseline was 3.9 [42.8%] at week 4, 4.9 [29.9%] at week 24, and 4.7 [28%] at week 48) (Figure 2, Supplementary data).17,18 Overall, 64.5% and 64.6% of the patients achieved a response (health-related QoL [HRQoL]; i.e., minimally important difference) in the FACT-Lym TS and 55.8% and 51.5% in the FACIT-Fatigue scale at 24 and 48 weeks, respectively (Figure 4).

Figure 4.

Proportion of patients achieving response (HRQoL) by the lower limit of MID.

(0.1MB).

The estimated PFS probability at 48 weeks was 91% (95% CI, 85%–97%). The MF transformed into leukemia in three patients during the study. The estimated LFS probability at 48 weeks was 91% (95% CI, 86%–97%). The estimated OS probability at 48 weeks was 93% (95% CI, 89%–98%) for the Brazilian patient pool (Table 3).

Investigator-determined causes of death included MF (n=2), cardiac arrest (n=2), cardiogenic shock (n=2), pneumonia (n=2), sepsis (n=2), respiratory failure (n=2), and pulmonary embolism (n=2). All other causes were undetermined or reported for one patient each.