Clinical factors associated with response to ruxolitinib in patients with myelofibrosis

A dysregulated Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is characteristic of myelofibrosis (MF). Ruxolitinib, a potent JAK1/JAK2 inhibitor, was approved in 2011 for the treatment of primary and secondary intermediate-/high-risk MF. The approval was based on the results of the pivotal phase III COMFORT studies in patients with intermediate-2- or high-risk MF. In these studies, ruxolitinib demonstrated superiority over placebo and best available therapy with durable improvements in splenomegaly, MF symptoms, and quality of life (QoL), and was also associated with better overall survival.

Due to limited data on patients with intermediate-1-risk MF, the phase IIIb expanded-access JUMP study (NCT01493414) was initiated with the aim to collect safety and efficacy data for ruxolitinib in this population of patients. This study enrolled 2,233 patients, and initial results from patients treated with ruxolitinib for ≥ 1 year (n = 1,144), including those with intermediate-1-risk disease, showed reductions in spleen length and MF symptoms.¹

A recent publication in Leukemia & Lymphoma by Vikas Gupta further evaluated clinical factors associated with response to ruxolitinib using data from the JUMP study.² Here, we report key findings from this study.

Study design^1,2

The JUMP study is an open-label, multicenter, single-arm, phase IIIb expanded-access study in patients with MF. Eligibility criteria and study design are shown in Figure 1.

The starting doses of ruxolitinib were based on platelet count at baseline (Figure 1).

Spleen response was assessed using the International Working Group–Myeloproliferative Neoplasms Research and Treatment (IWG–MRT) criteria.

Endpoints

The primary endpoint was safety and tolerability of ruxolitinib.

Additional endpoints included:

• Proportion of patients with a ≥ 50% reduction in palpable spleen length
• Change from baseline in patient-reported symptom response:
  • Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-F] scale
  • Functional Assessment of Cancer Therapy–Lymphoma [FACT-Lym] total score

IPSS, International Prognostic Scoring System; MF, myelofibrosis.

Patient characteristics²

Baseline characteristics of the 2,233 patients treated in the JUMP study from 2011 to 2017 and included in this analysis are shown in Table 1.

• Mean FACT-Lym total score at baseline, 113.9; mean FACIT-F score, 32.7

Table 1. Baseline characteristics of patients²

DIPSS, Dynamic International Prognostic Scoring System; Hb, hemoglobin; IPSS, International Prognostic Scoring System; MF, myelofibrosis; SD, standard deviation; WBC, white blood cell.
Characteristic	Patients (N = 2,233)
Median age (range), years	67.0 (18–89)
Mean time since initial diagnosis (SD), months               n evaluable               ˃ 2 years, n (%)               ≤ 2 years, n (%)	51.7 (64.4) 2,229 1,152 (51.6) 1,081 (48.4)
MF subtype, n (%)               Primary               Secondary               Missing	1,326 (59.4) 906 (40.6) 1 (< 0.1)
IPSS risk, n (%)               Low/intermediate-1               Intermediate-2/high               Missing	365 (16.3) 772 (34.6) 1,096 (49.1)
DIPSS risk, n (%)               Low/intermediate-1               Intermediate-2               High               Missing	895 (40.1) 755 (33.8) 194 (8.7) 389 (17.4)
Hb level, mean (SD), g/dL               n evaluable               < 10g/dL, n (%)               ≥ 10g/dL, n (%)	10.9 (2.3) 2,226 856 (38.5) 1,370 (61.5)
Platelet count, mean (SD), × 109/L                n evaluable               < 100 x 109/L, n (%)               ≥ 100 x 109/L, n (%)               Missing, n (%)	318.9 (238.6) 2,225 138 (6.2) 2,087 (93.8) 8 (0.4)
Palpable spleen length, median (range), cm               n evaluable               ≥ 10 cm, n (%)               < 10 cm, n (%)	12.0 (0.5–45.0) 2,079 1,472 (65.9) 761 (34.1)

Results²

Data on drug exposure are shown in Table 2.

Table 2. Ruxolitinib exposure²

Ruxolitinib exposure	Patients (N = 2,233)	n evaluable
Median duration of exposure, months (range)	12.4 (< 0.1─59.7)	2,233
Mean daily dose, mg	28.7	2,233
Starting dose, %               > 20 mg/day               ≤ 20 mg/day	93.1 6.9	2,233
Ruxolitinib dose > 20 mg/day at Week 12, %               Hb level > 10 g/dL and platelet count > 100 × 109/L               Either Hb level < 10 g/dL or platelet count < 100 × 109/L               Both Hb level < 10 g/dL and platelet count < 100 × 109/L	67.2 56.1 5.0	1,162 813 60
Exposure to ruxolitinib, %               > 1 year               > 2 years               > 3 years	51.0 30.0 13.0	2,101

Spleen response

• A reduction in spleen size was observed in most patients, with a mean change from baseline of –68.3% (median, –75.0%; range, –100.0% to 133.3%) in the 2,049 patients assessed
• Factors predicting higher spleen response rates in univariate analysis were generally associated with:
  • Better disease status (International Prognostic Scoring System [IPSS] intermediate-1/low risk status, Hb level ≥ 10 g/dL, platelet count ≥ 100 × 10⁹/L, blasts < 1%)
  • Early treatment initiation with ruxolitinib (time since MF diagnosis of ≤ 2 years), ruxolitinib as first-line treatment, ruxolitinib dose > 20 mg/day
  • Prior treatment vs no prior treatment, only in patients in the Dynamic IPSS (DIPSS) intermediate-2/high-risk group (37.3% vs 26.8%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.45–0.84)
• Of these, only three factors were confirmed in a multivariate analysis to predict higher spleen response rates (Table 3):
  • IPSS intermediate-1/low
  • Ruxolitinib as first-line treatment
  • Ruxolitinib dose of > 20 mg/day at Week 12

Table 3. Factors associated with higher spleen response rates in multivariate analysis²

CI, confidence interval; IPSS, International Prognostic Scoring System; OR, odds ratio.
Factor predicting higher spleen response rates	n/N	%	OR (95% CI)
IPSS               Intermediate-2/high               Intermediate-1/low	198/647 151/350	30.6 43.1	0.65 (0.44–0.95)
Prior treatment               Ruxolitinib as 2nd line or beyond               Ruxolitinib as 1st line	417/1,325 255/635	31.5 40.2	0.53 (0.38–0.75)
Ruxolitinib dose at Week 12               ≤ 20 mg/day               > 20 mg/day	206/678 466/1,127	30.4 41.3	0.47 (0.33─0.68)

Factors predicting symptom improvement

• In the univariate analysis, the only factor predicting symptom improvement was a titrated dose of ruxolitinib of > 20 mg/day at Week 12.
  • FACT-Lym total score-based symptom response achieved, ≤ 20 mg/day vs > 20 mg/day: 48.2% vs 56.7% (OR, 0.71; 95% CI, 0.57–0.88)
  • FACIT-F scale-based symptom response achieved, ≤ 20 mg/day vs > 20 mg/day: 44.9% vs 51.5% (OR, 0.77; 95% CI, 0.62–0.96)
• No correlation with ruxolitinib dose and symptom score improvement was seen in the multivariate analysis

Overall survival

• The median overall survival was not reached in patients in the DIPSS intermediate-1/low risk group
• In patients in the DIPSS intermediate-2/high risk group, overall survival was 229.1 weeks vs 253.6 weeks in those who achieved a spleen response at Week 24 vs those who did not respond. However, because of the small sample size (with only 32 patients achieving spleen response), these results should be interpreted with caution

Conclusion²

This analysis revealed that lower IPSS risk, doses of ruxolitinib > 20 mg/day, and ruxolitinib given as first-line therapy are independent factors associated with higher spleen response rates.

No correlation between dose or demographic factors and patient-reported symptom improvement under ruxolitinib treatment was seen.

The limitations of the study include the lack of MF-specific health-related quality of life data and of cytogenetic and molecular data, and the limited length of follow-up time.