Beginning ruxolitinib (Jakafi) therapy at lower doses may limit the anemia frequently seen early in treatment in patients with myelofibrosis while still providing clinical benefits like improvements in splenomegaly, according to the results of a 24-week open-label phase II dose escalation study.
The study authors, led by Moshe Talpaz, MD, of the University of Michigan, noted that current recommendations, including those detailed in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms, adhere to ruxolitinib dosing as described in the product label, which is based on baseline platelet count.
“However, the NCCN does recognize that there are specific clinical situations that may support the initiation of ruxolitinib at a lower dose, followed by dose increases,” Talpaz et al wrote in theJournal of Hematology & Oncology. “Alternative strategies [like reduced initial dosing] should be considered for patients who have anemia or are likely to become anemic.”
The investigators based their study design on the earlier COMFORT-I and COMFORT-II trials, which showed an initial drop in participants’ hemoglobin during the first 8 to 12 weeks of therapy.2,3They enrolled 45 patients with either primary MF, post-polycythemia vera MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF). About two-thirds of participants (68.9%) had a Dynamic International Prognostic Scoring System (DIPSS) score of 1 to 2, meaning they had intermediate-1 disease risk, while the remaining patients (28.9%) had DIPSS scores indicating intermediate-2 or high-risk disease.
The investigators assessed the effects of starting ruxolitinib at 10 mg BID on spleen volume at week 24 measured by MRI as the primary outcome. Secondary outcomes were palpable spleen length and symptom burden as measured using the Myelofibrosis Symptom Assessment Form Total Symptom Score (MFSAF TSS). They also assessed the safety and tolerability of ruxolitinib by evaluating new-onset transfusion dependence and grade ≥3 anemias.
Participants received dose increases of 5 mg at week 12 if needed and then again at week 18 if the lower doses were ineffective. The maximum dose was 20 mg BID.
At 24 weeks, the median percentage change in spleen volume was 17.3% with a clear dose response. More than half the patients (n =26, 57.8%) achieved ≥ 10% volume reduction.
In comparison, COMFORT-I and COMFORT-II mean week 24 reductions in spleen volume were 31.6% and 29.2%, respectively. Those patients took initial ruxolitinib doses of 15 or 20 mg BID, with some patients decreasing to 10 to 15 mg BID during the first 8 to 12 weeks as necessary.
The authors noted that spleen volume decreased less at week 24 across all dose levels in the present study compared with the COMFORT trials. Of the patients originally randomized to ruxolitinib in COMFORT-I and COMFORT-II, 58.7% and 32% achieved a ≥ 35% reduction in spleen volume during study follow-up, most by week 12. This compares with 15.6% in the current study. The authors also found that reductions in spleen volume and length were more correlative in COMFORT-I than the current study.
The mean reduction in palpable spleen length from baseline was 47.6% at week 24. At weeks 6 and 24, 44.4% of patients achieved a ≥ 40% reduction from baseline in palpable spleen length. This proportion dipped to 35.6% at week 12 and 31.1% at week 18.
The mean baseline MFSAF TSS of 16.6 improved to 9.3 at week 24. The median percentage changes in MFSAF TSS from baseline to week 24 was 45.6%. At week 24, 30 patients (66.7%) had a ≥ 20% reduction in MFSAF TSS from baseline.
At week 24, MFSAF TSS reductions ≥ 20% were observed in 56.3% of patients who received ruxolitinib ≤ 10 mg daily. Nearly three quarters of patients (72.4%) who received > 10 mg daily showed MFSAF TSS reductions ≥ 20%. Eighteen patients (40.0%) achieved a ≥ 50% improvement in MFSAF TSS from baseline to 24 weeks.
In reviewing hematologic parameters, the authors found that the median hemoglobin declined slightly at week 4. Median hemoglobin levels returned to baseline at week 10 and remained close to that level through week 24. No patients had a grade 4 decrease in hemoglobin level during the study, but 20 patients (44.4%) experienced a grade 3 decrease.
During the first 4 weeks of treatment, median platelet count declined to 176 × 109/L from baseline (277 × 109/L) before increasing. The median then remained in a range of 193.5 × 109/L to 230.0 × 109/L from week 6 to week 20. At week 24, the median platelet count was 172 × 109/L. One patient each developed a grade 3 and grade 4 thrombocytopenia on study. In general, median ANC counts remained stable through week 24.
The authors also included adverse event data. Overall, 42 patients (93.3%) experienced a treatment-emergent AE (TEAE). The most common was anemia (26.7%), followed by fatigue (22.2%) and arthralgia (20.0%).
Seventeen patients (37.8%) had a TEAE of grade 3 or higher, and 24 patients (53.3%) had treatment-related AEs. Two patients (4.4%) developed serious AEs, with one each developing cholelithiasis and dehydration. One patient discontinued ruxoitinib upon developing what became a fatal case of myelodysplastic syndrome.
Nine patients (20.0%) had TEAEs that required dose reduction. The most frequent reasons for dose reduction were anemia (n = 5, 11.1%) and thrombocytopenia (n = 3, 6.7%).