Page 106 - 2019_05-HaematologicaMondo-web

A.M. Vannucchi et al.
titration in both S1 (n=3) and S2 (n=10). In patients without a dose down-titration, a decrease in best percentage change from base- line in spleen length was seen in 94.1% (16 out of 17) of patients in S1 and 87.5% (7 out of 8) of patients in S2.
Symptom response. An improvement (i.e. decrease) in TSS was observed at the MSSD in both strata. The mean change in TSS from baseline at week 24 was –7.7 (SD=9.70) in S1 and –3.9 (SD=11.36) in S2. Compared to the baseline symptom score, the mean individual symptom scores decreased (improved) for all categories except bone/muscle pain (slight worsening) at week 24 (Figure 5). A trend in symptom improvement was also observed in patients with early dose titration (Online Supplementary Table S9 and Online Supplementary Figure S3).
Discussion
Only a few clinical trials are currently evaluating the treatment options for patients with MF with thrombocy- topenia (platelet counts <100x109/L), highlighting the need for conducting this analysis. The JAK inhibitors that have been evaluated in this setting include ruxolitinib, pacri- tinib, momelotinib, and fedratinib;34-36 however, only ruxolitinib is currently approved for the treatment of patients with MF. Ruxolitinib was approved for the treat- ment of intermediate- and high-risk patients with MF
based on the COMFORT studies in patients with normal platelet counts (≥100x109/L).9-12,28 Findings from a post hoc analysis of COMFORT-I showed that patients with cytopenias at baseline could be effectively managed with ruxolitinib dose adjustments and that doses of ≥10 mg bid yielded clinically meaningful reductions in spleen volume and symptom improvement.28 These findings support the use of ruxolitinib as a therapeutic option for patients with MF with low baseline platelet counts (<100x109/L).
The preliminary observations based on toxicity during the first cycle of treatment indicated ruxolitinib 15 mg and 10 mg bid as MSSDs for S1 and S2, respectively. However, observations from the interim analysis showed that the majority of patients receiving the 15 mg bid MSSD dose in S1 experienced thrombocytopenia, thus requiring dose reductions after the first cycle. These patients subsequently continued study treatment at the 10 mg bid or lower dose. Clinical benefit was observed across all starting dose levels, including in those patients who start- ed treatment at the 10 mg bid dose level. Based on these observations, the initially stated MSSD of 15 mg bid for S1 was revised to 10 mg bid as per protocol amendment. Based on the results from the interim and 48-week analy- ses of EXPAND, 10 mg bid was established as the MSSD for both strata (S1: platelet count=75-99x109/L; S2: platelet count=50-74x109/L).
Table 3. New or worsened hematologic abnormalities (week 48 analysis; maximum safe starting dose cohort).
Parameter
Platelets (×109/L)
Hemoglobin (g/dL)
MSSD: maximum safe starting dose.
Worsening from Stratum 1 (N=20)
baseline to the Total N (%) Total
following
Grade1200
Stratum 2 (N=18)
N (%)
15 5 (25.0) 1 19 9 (45.0) 18 20 1 (5.0) 18 5 2 (10.0) 1 13 3 (15.0) 9 18 5 (25.0) 12
0
1 (5.6) 7 (38.9) 7 (38.9) 0
6 (33.3) 1 (5.6)
Grade 2
Grade 3
Grade 4
Grade 1
Grade 2
Grade 3
Grade4 20 0 18 0
AB
Figure 4. Waterfall plot of best response in spleen length by stratum at maximum safe starting dose.
952
haematologica | 2019; 104(5)