Page 104 - 2019_05-HaematologicaMondo-web

A.M. Vannucchi et al.
A
B
Figure 2. Blood parameters over time. (A) Hemoglobin levels. (B) platelet counts. BL: baseline.
Table 1. Patient disposition (week 48 analysis; maximum safe starting
n=4 (22.2%)], treatment duration completed [S1, n=0; S2, n=3 (16.7%]), physician decision [S1, n=1 (5.0%); S2, n=3 (16.7%)], disease progression [S1, n=3 (15.0%); S2, n=1 (5.6%)], and death [S1, n=0; S2, n=2 (11.1%)].
Dosing and exposure. The median exposure to ruxolitinib was 54.8 weeks (range, 4.3-210.0 weeks) in S1 and 83.2 weeks (range, 4.4-161.1 weeks) in S2. Overall, 45.0% (9 out of 20) of patients in S1 and 88.9% (16 out of 18) of patients in S2 had at least 1 dose reduction/interruption (Online Supplementary Table S7). The mean total daily dose over time plot by stratum at MSSD (10 mg bid in both S1 and S2) is shown in Figure 3. The mean dose intensity was 17.96 mg/day [standard deviation (SD)=3.055] in S1 and 13.27 mg/day (SD=5.030) in S2.
Dose modifications were observed during the first 12 weeks of treatment in some patients; 30.0% (6 out of 20) of patients in S1 and 61.1% (11 out of 18) of patients in S2 had at least 1 dose reduction/interruption (Online Supplementary Table S8). Among these patients with a dose down-titration, 3 of 6 patients in S1 and 10 of 11 patients in S2 did not resume the initial 10 mg bid dose. Thrombocytopenia was the most frequent AE leading to an early dose titration.
dose cohort).
Patient disposition
Patients treated End of treatment Treatment ongoinga
Primary reason for end of treatment
AE
Completed
Death
Other
Physician decision Progressive disease Withdrawal by patient
Stratum 1 (N=20) N (%)
6 (30.0) 14 (70.0)
1 (5.0) 0
0
1 (5.0) 1 (5.0) 3 (15.0) 0
Stratum 2 (N=18) N (%)
15 (83.3) 3 (16.7)
4 (22.2) 3 (16.7) 2 (11.1) 0
3 (16.7)
1 (5.6)
2 (11.1)
Safety in the maximum safe starting dose cohort
AE: adverse event. aPatients under ongoing treatment at the time of data cutoff (December 7, 2017).
relationship (any SOC)] was observed in 45.0% (9 out of 20) of patients in S1 and 66.7% (12 out of 18) of patients in S2. Thrombocytopenia was the primary reason for dose adjustment/interruption in both strata [S1, n=4 (20.0%); S2, n=12 (66.7%)]. Overall, 25% (5 out of 20) of patients in S1 and 38.9% (7 out of 18) of patients in S2 experienced a serious AE [regardless of study drug relationship (any SOC)]. Thrombocytopenia (grade 4, related to study drug) was the only DLT reported in both strata at 10 mg bid [S1, n=1; S2, n=2 (1 DLT in S2 was reported at the interim analysis)]. Grade 4 worsening from baseline in platelet count was observed in 1 patient (5.0%) in S1 and 7 patients (38.9%) in S2 (Table 3). No grade 4 worsening from baseline was reported in either stratum for hemoglobin levels. Reasons for on- treatment death (in the MSSD cohort) included acute myeloid leukemia (1 patient) and cardiac arrest (1 patient) in S1, and multi- ple organ failure (1 patient) in S2 (Online Supplementary Table S5).
Adverse events (in ≥15% of patients in either stratum, regard- less of study drug relationship) in the MSSD cohort are presented in Table 2. As observed in the interim analysis, anemia and thrombocytopenia (all grades) were the most common hemato- logic AEs in both strata [anemia: S1, n=9 (45.0%); S2, n=8 (44.4%) and thrombocytopenia: S1, n=8 (40.0%); S2, n=14 (77.8%)]. Grade 3 or 4 AEs were reported in 70.0% (14 out of 20) of patients in S1 and 88.9% (16 out of 18) of patients in S2. The AEs [regard- less of study drug relationship; any system organ class (SOC)] led to treatment discontinuation in 15.0% (3 out of 20) of patients in S1 and 33.3% (6 out of 18) of patients in S2, with thrombocytope- nia being reported as the most common reason for treatment dis- continuation [S1, n=1 (5.0%); S2, n=3 (16.7%)]. Dose adjustment or study drug interruption due to AEs [regardless of study drug
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haematologica | 2019; 104(5)