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EXPAND: 48-week follow-up analysis
Figure 5. Change in total symptom score and individual symptom scores of Myelofibrosis Symptom Assessment Form diary from baseline to week 24 by stratum at maximum safe starting dose.
Ruxolitinib was generally well tolerated at all dose levels, including the MSSDs, and no new safety signal was observed. However, as expected, a higher frequency of thrombocytopenia was observed, which was managed by dose reduction/interruption. Evidently, the 10 mg bid dose was better tolerated in S1 versus S2; 3 out of 6 patients in S1 versus 10 out of 11 patients in S2 did not resume the 10 mg bid dose after the initial dose reduction (first 12 weeks). A medically meaningful spleen size response was observed with ruxolitinib treatment at the 10 mg bid dose. In the MSSD cohort, at least 50% of reduction in the spleen length was observed in 33.3% of patients in S1 and 30.0% of patients in S2 at week 48, whereas a spleen response at any time point was achieved by 40.0% of patients in S1 and 66.7% of patients in S2. A decrease in the best percentage change from baseline was observed at the MSSD in 95.0% of patients in S1 and 94.4% of patients in S2. An improvement in symptom response (decrease in the MFSAF-TSS) was also observed at the MSSD in both strata.
During the first 12 weeks of treatment, the ruxolitinib dose was reduced below 10 mg bid in some patients, mostly due to ruxolitinib-associated hematologic toxicity. However, spleen and symptom benefit was observed in these patients despite the early dose titration, and the treatment was continued at the reduced dose, suggesting that a starting dose of 10 mg bid may still be effective in the long-term (as was also observed in the COMFORT-I study).28
In the subgroup with dose down-titration in S1 (3 out of 6 patients), a decrease in the best percentage change from baseline in spleen length was observed; however, none of these patients achieved an at least 50% reduction in spleen length. All patients in S2 (n=10) who had a dose down-titration achieved a decrease in the best percentage change from baseline in spleen length; 7 out of 10 patients achieved an at least 50% reduction in spleen length (Online Supplementary Figure S2). A trend in symptom improvement was also observed in patients with early
dose titration at the MSSD; this effect was more pro- nounced in S1 than in S2 (Online Supplementary Table S9 and Online Supplementary Figure S3).
The observations from the EXPAND study are consistent with the findings from other clinical trials evaluating the use of ruxolitinib in patients with MF with baseline throm- bocytopenia. In the Study 258, the median percentage change from baseline in spleen length at week 24 in the 30 evaluable patients was –29.7% (range, –100.0% to 58.3%). In the EXPAND study, the median percentage change from baseline in spleen length at week 24 for the overall popula- tion (n=69) was –36.9% (range, –100.0% to 55.6%). As expected (owing to baseline patients’ characteristics and the mechanism of action of ruxolitinib), thrombocytopenia was frequent in both the Study 258 and the EXPAND study (64.0% vs. 68.1%, respectively). Low-dose ruxolitinib was shown to be generally well tolerated and efficacious in patients with MF with low platelet counts in JUMP.23
The findings to date from the 48-week follow-up analysis of the EXPAND study provide evidence to sup- port a starting dose of ruxolitinib at 10 mg bid for patients with MF with low baseline platelet counts of 75-99x109/L (S1) but are less conclusive for baseline platelet counts of 50-74x109/L (S2). The reported AEs were consistent with the known safety profile of ruxolitinib, with the exception of thrombocytopenia in S2, which was expected. Ruxolitinib treatment was generally well tolerated and provided spleen size reduction and symptom response benefit. The tolerability of ruxolitinib in this previously unstudied patient population with MF with low platelet counts at baseline was acceptable at doses of 10 mg bid in both strata. The study is ongoing, and further evaluations will be performed at the end of the study to confirm the safety and efficacy of ruxolitinib in the study cohorts.
Acknowledgments
The authors would like to thank Archana Rai and Ambrin Fatima, PhD (Novartis Healthcare Pvt Ltd) for providing medical writing assistance.
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