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Ruxolitinib in advanced relapsed/refractory HL
and even intensive chemotherapy.35-38 In vitro data have shown that ruxolitinib could restore the sensitivity of cis- platin-resistant cell lines with higher Jak2 expression.39 Interestingly, the combination of BV with ruxolitinib resulted in additive and synergistic killing in a xenograft mouse model of HL through a mechanism involving mitochondrial control of apoptosis.40 Another means to boost ruxolitinib’s potential would be to combine it with agents blocking other signaling pathways. Interestingly, the combination of ruxolitinib with a Bcl2/Bcl-xL inhibitor displayed dramatic synergy in an adult T-cell leukemia cell line via a mechanism implying BAX activa- tion.41 Finally, the effect of combining chemical JAK blockade and an anti-PD1/L1 strategy should be analyzed in HL, keeping in mind, however, that a potential antag- onism may be encountered due to these two drugs acting on the same target, given that PD1-L1 expression is dependent on JAK2 activity.
In conclusion, based on a strong biological rationale for clinical evaluation of JAK2 blockade in HL, we initiated a
phase II study of ruxolitinib in R/R HL patients. The study failed to fulfill the efficacy criteria for further devel- opment of the drug as monotherapy. Nonetheless, in patients with very advanced disease ruxolitinib showed hints of activity that surpassed solely an anti-inflammato- ry effect. This may suggest that further improvements will come from a more complete inhibition of signaling pathways involved in HRS cell survival or from combina- tion with chemotherapy, such as BV.
Acknowledgments
The authors would like to thank the patients, their families and their caregivers who made this study possible. We also thank all the study investigators and study staff at each of the clinical sites. For the LYSARC, we acknowledge the project manager and all members of the data monitoring committee. We express our thanks to Loïc Chartier and Sami Boussetta, biostatisticians at the LYSARC, who contributed to the statistical design and analy- sis of the study. Editorial assistance was provided by Cremer Consulting.
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