Treatment of SR-aGVHD has remained unsatisfactory for decades. Novel therapeutic agents, which decrease aGVHD severity but preserve graft-versus-leukemia (GvL) effect and possess favourable toxicity profile remain unmet need. Janus Kinase 1 (JAK1) and 2 (JAK2) are among the most intensively studied targets due to their role in cytokine production (e.g. interleukin-1 and -6, tumor necrosis factor, interferon-gamma) and inflammatory T-cell actions [10,11,12]. RUX is reported to block dendritic cell activation, reduce the migration of neutrophils into GVHD affected organs and limit T-cell proliferation [13, 14].
Benefits of RUX therapy in SR-aGVHD have been showed in 2 pivotal clinical trials: REACH1 and REACH2 [5, 15]. The former focused on the efficacy of RUX treatment in combination with CS in GII–IV aGVHD. The best overall response rate (ORR) among 71 treated patients was 73% with median duration of response of 345 days. Responses were demonstrated across all affected organs, but skin remained the most prone to RUX therapy. REACH2 trial aimed to compare the efficacy of RUX versus standard immunosuppressive treatment. Although OS did not differ between groups, patients treated with RUX showed significantly higher ORR at day 28 (62% vs 39%). It should be mentioned that among studied patients, 34% manifested G II disease in which prognosis was found to be much better compared to more advanced stages. This particular group was proved to have the response rate of 75% and this was significantly higher if compared to grade III—56% and IV—53% .
Other studies seem to confirm the beneficial effect of RUX in SR-aGVHD. 19 patients with GIII and IV SR-aGVHD were analysed by Abedin et al. The authors reported unexpectedly promising response rate of 84% at day 28 with 6-month OS of 58% . Among RUX-responders, 9 patients achieved CR and 7 patients PR. However, if compare to our study, RUX was administered as early as after median of 2 prior unsuccessful GVHD therapies. What is more, 61% of our patients had GIV disease if compared to only 21% in abovementioned study. Similarly, another analysis on 23 Chinese patients with SR-aGVHD reported almost 87% ORR for RUX treatment with 1-year OS of 82% . These results were significantly better for RUX-responders than non-responders (90% vs 33.3%). Again, it should be noticed that this study included also patients with GII aGVHD (which accounts for ~ 40% of the entire cohort) and in none of the patients more than 2 organs were involved. Of note is that RUX was initiated after median of 5 days of GVHD duration.
Yet, one more real-life data reported 6-month OS of 47% for 23 patients with GII–IV SR-aGVHD (62% for RUX-responders and 28% for non-responders) . Of note is that only 5 out of 23 patients reached CR during RUX. These results are in line with those presented by us.
Based on the mentioned data, one may speculate that it would be reasonable to use RUX as GVHD prophylaxis. Significantly lower incidence of GII–IV aGVHD was demonstrated for patients who received RUX as prophylaxis in comparison to other immunosuppressive drugs (42% vs 12.2%) .
Of note is that our ORR of 28% (5/18) was markedly lower than reported in REACH trials as well as in the other cited papers [16, 17]. It should be, however, mentioned that we focused only on patients with GIII–IV SR-aGVHD which is known to have the poorest outcome. From the clinical point of view this is the most demanding group of patients with the highest need for efficient salvage therapy. Furthermore, lower ORR demonstrated in our report could be partially explained by relatively late RUX initiation, namely after failure of 3 prior immunosuppressive therapies. In the RUX registration trials, RUX was administrated simultaneously with CS (REACH1) or as a second-line treatment (REACH2).
It should be mentioned that our study included relatively small number of patients and it may have an impact on the results which should be treated with caution.
Although we did not observe significant differences in mortality between RUX-responders and non-responders group, a 12-month OS stands in favour for RUX-responders vs RUX non-responders (60% vs 31%). Among all studied factors, only duration of RUX therapy over 29.5 days significantly influenced OS. No other factors showed an impact on OS in our analysis. Despite some investigations showing efficacy of RUX across affected organs [15, 18, 20], some other data bring the opposite results. None of 4 patients with SR-aGVHD and active gut involvement responded to therapy with RUX in a small study published by Neumann et al. . Another report suggests that hepatic aGVHD responds worse than skin and intestines: 30% vs 79% and 71%, respectively . No correlations between the type of involved organ nor the number of affected organs and RUX efficiency were demonstrated in our study.
RUX therapy is known to be associated with some side effects. Hematologic toxicity of RUX results from the blockade of JAK2 signalling processes involving thrombo- and erythropoiesis . Real-life data agreeably showed high incidence of G3-4 cytopenia in 30%–60% of patients during RUX treatment [16, 20, 23]. Cytopenias were the most common adverse events also in our study. G3-4 thrombocytopenia and neutropenia were observed in 61% and 22%, respectively. Hematologic toxicity often leads to dose reductions and occasionally discontinuation of therapy, limiting the efficiency of RUX. Itacitinib- a selective JAK1 inhibitor is currently in a phase of experimental studies but some early data show that G3 cytopenia could be reduced to less than 30% [24, 25].
Among infectious complications CMV and Polyoma BKV reactivations were common: 50% and 33%, respectively. The incidence of CMV reactivation seems to be comparable with other studies. [20, 23, 26]. Till today, no data on the incidence of Polyoma BKV reactivation while on RUX were provided. Nevertheless, all these viral reactivations were manageable and did not result in patient’s death. The incidence of life-threatening bacterial infections was rare. Serious bacterial infections were demonstrated in only 2 patients with 1 death due to septic shock. In contrast, 52% of patients treated with RUX presented bacterial infection in Abedin study .
In conclusion, our study seems to prove that RUX could be a promising therapeutic option for SR-aGVHD, however, more data are warranted.