Impact of Pre-Transplant Ruxolitinib in Myelofibrosis Patients on Outcome after Allogeneic Stem Cell Transplantation

Introduction

Ruxolitinib is the first approved drug for treatment of myelofibrosis. Major effects are reduction in spleen size and improvement of constitutional symptoms. Because spleen size and constitutional symptoms may influence outcome after allogeneic stem cell transplantation (ASCT), ruxolitinib is recommended before stem cell transplantation in order to reduce therapy-related morbidity and mortality and improve outcome (EBMT/ELN recommendation, Leukemia 2015) The aim of this retrospective study was to evaluate the impact of pretreatment with ruxolitinib in comparison to transplantation of ruxolitinib-naïve MF patients with regard to outcome after ASCT.

Patients and methods

We included 171 myelofibrosis patients (pts) with a median age of 59 years (r: 28 - 74) who received ASCT between 2000 and 2015 from related (n = 25), matched (n=94) or mismatched (n=52) unrelated donor. Stem cell source were more peripheral blood stem cells (n = 167) than bone marrow (n = 4). All patients received busulfan-based reduced intensity conditioning. While 113 pts (66%) did not receive ruxolitinib, 58 pts (34%) received ruxolitinib at any time point prior to ASCT. The median daily dose of ruxolitinib was 30mg (range 10-40mg) and the median duration of treatment was 28 days (range 12-159 days). In 11 pts ruxolitinib was stopped before stem cell transplantation because of no response or loss of response, while in 35 pts ruxolitinib was given until start of conditioning and in 12 pts ruxolitinib was given until stable engraftment. GvHD prophylaxis consisted of CNI plus short course MTX or MMF and anti-lymphocyte globulin. According to dynamic IPSS (DIPSS) (n = 170) the patients were either low (n = 2), intermediate-1 (n = 37), intermediat-2 (n = 81), or high risk (n = 38). 74 patients (43%) were transfusion dependent.

Results

As the median follow up was shorter for patients treated with ruxolitinib (15 vs 73 months, p<0.001), we analyzed only 2 years RFS, OS, NRM and relapse incidence. Primary graft failure was seen in 2 pts in the ruxolitinib and 3 in the non-ruxolitinib group. The median leukocyte engraftment was 13 days (r., 9-32) in the ruxolitinib and 14 days (r., 7-34) in the non ruxolitinib group (p=0.7). The median age in the ruxolitinib group was slightly older ( 62 vs 58 years , p= 0.09). The incidence of acute GvHD grade I to IV was significantly lower in the ruxolitinib group (49% vs 64%, p=0.05), while aGvHD grade II-IV (33% vs 44%, p=0.14) and grade III/IV (23% vs 25%, p=0.48), did not differ significantly. The CI of NRM at 1 year was 18% (95% CI: 6-30%) for the ruxolitinib group and 22% (95% CI: 14-30%) for the non-ruxolitinib group (p=0.58), and the CI of relapse at 2 years was 8% (95% CI: 0-16%) vs 20% (95%CI: 12-28%, p=0.25). The 2 years RFS and OS was 66% (95%CI: 50-82%) and 69% (95%CI: 51-87) for the ruxolitinib group and 59% (95% CI: 49-69%) and 70% (95% CI:62-78%) for the non-ruxolitinib group (p=0.29 and p=0.45, respectively). Within the ruxolitinib group (n=53), 24 pts responded to ruxolitinib (more than 25% spleen size reduction), while 29 pts did not respond or lost response prior to stem cell transplantation. Here, no significant difference could be seen between the responding and non-responding group for NRM (19% vs 17%, p=0.69), Relapse (4% vs 13%, p=0.62), RFS (61% vs 72%, p=0.81) and OS (63% vs 75%, p=0.89). In a multivariate analysis including ruxolitinib treatment as variable there was a non-significant trend in favor for ruxolitinib pretreatment regarding NRM (HR 0.79; 95%CI: 0.38-1.66, p=0.54), relapse (HR 0.48; 95%CI: 0.18-1.31, p=0.15), RFS (HR 0.55; 95%CI: 0.29-1.03, p=0.06) and OS (HR 0.83; 95%CI: 0.41-1.67, p=0.61).

Conclusions

These results suggest that ruxolitinib pretreatment in myelofibrosis patient does not negatively influence outcome after allogeneic stem cell transplantation. To confirm the observed favorable trend in outcome after ruxolitinib treatment more patients and a longer follow-up is needed.