Ruxolitinib As Pretreatment Before Allogeneic Stem Cell Transplantation For Myelofibrosis

We investigate early outcome after allogeneic SCT in 22 patients – male (n = 13) and female (n = 9) – with myelofibrosis who received ruxolitinib prior to transplantation in order to reduce spleen size and constitutional symptoms.

The median age of the patients was 59 years (r: 42 – 74 y) and ruxolitinib was given at doses between 2 x 5 mg (n = 5), 2 x 15 mg (n = 5), and 2 x 20 mg (n = 12) before first (n = 19) or second (n = 3) fludarabine-based reduced intensity conditioning from related (n = 2), and matched (n = 14), or mismatched (n = 6) unrelated donor. Thirteen patients had primary myelofibrosis and 9 post ET/PV myelofibrosis. Before ruxolitinib the patients were classified according to DIPSS as intermediate-1 (n = 3), intermediate-2 (n = 14), or high risk (n = 5). Stem cell source was PBSC (n = 21) or bone marrow (n = 1) with a median CD34+ cell count of 7.1 x 10⁶/kg. Before ruxolitinib 21 patients (96%) had constitutional symptoms and all patients had splenomegaly. The median time from start of ruxolitinib to allogeneic SCT was 133 days (r: 27 – 324) and the median treatment duration was 97 days (r: 20 – 316). Most patients (n = 82%) received ruxolitinib until start of conditioning therapy. Four patients (18%) discontinued ruxolitinib between 28 and 167 days before transplantation due to progressive disease or no response (n = 3) or cytopenia (n = 1).

At time of transplantation 86% had improvement of constitutional symptoms and 45% had major response (>50% palpable) of spleen size, 28% had response of spleen size which was less than 50%, and 27% had no response or progressive spleen size after ruxolitinib treatment. After discontinuation of ruxolitinib at first day of conditioning regimen no “rebound” phenomenon was seen. One patient transformed to sAML before transplantation despite response of spleen size and constitutional symptoms.

After busulfan (n = 16), treosulfan (n = 3), or melphalan (n = 3) dose reduced conditioning no graft failure was observed and the median time for leukocyte and platelet engraftment was 15 days (r: 10 – 66) and 17 days (r: 8 – 122) respectively. Acute GvHD I-IV was seen in 50% of the patients which was severe (III/IV) in 18%.

During follow-up 4 patients died, 1 patient with sAML at time of transplant due to relapse on day 102 and 3 patients due to therapy-related mortality. One female patient who received a second unrelated HLA-matched transplantation after treosulfan-based regimen died of CMV pneumonitis on day 75. She did not response to ruxolitinib regarding spleen size and constitutional symptoms. A second patient with iron overload and liver fibrosis died of liver toxicity on day 47. This patient initially responded to ruxolitinib but progressed regarding spleen size prior to transplantation. One patient who responded to ruxolitinib regarding constitutional symptoms and spleen size (< 50%) died of GvHD on day 77. The estimated 1-year OS and PFS was 76% (95% CI: 54 – 98%).

Ruxolitinib reduces spleen size and constitutional symptoms in the majority of patients before allogeneic stem cell transplantation. Discontinuation of ruxolitinib at start of conditioning did not induce rebound phenomenon and did not negatively impact engraftment after transplantation. Longer follow-up is needed to determine late outcome.

Wolf:Novartis: Research Funding.