Abstract

INTRODUCTION: Allogeneic stem cell transplant (ASCT) is currently the only curative therapy for myelofibrosis (MF). Ruxolitinib, an inhibitor of the JAK-STAT pathway, has been FDA-approved since November 2011 for the treatment of intermediate and high-risk myelofibrosis. Off-label, the medication has been administered prior to ASCT in an effort to reduce spleen size before conditioning and improve subsequent engraftment. In the published literature, there are mixed results for this strategy. Notably, French researchers announced preliminary results of a prospective study of 23 patients in December 2013. They reported several severe adverse events (SAE) following Ruxolitinib discontinuation, including two fatalities. These events included three cases of cardiogenic shock and three cases of tumor lysis syndrome (TLS). Since 2012, all patients with MF receiving ASCT at our institution have been pre-treated with Ruxolitinib until 48 hours prior to the start of conditioning. Herein, we report on outcomes of these patients.

METHODS: After receiving approval by the Medical College of Wisconsin Institutional Review Board, we collected data on all patients who received Ruxolitinib prior to an ASCT. Our eligibility criteria included receipt of an HLA-matched sibling or unrelated ASCT for myelofibrosis at the Medical College of Wisconsin between Jan 2012 and March 2014 and treatment prior to transplantation with Ruxolitinib. Patient characteristics, drug-related adverse events including cardiac toxicity, and outcomes including response, relapse, graft-versus-host disease (GvHD), and overall survival were analyzed.

RESULTS: Our cohort included ten patients with a median age of 56 years (range: 47-60 years) at the time of transplant. Four patients had de-novo disease and the remaining had myelofibrosis which had evolved from another myeloproliferative neoplasm. Four patients received one or more therapies for myelofibrosis prior to starting Ruxolitinib. One of the ten patients had undergone a splenectomy as part of prior treatment. The majority (6/10) had intermediate II-risk disease by the Dynamic International Prognostic Scoring System (DIPSS). Six of the ten patients received myeloablative conditioning.

All ten patients received Ruxolitinib as pre-treatment prior to transplant and a standard taper schedule was employed starting six days prior to conditioning. Patients were slowly transitioned off the medication from a steady-state dose (maximum of 25 mg BID) to 5 mg once a day with the last dose taken 48 hours prior to conditioning. Two patients stopped taking their Ruxolitinib prior to the tapering protocol – one with progressive disease and one due to severe headache.

Of the nine patients with splenomegaly, five had reduction of spleen size attributed to the medication. One of nine patients experienced rebound splenomegaly after discontinuation of Ruxolitinib. No patient experienced clinical symptoms of TLS. No patient experienced cardiac toxicity. After ASCT, acute GvHD occurred in two patients but was ≤ grade II in both. Chronic GvHD occurred in four patients, two were graded as mild and two were graded as moderate.

After a median follow-up of 14.5 months (range: 5 – 23 months), all ten patients are alive. No patients require transfusions, one patient remains on intermittent granulocyte-colony stimulating factor. By International Working Group for Myelofibrosis Research and Treatment Criteria (IWG-MRT), four patients achieved complete remission, two achieved partial remission, one had clinical improvement and three had stable disease. No patient has experienced treatment-related mortality or graft failure.

CONCLUSION: Administration of Ruxolitinib before ASCT has beneficial effects on spleen size and engraftment. We did not observe any serious adverse events with Ruxolitinib pre-treatment and no special safety concerns related to transplant.

Table.
Variable
 
N=10
 
%
 
Toxicities to Ruxolitinib   
Thrombocytopenia 30 
Anemia 30 
Headache 20 
Arthralgia 10 
Dizziness 10 
Rebound Splenomegaly following discontinuation 10 
Toxicities after ASCT   
Mucositis 20 
Sinusitis with RSV 10 
CMV Reactivation 10 
Acute GvHD 20 
Grade III/IV  
Chronic GvHD 40 
Mild 20 
Moderate 20 
Severe  
Median time to Engraftment in days (range)  17 (13 – 22) 
Graft Failure 
Variable
 
N=10
 
%
 
Toxicities to Ruxolitinib   
Thrombocytopenia 30 
Anemia 30 
Headache 20 
Arthralgia 10 
Dizziness 10 
Rebound Splenomegaly following discontinuation 10 
Toxicities after ASCT   
Mucositis 20 
Sinusitis with RSV 10 
CMV Reactivation 10 
Acute GvHD 20 
Grade III/IV  
Chronic GvHD 40 
Mild 20 
Moderate 20 
Severe  
Median time to Engraftment in days (range)  17 (13 – 22) 
Graft Failure 

Disclosures

Off Label Use: Ruxolitinib and myelofibrosis prior to transplant.

Author notes

*

Asterisk with author names denotes non-ASH members.