Ruxolitinib for Myelofibrosis Patients Relapsing after Allogeneic Hematopoietic Transplantation
Authors: Janson Dietlinde , Ayuk Francis A , Wolschke Christine , Christopeit Maximilian , Badbaran Anita , von Pein Ute-Marie , van Randenborgh Andre , Kroeger Nicolaus 
Published: October 2019

Abstract
Introduction
The Janus-Activated Kinase (JAK) 1/2 -inhibitor ruxolitinib is approved for the treatment of symptomatic myelofibrosis (MF) regardless of the JAK2 mutational status. Ruxolitinib can reduce constitutional symptoms and spleen size resulting in an improvement of the performance status and also in a potential prolonged survival. Here we investigated the efficacy and toxicity of ruxolitinib in MF patients who relapsed after allogeneic stem cell transplantation.
Patients and methods
Between the years 2012 and 2016, 10 myelofibrosis patients of our department who relapsed after allogeneic stem cell transplantation received ruxolitinib. Stem cell donor was matched related (MRD) in two patients, matched unrelated (MUD) in six and mismatch unrelated MMUD in two patients. The median age of the patients was 61 years (r: 41-72). The median time from allogeneic transplantation until the start of ruxolitinib treatment was 23.8 months (r: 2.7-85.7). The median treatment duration was 143.5 days (r: 12-369). The median dose of ruxolitinib was 10 mg bid (r: 5-20mg) according to toxicity. Two patients had already received ruxolitinib prior to allogeneic transplantation. All patients had mixed chimerism at start of ruxolitinib. Two patients had already received donor lymphocyte infusions (DLI) prior to ruxolitinib. Two patients started with DLI beginning at day +30 and at day +147 within ruxolitinib treatment. Seven patients were positive for the JAK2V617 mutation and one patient for CALR mutation. Constitutional symptoms were observed in seven patients and splenomegaly in six patients before treatment start. One patient had aGvHD (skin) and three had cGvHD (oral mucosa, skin, liver) at the time of treatment start. In seven patients bone marrow histology was available before and during ruxolitinib treatment.
Results
We observed an improvement of constitutional symptoms in six patients (86%). The palpable spleen size was reduced in five patients (83%) with splenomegaly (≥50% n=4, <50% n=1). In five of six patients who were dependent on blood and/or thrombocyte transfusions a reduction of the transfusion frequency was seen. Due to thrombocytopenia (CTC grade 3 and 4) dose reduction was necessary in two patients. One patient newly developed leukocytopenia within ruxolitinib treatment (CTC grade 3); before ruxolitinib one patient had grade 1 leukocytopenia and worsened to grade 3. Prior to ruxolitinib the median chimerism was 57% (r: 0-99.7) whereas during ruxolitinib treatment the median chimerism dropped to a median of 0% (r: 0-93.8). The median JAK2-alllele-level before ruxolitinib was 0.87 (r: 0.03-91.3) versus 8.35 (r: 1.83-29.9) during ruxolitinib treatment. The one patient harboring the CALR mutation had an increase of the allelic burden from 0.56 to 1.68. In five of the patients with an available bone marrow biopsy an aggravation of bone marrow fibrosis could be seen whereas no progression could be seen in two patients. The peripheral blast count increased in three patients, in one patient peripheral blasts newly developed. Progressive disease could be seen in all patients (100%) despite of reduction of spleen size, improvement of constitutional symptoms or a prolonged transfusion interval. Three patients transformed to AML. All patients with GvHD had an improvement and or even complete resolution of their GvHD. One patient developed aGvHD of the skin during ruxolitinib treatment but in this patient immunosuppressive therapy had already been stopped at day +30 due to mixed chimerism. No severe infectious complications were seen. None of the patients had to stop ruxolitinib due to side effects.
Conclusion
The Janus-Activated Kinase (JAK) 1/2 -inhibitor ruxolitinib can lead to a reduction of spleen size, an improvement of MF-associated constitutional symptoms and a reduction of the blood transfusion-interval in patients with relapse after allogeneic transplantation. However, ruxolitinib does not lead to an increase of donor chimerism. It seems to have little impact on the JAK2V617F-allele level. A further aggravation of bone marrow fibrosis was seen in most of the patients. Despite of clinical improvement all patients experienced further progression of myelofibrosis and three patients even transformed to AML. Furthermore in those patients with GvHD an improvement or even complete resolution of the GvHD was seen.

Disclosures
Kroeger: Novartis: Honoraria, Research Funding.