Acute graft-versus-host disease (GVHD) is a multisystem disorder that is a common, life-threatening complication of allogeneic transplant, it is driven by alloreactive donor T cells, and it remains a major cause of morbidity and nonrelapse mortality in allo-HSCT recipients. JAK-STAT signaling pathways help regulate the development, proliferation, and activation of immune cell types important for GVHD.
We report in this case series the findings in three of our patients who underwent allogenic transplant for Myelofibrosis. All three patients received treatment with ruxolitinib for Myelofibrosis for at least 6 months before the transplant, however this treatment was stopped at least 2 weeks before the transplant. All three patients continued to have splenomegaly and pancytopenia after engraftment. Patient number 2 required frequent Platelets transfusion, while patient number 1, and 3 required frequent red cell transfusions. Despite having good donors, and GVHD prophylaxis, all three patients had severe grade IV steroid refractory acute GVHD, and required the addition of ruxolitinib to control their disease. The timing and the rapid progression of their Acute GVHD, which started during the taper of their immune suppression and about 109 -140 days from the last dose of ruxolitinib. Our treatment approach was to initiate ruxolitinib after they failed high dose steroids. In our group of patients, we noticed that the combination of stopping ruxolitinib before transplant, and the lack of the inhibition of JAK1/JAK2, after transplant might have contributed to the development and the severity of Acute GVHD.
All three patients noticed improvement in their symptoms after the treatment with ruxolitinib was started. The lack of JAK-STAT signaling inhibition could have contributed to the development, proliferation, and activation of immune cell types important for GVHD, also increased the production of proinflammatory cytokines, and the trafficking of T cells and innate immune cells to tissues. Furthermore, the loss of this inhibition after the transplant could have contributed to the higher grade of Acute GVHD and the severity of their symptoms. We noticed that starting ruxolitinib to treat GVHD after they failed the initial course with high dose steroids, helped in controlling their symptoms, and the stabilization of their disease.
Ruxolitinib is an oral selective inhibitor of JAK1/JAK2. It has been approved for the treatment of steroid refractory Acute GVHD. In our group of patients with Myelofibrosis the common denominator was the treatment of myelofibrosis with ruxolitinib for at least 6 months before the transplant, and stopping it at least 2 weeks before the transplant. It is worth noting that continuing to establish the inhibition of JAK1/JAK2 after the transplant might be needed to reduce the risk of this group of patients of developing Acute GVHD.
|patient||Age||Myelofibrosis/grade||Ruxolitinib stop date prior to SCT||Conditioning regimen||Donor||Onset of Acute GVHD||Ruxolitinib initiation day|