A Single Institution Experience of Bortezomib for Gvhd in a Pediatric HSCT Population
Authors: Shah Devangi , Reichbach Douglas Jennifer , Ashy Jumana , Suhrheinrich Gregory , Ziga Edward Dela , Pillai Asha B. , Barredo Julio C , Alperstein Warren 
Published: November 2019

Background
Graft vs Host Disease (GVHD) is a common but revered complication after allogenic hematopoietic stem cell transplants (HSCT). Corticosteroids are the first-line therapy for GVHD, yet a consensus is lacking for second-line therapy in patients who experience worsening of symptoms when doses are reduced after initial response (steroid dependent), or who progress despite optimum steroid therapy (steroid refractory) GVHD.
Bortezomib is a first-generation reversible proteasome inhibitor that inhibits T cells and prevents activation of dendritic cells that mediate antigen presentation and cytokine transcription. Though promising in adult clinical trials, there is a paucity of data on children less than 18 years for the prevention and treatment of GVHD. We hereby report on a single institutional case-series of bortezomib in pediatric HSCT treatment of GVHD.
Results
Our first case, a 7 year old male with history of acute myeloid leukemia, developed stage 1 acute gastrointestinal GVHD 23 days post-HSCT, and stage 4 skin GVHD beginning 39 days post-HSCT. His skin GVHD failed multiple attempts to wean off steroids, hence the addition of bortezomib at 364 days post-HSCT, receiving weekly doses for 30 weeks ranging from 0.5 mg/m2 to 1.0 mg/m2. This allowed us to wean him off prednisone and discontinue all immune suppression without additional flares.
Our second case, a 4 year old male, presented with acute stage 4 skin and stage 2 liver GVHD 108 days and 341 post-HSCT, respectively. Bortezomib was started for the skin GVHD after unable to wean him off steroids. He received a total of 15 doses administered weekly and ranging from 0.4 to 0.87 mg/m2. While on bortezomib his skin GVHD resolved allowing discontinuation of steroids and other immune-suppressive agents. He later developed liver GVHD, which was not responsive to bortezomib.
Our third case, a 1 year old female, presented with steroid-dependent acute skin GVHD 177 days post-HSCT. She responded remarkably to steroids but experienced multiple flares of skin GVHD any time the steroid dose was reduced below 1 mg/kg/day. After multiple attempts employing different combinations of immunosuppressive regimens, bortezomib was started. She showed initial response to bortezomib at doses ranging from 0.1 mg to 1.3/m2 mg but was unable to be completely weaned off steroids.
Our fourth case, a 19 year old male with lung GVHD who was on long-term steroids, received bortezomib after failing steroid dose reduction when combined with sirolimus and extra-corporeal photopheresis. He received weekly doses of bortezomib for 12 weeks, ranging from 0.2 mg to 1.3/m2 mg, that permitted a successful wean off steroids. However, he later died from pulmonary GVHD.
Conclusion
We hereby report, based on these cases that bortezomib is a safe option for adjuvant GVHD therapy in children after HSCT. It resulted in successful discontinuation of steroids in two of the three patients with skin GVHD. Well-designed studies of GVHD management with bortezomib in pediatrics are necessary to elucidate this initial finding. We plan to explore this further in a multi-center trial.

OffLabel Disclosure:
Bortezomib is off label - FDA indications are for treatment of multiple melanoma and second line mantel cell lymphoma