Bortezomib Is a Successful Therapeutic Agent for Refractory Autoimmune Cytopenias in Children: A Single Center Experience

Refractory autoimmune cytopenias are a significant complication of allogeneic stem cell transplantation. Autoreactive plasma cells are hypothesized to be responsible for persistent cytopenias.  Bortezomib, a proteasome inhibitor, has been used successfully to treat antibody mediated rejection of renal allografts in adults. Seven patients, median age 9 years (range 1.25- 25 years) received bortezomib at a median of 85 days (range 14-178 days) from laboratory confirmation of autoimmune cytopenia(s) (Table 1). All patients failed at least 2 standard treatments, including rituximab (n=4), IVIG (n=7), corticosteroids (n=7) and plasmapheresis (n=5) .Six patients received a single dose of rituximab at 375 mg/m2 on the first day of therapy due to presence of B cells. Four doses of bortezomib were administered (1.3 mg/m2) 72 hours apart, either subcutaneously (n=1) or intravenously (n=6), and plasmapheresis was performed in all patients 2 hours prior to drug administration .Six patients (85%) responded with normalization of cytopenia(s), at a median time of 11.5 days (range 3-20 days) for autoimmune neutropenia, and 27 days (range 13-133 days) for autoimmune thrombocytopenia. Two patients with autoimmune hemolytic anemia had a normal reticulocyte count by 13 days and normal haptoglobin by an average of 25 days from first dose of bortezomib.  While the DAT continued to be positive, they remained transfusion independent.  Reoccurrence of cytopenia(s) occurred in 2 patients at an average of 53.5 days after achieving resolution. Adverse effects of bortezomib include cellulitis at the subcutaneous injection site (n=1), febrile neutropenia (n=1), Clostridium difficle colitis (n=1), transient thrombocytopenia (n=2) and pneumatosis intestinalis (n=2). One patient had asymptomatic BK viremia and 1 had a Klebsiella bacteremia, both successfully treated. Two patients died at 173 and 347 days from first dose of bortezomib, due to encephalopathy leading to cardiorespiratory failure and idiopathic pulmonary syndrome leading to respiratory failure respectively. Bortezomib is an effective therapeutic agent for refractory autoimmune cytopenias. Further trials are needed to evaluate efficacy.

Age ( years)	Pre/Post transplant                ( Day of onset after BMT)	Underlying Diagnosis	Type of  autoimmune cytopenia
9	Post ( 143 days)	Combined Immune Deficiency ( CID)	Neutropenia
1.25	Post( 233 days)	SCID	Hemolytic anemia
17.6	Post (140 days)	Relapsed AML	Thrombocytopenia Neutropenia
10	Post (156 days)	SCID	Thrombocytopenia Neutropenia
1.25	Pre	Evan's syndrome	Hemolytic anemia Thrombocytopenia
25	Pre	CID	Thrombocytopenia
2.25	Pre	Unspecified Immune deficiency	Thrombocytopenia

Table 1. Patient characteristics and type of autoimmune cytopenia.