Bortezomib in autoimmune hemolytic anemia and beyond

Abstract

Bortezomib is a first-in-class, potent, selective and reversible proteasome inhibitor approved for the treatment of multiple myeloma (MM) and relapsed/refractory mantle cell lymphoma. In these diseases, bortezomib targets plasma cells and lymphocytes reducing tumor burden. Recently, preclinical evidence highlighted its efficacy in reducing long-lived plasma cells responsible of autoantibodies production in several models of autoimmune conditions. These findings paved the way to a number of experiences of bortezomib use in patients with various autoimmune conditions, including autoimmune hemolytic anemia (AIHA). The latter is a nice model of autoimmunity in hematology and is caused by the production of autoantibodies against erythrocytes resulting in various degrees of hemolytic anemia. AIHA is classified in warm and cold forms according to the thermal characteristics of the autoantibody, and first-line treatment mainly relies on steroids for warm cases and the anti-CD20 rituximab for cold ones. Relapsed/refractory cases are still an unmet need, and bortezomib has been proposed in this setting with intriguing efficacy. In this review, we collected available literature on bortezomib use in AIHA and in other immune-mediated hematologic and non-hematologic diseases. Overall, most experiences highlight bortezomib efficacy even in multi-relapsed/refractory patients and suggest to consider its use in AIHA after rituximab failure.

Enterovirus 71-Induced Autoimmune Hemolytic Anemia in a Boy

“…Currently, monoclonal antibodies targeting specific effector cells or molecules responsible for AIHA are being developed 32 and successful treatment with these monoclonal antibodies have been increasingly reported. 33 - 36 For example, complement can be responsible for opsonization of red blood cells leading to phagocytosis of these cells, complement inhibition with eculizumab was reported to be effective in treatment of PCH in one case report. 35 Although PCH was the most likely diagnosis in this patient and corticosteroid efficacy in PCH is uncertain, 37 this patient received prednisone upon AIHA diagnosis because the type of AIHA could not be determined initially and the patient had very low hemoglobin level and anemic symptom.…”

Refractory autoimmune hemolytic anemia in a systemic lupus erythematosus patient: A clinical case report

“…Recently, bortezomib (a 26S proteasome inhibitor) 15 has been used as a successful therapy for immune hemolytic anemia. Bortezomib functions to inhibit the ubiquitin‐proteasome pathway which then brings about apoptosis through an augmented unfolded protein response in antibody‐producing cells 16,17 . Additionally, it has widespread immune system effects by downregulating NF‐kB’s inflammatory signaling, impairing antigenic presentation, and depleting autoreactive T cells, B cells, and plasma cells—thereby reducing antibody and autoantibody responses.…”

“…Bortezomib functions to inhibit the ubiquitinproteasome pathway which then brings about apoptosis through an augmented unfolded protein response in antibody-producing cells. 16,17 Additionally, it has widespread immune system effects by downregulating NF-kB's inflammatory signaling, impairing antigenic presentation, and depleting autoreactive T cells, B cells, and plasma cells-thereby reducing antibody and autoantibody responses. Since AIHA is an immune autoantibody-mediated process, agents suppressing Bcell and plasma cell autoimmunity have been proven effective in its therapy.…”

Development of New Drugs for Autoimmune Hemolytic Anemia

“…Bortezomib has been reported to be effective in the setting of hematopoietic and solid organ transplant-associated AIHA in a number of case reports [ 162 , 163 , 164 , 165 , 166 , 167 ]. In retrospective case series and case reports on relapsed refractory wAIHA, bortezomib in combination with dexamethasone had an overall response rate of 85%, with five CR (35%) and seven PR (50.0%) [ 168 , 169 , 170 ] ( Table 2 ). In a GIMEMA study—a phase 2 prospective, open-label, multicenter, clinical trial which evaluated the efficacy of a single course of bortezomib (1.3 mg/m 2 on day 1, 4, 8, 11) in CAD—among the 19 heavily pretreated patients, the overall response rate was 31.6%, with 66.7% maintaining response after a median follow-up of 16 months, with low rates of toxicity [ 54 ] ( Table 2 ).…”