Bortezomib and daratumumab in refractory autoimmune hemolytic anemia

Autoimmune hemolytic anemia (AIHA) mostly includes cold agglutin disease (CAD), warm AIHA (wAIHA), and mixed AIHA. It arises from autoantibody destruction of erythrocytes (RBCs) with or without complement fixation but emerging evidence has demonstrated more diverse pathophysiology involving imbalance of T-helper 1/2 cytokines, increased activity of cytotoxic CD8+ T lymphocytes, and bone marrow compensation.1 This newer understanding has helped explain the intractable nature of AIHA refractory to standard immunosuppressive or B-cell-directed agents.2 One mechanism for treatment failure of AIHA involves an inability to deplete long-lived bone marrow and splenic plasma cells responsible for chronic autoantibody production in classic immunosuppressant and CD20 therapy. As a result, therapy targeting short- and long-lived plasma cells has been proposed as a method to treat the origin of these antibodies. There is currently a growing body of evidence of the efficacy of plasma cell-directed therapies in refractory AIHA. Two agents that have notably demonstrated clinical efficacy for refractory AIHA are bortezomib and daratumumab. Daratumumab—a CD38 monoclonal antibody—has shown potential in refractory AIHA through its mechanism of targeting long-lived plasma cells responsible for autoantibody production involved in AIHA. Daratumumab currently has documented potential benefit in as many as 12 select case reports for refractory AIHA but the majority of these studies are limited to pediatric patients or hematopoietic stem cell transplant recipients.3 A second treatment under investigation for refractory AIHA is the proteasome inhibitor bortezomib which induces apoptosis in both clonal and reactive antibody-producing cells. Bortezomib has demonstrated efficacy in one prospective, open-label study for CAD in addition to multiple case reports.4 We aim to demonstrate clinical safety and efficacy of plasma cell-directed therapies daratumumab and bortezomib for refractory AIHA through a single-institution retrospective review. After obtaining IRB approval, we retrospectively reviewed the medical records of patients with AIHA seen at our institution between 2012 and 2022. Eligible patients included adults with AIHA who were treated with either bortezomib or daratumumab or both. Additional inclusion criteria were all of the following: (A) age ≥ 18 years; (B) diagnosis of WAIHA (direct antiglobulin test [DAT] IgG+ ± C3+), CAD (DAT IgG-/C3+ with cold agglutinin titer >1:64), or mixed disease; (C) active disease (hemoglobin [Hb] <10 g/dL plus biochemical evidence of hemolysis); and (D) relapsed from or refractory to other treatments. Responses were based on the international consensus criteria and classified as complete (CR; normal Hb or Hb ≥12 g/dL, with normalized laboratory markers of hemolysis), partial response (PR; Hb >10 but <12 g/dL or at least an increase by >2 g/dL, with or without biochemical resolution of hemolysis) or no response (neither complete nor PR). Adverse events were measured using Common Terminology Criteria for Adverse Events v5.0. The primary objective of the study was to describe the efficacy and duration of responses. Eight patients met our study criteria. The clinical features and treatment outcomes are summarized in Table 1. Over half of the patients (5/8; 63%) were males. The median age at the time of treatment was 61 years (range, 34–78) and the median duration of follow-up was 10.4 months (range, 4–42 months). Six patients had WAIHA and 2 had CAD (2). Three patients received bortezomib alone, 2 daratumumab alone, and 3 bortezomib + daratumumab. Seven of the eight patients had secondary hematologic diseases including low-grade B cell lymphoma, monoclonal gammopathy of undetermined significance (MGUS), chronic myelomonocytic leukemia (CMML), idiopathic thrombocytopenic purpura (ITP) and therapy-related acute myeloid leukemia (AML). A majority of patients (6/8; 67%) had received at least three lines of treatment prior to initiating either daratumumab or bortezomib. Overall response rate was 88% (7/8), with 63% (5/8) and 25% (2/8) achieving complete response (CR) and PR, respectively. The median length of treatment for patients who demonstrated CR was 2 months. Five (62%) patients were transfusion dependent. Median time to treatment was 2.1 months (range, 1–5 months). Additionally, the mediation duration of response was 24.5 months (range, 15–42 months). The only patient who did not respond to treatment (patient 5) had WAIHA and Waldenström macroglobulinemia and received the combination of bortezomib and daratumumab. This patient subsequently died from sepsis and pulmonary embolism unrelated to treatment. Of the remaining 7 patients who responded to treatment, all are alive at the time of this report. Four of the 8 patients tolerated their treatments with no adverse events. One patient developed grade 1 injection site reaction and one patient developed grade 1 dizziness. One patient developed grade 2 nausea and vomiting and another developed grade 3 atrial fibrillation. While refractory AIHA remains an intractable condition with low response rates to first- and second-line therapies, newer pharmacologic interventions targeting alternative pathways such as complement inhibition, B-cell therapy, and autoantibody production have shown early clinical promise. Specifically, plasma cell-directed therapies have generated recent interest for refractory AIHA with emerging evidence suggesting promising safety and efficacy profiles in this setting. We demonstrate the safety and efficacy of plasma-cell-directed therapies daratumumab and bortezomib for refractory AIHA. Our study shows a high rate of clinical response with over 50% of patients achieving a CR. Additionally, the median length of treatment to response was relatively short at <2 months. The duration of response was also long lasting with an average of >2 years and the longest duration was >3 years. The relative safety of these therapies is also demonstrated by the lack of side effects in half of the patients with only one patient having a grade 3 adverse event. Despite a growing body of evidence for bortezomib and daratumumab in refractory AIHA, the overall duration of response in these studies has been small and is demonstrated predominately in patients who are status-post HSCT.5 Here we demonstrate the use of these therapies in patients who have not had HSCT. The combination of clinical response with long-lasting duration and a strong safety profile supports the promising nature of bortezomib and daratumumab in refractory AIHA. With emerging evidence that CD20-negative plasma cells might propagate the immune response responsible for intractable AIHA, these findings could help guide clinical management for refractory AIHA moving forward. One limitation of the study is its retrospective nature. While there is one prospective study assessing the safety and efficacy for bortezomib in the setting of CAD, prospective studies will be helpful in validating plasma-cell therapies for future clinical use.4 Although this study has a relatively small dataset that limits its generalizability, it is also one of the few case series that adds to the growing body of evidence for both daratumumab and bortezomib safety and efficacy in refractory AIHA. This study demonstrates the efficacy of plasma cell-directed therapies, bortezomib, and daratumumab, in the treatment of refractory AIHA patients. Additionally, our results highlight that these agents are generally well tolerated and can provide long-lasting remissions. Future prospective studies will hopefully continue to corroborate these findings and allow for more widespread use of impactful therapy in refractory AIHA. This project has no funding source and has no disclosure. Rajiv K. Pruthi MD: Bayer Healthcare AG: Honoraria, Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Instrumentation Laboratory: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Genentech Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees. Meera Sridharan MD: Alexion Pharmaceuticals: Consultancy. The remaining do not have any financial conflict of interest to disclose regarding this work. This study was approved by the Mayo Clinic Institutional Review Board which was deemed to be no more than minimal risk and informed consent for patients was waived. Permission was granted to reproduce material from other sources. This study does not qualify as a clinical trial. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.