Bortezomib and/or Daratumumab for Treatment of Refractory Autoimmune Hemolytic Anemia

BACKGROUND Autoimmune hemolytic anemias (AIHA) refractory to standard immunosuppressive or B-cell directed agents (steroids and rituximab), splenectomy, or chemo-immunotherapy are very challenging to treat. It is possible that plasma cells may be the source of the antibodies. We report our retrospective institutional experience in the use of plasma cell-directed therapies, bortezomib and daratumumab, in the treatment of refractory warm AIHA (WAIHA) and cold agglutinin disease (CAD).

METHODS We included a single institution, retrospective review of adult patients with AIHA who were treated with either bortezomib or daratumumab or both. Inclusion criteria included 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 partial response). 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.

RESULTS Eight patients were included in the study. The clinical features, treatment schedule, and treatment outcomes are summarized in the Table. Five patients (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. Three patients received bortezomib alone, 1 daratumumab alone, 1 patient initially bortezomib followed by daratumumab later, and 3 bortezomib + daratumumab simultaneously (1 patient received both concurrently and then was continued on daratumumab alone). Overall response rate was 88% (7/8), with 63% (5/8) and 25% (2/8) achieving CR and PR, respectively. The median time to response was 2.92 months. The median duration of response was 24.0 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. He 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. Five 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 3 atrial fibrillation the day after receiving bortezomib.

CONCLUSION We demonstrate the potential efficacy of plasma cell directed therapies, bortezomib and daratumumab in the treatment of refractory AIHA patients. Our results suggest that this treatment approach is well tolerated and can provide long-lasting remissions. A prospective study with more robust patient numbers is warranted to validate our findings.

Pruthi: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. Sridharan:Alexion Pharmaceuticals: Consultancy.

Bortezomib intended use for multiple myeloma and mantle cell lymphoma and Daratumumab for multiple myeloma and light chain amyloidosis