Weekly bortezomib-dexamethasone as a third-line therapy for patients with warm autoimmune hemolytic anemia

Introduction

Warm autoimmune hemolytic anaemia (wAIHA) is a rare disease with an estimated annual incidence of  5-10 per 100,000 population. It is characterized by hemolysis with a strongly positive direct agglutination test for IgG + C3d. It is a chronic condition with frequent relapses and a need for multiple treatment lines to sustain transfusion independence. Despite high initial responses with the first 2 treatment lines (corticosteroids and rituximab), relapses are frequent. For third-line and later, immunosuppressive (IS) drugs (azathioprine, mycophenolate mofetil, cyclosporine) and splenectomy are the available options, albeit with an increased risk of life-threatening infections. Anti-plasma cell therapies (bortezomib, daratumumab) in combination with dexamethasone target long-term memory B-cells and plasma cells resulting in a reduction of the autoantibody production. Bortezomib has shown promising preclinical activity in autoimmune disorders like systemic lupus erythematosus (SLE) and immune thrombocytopenia. Anecdotal case reports and retrospective case series indicate the efficacy of bortezomib in both warm and cold AIHA. In the present study, we prospectively evaluated the efficacy, safety, and feasibility of achieving treatment-free remission (TFR) with weekly bortezomib- dexamethasone in patients with wAIHA in the third-line setting as an alternative to IS drugs and splenectomy.

Study Objectives:1.   To evaluate the efficacy and safety of bortezomib-dexamethasone as a third-line therapy in patients with warm autoimmune hemolytic anaemia 2. To assess the feasibility of achieving a treatment-free remission (TFR) after bortezomib  discontinuation

Methods

This prospective pilot study will be conducted in the department of haematology of the Safdarjung hospital, New Delhi. Five adult patients 18-60 years of age 18 and of either sex diagnosed with wAIHA (idiopathic, or secondary to an autoimmune disorder) who were relapsed, or refractory (RR) to prednisolone and single agent rituximab as first and second-line therapies, respectively and require initiation of third-line treatment will be included. Patients with wAIHA less than 18 years of age, wAIHA secondary to a lymphoproliferative disorder (LPD) and those unwilling to participate in the study will be excluded. Per protocol, patients will be treated with bortezomib- 1.3 mg/m2 subcutaneously/week and dexamethasone- 40 mg per oral/week (Vd, 4 weeks=1 cycle). Acyclovir (400 mg twice a day) will be used as prophylaxis for herpes zoster reactivation during treatment and until 3 months following bortezomib discontinuation. Initially, weekly assessments will be done with complete blood count, corrected reticulocyte count, serum lactate dehydrogenase (LDH), and liver function tests till partial response (PR), after which, the frequency of testing will be reduced to monthly intervals, or earlier, in case of clinical suspicion of relapse (worsening dyspnea, fatigue). Once sustained complete response (CR) was achieved with weekly Vd, treatment will be gradually tapered in an attempt to achieve TFR. During tapering, Vd will be administered once every 2-weeks (2-weekly Vd). For patients relapsing on 2-weekly Vd, treatment will be changed to Vd-lite (bortezomib-1.3 mg/m2 subcutaneous/week and dexamethasone-20 mg/week, 4- weeks=1 cycle). Treatment will be discontinued once sustained CR is achieved with either 2-weekly Vd, or Vd-lite. Patients will be followed up for a minimum of 1 year. Responses will be recorded as PR, CR, sustained CR, and no response (NR) and duration of response (DOR), and bortezomib exposure (BE) will be calculated. At each visit, patients will be assessed clinically for the side effects of bortezomib (peripheral neuropathy, myelosuppression, gastrointestinal disturbance) and dexamethasone (cushingoid features, weight gain, pedal edema, cataracts, glaucoma, sleep, and behaviour changes). Treatment interruptions for side effects will be allowed at the physician’s discretion. Results will be reported using descriptive analysis and compared with the available literature.