Combination Treatment of Rituximab, Cyclophosphamide, and Dexamethasone for Warm Autoimmune Hemolytic Anemia

Introduction

Warm autoimmune hemolytic anemia (WAIHA) is an uncommon blood disorder characterized by autoantibody destruction of red blood cells. Although the initial response rate to corticosteroid therapy is 70-85%, less than 20% of patients are cured by corticosteroid therapy alone (Murphy and LoBuglio, 1976). Treatment options for refractory disiease include splenectomy, rituximab, immunosuppression, and cytotoxic therapy. The combined regimen of rituximab, cyclophosphamide and dexamethasone (RCD) has been reported to have significant efficacy in the treatment of WAIHA in patients with chronic lymphocytic leukemia (Gupta et al 2002; Kaufman et al 2009). Due to our experience of a poor response to single agent rituxumab, we treated a cohort of patients with primary and secondary WAIHA with RCD. We now report the outcomes of 19 patients treated with this regimen.

Methods

Between January 1, 2009 to August 1, 2016, a cohort of patients with primary and secondary WAIHA was treated with RCD at LAC-USC Medical Center, USC Norris Cancer Center, and Keck Hospital of USC. RCD was administered as follows: rituximab 375 mg/m2 IV D1, cyclophosphamide 750 mg/m2 D1 or D2, and dexamethasone 12 mg PO/IV D1-7. Treatment cycles were repeated at 3-to-4-week intervals until the best achievable response.

Complete response (CR) was defined as hemoglobin (Hb) > 12 g/dL and normalization of hemolytic markers (reticulocyte count, LDH, and indirect bilirubin). If Hb was > 12 g/dL and there was mild elevation in the hemolytic markers attributable to comorbid conditions, this was also considered a CR. Partial response (PR) was defined as Hb ≥ 10 g/dL or > 2 g/dL increase in Hb.

Results

19 patients with WAIHA received RCD. The median number of cycles was 4 (range 2-7). Median age was 37 (range 21-77). 16 were female. 7 had secondary WAIHA (1 with Graves disease, 2 with systemic lupus erythematosus [SLE], 1 with rheumatoid arthritis [RA]-SLE overlap syndrome, 1 with RA-Sjogrens overlap syndrome, 1 with autoimmune hepatitis, and 1 with likely autoimmune lymphoproliferative syndrome (APLS). 12 had primary WAIHA. 2 patients had Evans syndrome. RCD was first line treatment in 6 patients. In pre-treated patients, the median number of prior treatments was 2 (range 1-7). All pre-treated patients had received steroids; 3 had received rituximab; 1 had splenectomy. Other prior treatments included mycophenolate, azathioprine, cyclosporine, intravenous immunoglobulin, alemtuzumab, and sirolimus.

Overall response rate was 97% (18/19) (8 with CR, 10 with PR). Among those with CR, 4 had primary WAIHA and 6 had received prior treatment. Among those with PR, 7 had primary WAIHA and 5 had received prior treatment. 11 patients were placed on maintenance immunosuppression after completing RCD. Of the 7 patients who did not receive maintenance immunosuppression, the median duration of response was 8 months at the time of abstract submission. The longest duration of response was 22 months at the time of abstract submission.

1 patient who had a CR, relapsed 2 years later and received additional RCD without response. 1 patient with Evans syndrome, hypogammaglobinemia, and possible ALPS had received 7 prior lines of treatment, including rituximab and splenectomy. This patient had a CR of WAIHA and ITP with RCD. During and after RCD, she was continued on sirolimus and mycophenolate.

Cyclophosphamide was held for ≥ 1 cycle in 4 patients (1 due to patient refusal due to alopecia, 1 due to mouth pain, 1 due to scheduling issues, 1 due to unclear reason). 1 patient had dose-reduction of cyclophosphamide due to young age. There was 1 missed dose of rituximab due to patient non-adherence. Treatment delays occurred in 1 patient due to patient non-adherence.

Toxicities included GI symptoms (2), headache (1), oral pain with dysphagia (1), flu-like symptoms (1) syncopal episode (1), hypersensitivity reaction to rituximab (2), aplastic anemia from viral infection (1), alopecia (1), hospitalization for cellulitis (1), and thrombocytopenia (2).

Conclusions

RCD has a high overall response rate in the upfront and refractory treatment of patients with primary and secondary WAIHA with an acceptable toxicity profile.