Successful treatment of IgG and complement‐mediated autoimmune hemolytic anemia with bortezomib and low‐dose cyclophosphamide

IgG-mediated autoimmune hemolytic anemia (AIHA) may be isolated (“primary”) but more commonly develops in the setting of autoimmune and lymphoproliferative disorders. AIHA is usually acute in onset and while often treatable, the clinical course may be life-threatening or fatal. First line treatment is glucocorticoids and second-line treatment for steroid-refractory patients is either splenectomy or Rituximab [1]. For patients who do not respond to Rituximab and for whom splenectomy is prohibitively risky, chemotherapy and/or immunosuppressive agents are used but response rates are usually low, unpredictable and may entail significant toxicity. Novel therapies are needed for patients with steroid-refractory AIHA. Bortezomib is an inhibitor of the 26S proteasome and approved for treatment of multiple myeloma. In a recent report, bortezomib successfully treated a patient with steroid/Rituximab-refractory IgM-mediated cold-agglutinin disease although the autoantibody was not completely eliminated [2]. In addition, high-dose cyclophosphamide has been used for the treatment of steroid-refractory AIHA but at the expense of severe myelosuppression [3]. Based on these observations, a combination of bortezomib and low-dose cyclophosphamide was used to a patient with transfusion-dependent and steroid/Rituximab-refractory AIHA. A 60 year-old woman with a history of systemic lupus presented with severe anemia (Hgb = 2.2 gm/dl) plus a markedly elevated LDH level. Workup revealed a strongly positive direct antiglobulin test (DAT) with both IgG and C3d deposition on the red cells. The reticulocyte count was very low (reticulocytes = 0.3%, absolute value = 6.4 K/μl), a phenomenon which is occasionally seen in the early stage of AIHA [4] and consequently the patient required intensive transfusional support (1–3 units of PRBCs/day). High-dose prednisone (2 mg/kg) for 14 days yielded no response. After transfer to our hospital, IVIG (2 g/kg body weight), Rituximab (375 mg/m2 weekly × 3 doses), mycophenolate (1,000 mg twice per day) were added for another 14 days. Despite these interventions, brisk hemolysis continued with elevated LDH (up to 4 × ULN) and total bilirubin levels (up to 8.8 mg/dl) along with severely decreased haptoglobin levels and PRBC transfusions of 1–3 units per day. The patient received 27 units of PRBCs during a 2-week period. After 4 weeks of illness and following informed consent, a combination of bortezomib (1.3 mg/m2, days 1,4, and 8), cyclophosphamide (500 mg/m2, days 1 and 4), and dexamethasone (20 mg, days 1, 4, and 8) [BCD] was administered, resulting in Grade I thrombocytopenia. As shown in Fig. 1, during and after this treatment, the hemoglobin rose, the LDH level fell and the transfusional requirements markedly decreased as the reticulocyte count rebounded (to 262 K/μl). The patient was discharged on 40 mg/day of prednisone with taper and 2 g/day of mycophenolate. The patient appeared to develop a mild increase in hemolysis about 2 weeks after discharge, with a decrease in hemoglobin and an increase in LDH (to 1.5 × ULN). The BCD regimen was administered for a second time, with only Grade III neutropenia (ANC = 800/μl). The hemoglobin rose to a normal level and the DAT became negative for the first time since diagnosis. Two months later (∼3 months since completion of the second course of BCD) the DAT remained negative and the hemoglobin was stable at ∼12 g/dl. Hemogloblin (left side of figure) and LDH (right side of figure) levels vs. time in response to various treatments: Rituximab plus Mycophenolate = Rituximab 375 mg/m2 IV weekly and Mycophenolate 2 g orally daily; Prednisone = Prednisone 1–2 mg/kg/day; BCD = Bortezomib (1.3 mg/m2, Days 1, 4, and 8), Cyclophosphamide (500 mg/m2, Days 1 and 4), and Dexamethasone (20 mg IV, Days 1, 4, and 8); Mycophenolate = Mycophenolate 2 g/day orally; Prednisone taper = Prednisone 40 mg/day for 1 week, 20 mg/day for 1 week, 10 mg/day for 1 week and then stop; Red arrow = 1 unit of packed red-blood cells. Please note that the timeline is not drawn to scale [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com]. Our report suggests that bortezomib and low-dose cyclophosphamide [BCD] is a well-tolerated treatment which may be highly active against the CD20-negative plasma cell compartment that may be responsible for IgG anti-RBC autoantibody production. We thank the nurses of the University of Maryland Medical Center MICU and Greenebaum Cancer Center inpatient and outpatient units for outstanding care of this patient. Each author participated in the care of the patient and helped to write the article. Pongwut Danchaivijitr*, Jean Yared*, Aaron P. Rapoport*, * Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.