Prednisolone and mycophenolate mofetil as first-line therapy in warm autoimmune hemolytic anemia: A prospective pilot study

Abstract Background: Warm autoimmune hemolytic anemia (wAIHA) is a rare immune disorder characterised by autoantibody-mediated destruction of red blood cells. Corticosteroids are the standard initial treatment, but their use is often associated with significant toxicity and limited long-term efficacy. Mycophenolate mofetil (MMF) as part of initial therapy has shown efficacy in other autoimmune cytopenias. However, there is limited literature on the first-line use of the combination of prednisolone and MMF in wAIHA. Objective: To evaluate the efficacy, steroid-sparing potential, safety profile, and pharmacokinetic profile of combining MMF with prednisolone as first-line therapy in wAIHA. Methods: In this prospective single-centre study, newly diagnosed wAIHA patients (hemolytic anemia with positive direct antiglobulin test [DAT] for IgG autoantibodies) with age ≥12 years were enrolled after informed consent. Exclusion criteria were poor performance status at baseline (ECOG ≥3), active infection, active malignancy, pregnant and breastfeeding women, chronic liver disease, chronic kidney disease, and any contraindication to MMF or prednisolone. Bone marrow examination was performed in patients with age >40 years to rule out underlying chronic lymphoproliferative disorder. In addition to prednisolone (1 mg/kg/day), all patients received MMF (500 mg twice daily in week 1, 750 mg twice daily in week 2, 1 gm twice daily in week 3 and onwards). Methylprednisolone pulse (1 g/day for 3 days) was given to patients with baseline hemoglobin (Hb) <6 g/dL. Patients were followed once in 2 weeks for 12 weeks with hemogram, reticulocyte count, lactate dehydrogenase (LDH), and liver function tests. Complete response (CR) was defined as achievement of Hb ≥10 g/dL with normalisation of serum bilirubin, reticulocyte count, and LDH, along with no requirement for blood transfusion. Partial response (PR) was defined as Hb increase of ≥2 g/dL or normalisation of Hb (≥10 g/dL) without complete biochemical resolution of hemolysis, and no requirement of blood transfusion in preceding 7 days. Following 2 weeks of prednisolone and achievement of either PR or CR, tapering of prednisolone was initiated. Primary outcomes included time to CR, cumulative steroid use, and adverse events. Secondary outcomes included relapse rate and pharmacokinetic analysis of MMF’s area under the curve (AUC) over 0 to 10 hours (AUC0-10hr) on day 5 in a subset of patients by using colorimetric method. Results: Twenty patients were enrolled in this study. Their median age was 31 years (range 16-83 years); 80% were females. Underlying autoimmune conditions (e.g., systemic lupus erythematosus [SLE]) were present in 7/20 (35%) patients. Splenomegaly was present in 17/20 (85%) patients at diagnosis; median baseline Hb was 4.9 g/dL (range 3.5 - 6.5 g/dL). Methylprednisolone pulse was given to 16/20 (80%) patients. At 2 weeks, 95% patients achieved response (8/20 [40%] CR, 11/20 [55%] PR). At 4 weeks, 19/20 (95%) patients achieved CR. At 12 weeks, all patients (100%) achieved CR. The median time to achieve CR was 4 weeks (range 2 - 12 weeks). Median time to reach prednisolone dose <10 mg/day was 8 weeks; 70% patients were off prednisolone by week 12. Over a median follow up of 14 months, 90% patients remained relapse-free. Diarrhea was the most common adverse event, occurring in 9/20 patients (45%); CTCAE grade 1 diarrhea in 7 patients, grade 2 diarrhea in 2 patients. Gastritis was reported by 5 patients (25%). Eight patients (40%) did not report any treatment-related adverse events. None of the patients developed CTCAE grade ≥3 adverse events or any serious infection. Pharmacokinetic analysis in 6 patients showed mean AUC0-10hr of 38.4 µg.hr/mL (range 17.2 - 54.0) on day 5 of MMF 500 mg twice daily. Four patients achieving on-target exposure (AUC0-10hr ≥30 µg.hr/mL); all 4 patients achieved and maintain CR. Conclusion: This prospective study demonstrates that the combination of prednisolone with MMF as first-line therapy in wAIHA is safe, well-tolerated and highly effective. It leads to rapid and durable complete responses and allows early steroid-tapering. Although our study's sample size and single-centre design limit broader applicability, and the absence of a comparator arm calls for cautious interpretation, these promising findings warrant further evaluation in larger randomized controlled trials.