When All Else Fails: Complete Remission with Bortezomib in a Child with Life-Threatening Refractory Autoimmune Hemolytic Anemia

To the Editor,

Autoimmune hemolytic anemia (AIHA) is a rare but potentially life-threatening condition in childhood, with an incidence of approximately 0.2 cases per 1,000,000 children per year [1]. Corticosteroids remain the frontline therapy with a response rate of 50%-80%, but sustained remission is achieved in only 20%-30% of cases [2]. Second- and third-line agents including intravenous immunoglobulin (IVIG), rituximab, cyclosporine, mycophenolate mofetil, and plasmapheresis are frequently insufficient in the most refractory cases [3]. Here we describe a 3-year-old boy who, following failure of multiple immunosuppressive regimens including rituximab, achieved complete and sustained hematological remission with bortezomib.

The patient presented with pallor, jaundice, and hemoglobin (Hb) of 4 g/dL, with lactate dehydrogenase (LDH) of 1935 U/L and direct antiglobulin test (DAT) score of 3+. He had experienced 5 to 6 severe hemolytic relapses since infancy, most commonly following upper respiratory tract infections. Previous treatments administered at referring centers and our institution included corticosteroids, pulse methylprednisolone, IVIG, plasmapheresis, mycophenolate mofetil, tacrolimus, and multiple erythrocyte transfusions, resulting only in transient or partial responses. Rituximab (375 mg/m² weekly x4) had been completed 6 weeks before bortezomib initiation without clinical improvement. Secondary etiologies (e.g., autoimmune, infectious, immunodeficiency) were excluded. Given the unusually early onset and refractory disease course, immune dysregulation was investigated. Immunoglobulin levels, lymphocyte subsets, and double-negative T-cell percentage (0.75%) were normal. Whole-exome sequencing identified a rare heterozygous PIK3R1 variant of uncertain significance (c.1202T>C; p.V401A). However, the absence of recurrent severe infections, lymphoproliferation, or laboratory evidence of immune dysregulation precluded a diagnosis of activated PI3Kδ syndrome type 2 (APDS2). Bone marrow biopsy showed erythroid hyperplasia without dysplasia.

Given the life-threatening, multi-refractory course, bortezomib was initiated at 1.3 mg/m² on days 1, 4, 8, and 11. Hb began rising after the third dose and complete normalization of blood counts with reticulocytosis was achieved within 1 month. Erythrocyte transfusions were discontinued. The patient was discharged on a tapering course of methylprednisolone (stopped within2 weeks), tacrolimus, and mycophenolate mofetil. At 1 month, Hb was 13.4 g/dL, reticulocyte count was 1.1%, the DAT score had decreased to +1, and LDH had normalized (Figure 1). The DAT became negative at 6 months, with no further transfusion requirements over 10 months of follow-up. No adverse effects, including peripheral neuropathy, were observed.

Figure 1.

Treatment course and clinical evolution of hemoglobin and lactate dehydrogenase levels. The patient received rituximab (375 mg/m² weekly x4) at an external institution, which was completed 6 weeks before the initiation of bortezomib. Bortezomib was administered at 1.3 mg/m² on days 1, 4, 8, and 11.

Hb: Hemoglobin; LDH: lactate dehydrogenase; IVIG: intravenous immunoglobulin.

Bortezomib is a selective, reversible 26S proteasome inhibitor approved for multiple myeloma that depletes antibody-producing plasma cells and suppresses NF-κB-mediated inflammation [4, 5]. Its use in pediatric refractory AIHA and autoimmune cytopenias is emerging: among 24 cases reported in the literature, hematological response was achieved in 18 (75%), predominantly in post-hematopoietic stem cell transplantation or post-solid organ transplantation settings [6, 7, 8, 9]. Our patient is notable as a case of primary (non-transplant) refractory AIHA in a young child who responded rapidly and durably to a single course without adverse effects. Although a delayed effect of rituximab cannot be completely excluded, the patient remained transfusion-dependent and clinically active despite completion of rituximab therapy. Hematological recovery began shortly after the third bortezomib dose, suggesting a substantial contribution from plasma-cell depletion. Nevertheless, a synergistic effect between prior B-cell depletion by rituximab and subsequent plasma-cell targeting by bortezomib remains possible.

In conclusion, bortezomib constitutes a promising and well-tolerated therapeutic option in children with severe, multi-refractory primary AIHA. Prospective studies are warranted to establish optimal dosing, timing, and combination strategies.

Ethics

Informed Consent: Written informed consent was obtained from the patient’s legal guardian.