Case Report: Luspatercept for transfusion-dependent anemia of unknown etiology

Introduction

Anemia is a heterogeneous condition with multiple underlying etiologies, commonly classified by mean corpuscular volume (MCV) or dominant pathophysiological mechanisms such as hypoproliferation, maturation defects, or increased red blood cell (RBC) destruction (1). Unexplained anemia is a diagnosis of exclusion when common causes such as nutritional deficiencies, chronic diseases, or bone marrow disorders have been ruled out. It frequently presents as normocytic and hypoproliferative and accounts for up to one-third of anemia cases in the elderly (2).

Transfusion-dependent anemia (TDA) represents a complex and severe subset, operationally defined as an average transfusion volume of approximately 2 units of RBCs per month (1.92 ± 0.08 units), sustained for a minimum of 3 months (3.2 ± 0.24 months) (3). TDA is observed in a variety of disorders, including bone marrow failure syndromes, congenital dyserythropoietic anemias, and inherited hemolytic conditions. Diagnostic evaluation is often confounded by transfusion effects on laboratory parameters and the rapid clearance of abnormal RBCs (4).

Current treatment strategies typically involve erythropoiesis-stimulating agents (ESAs), immunosuppressive therapies, and immunomodulatory agents (5). Developing novel strategies to reduce the transfusion burden in transfusion-dependent anemia is crucial, as this may reduce complications such as iron overload, alloimmunization, and infections, as well as the negative impact on quality of life and healthcare costs. Moreover, reducing transfusion dependence has been associated with improved survival, with evidence showing decreased survival in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS) (6).

Luspatercept is a recombinant fusion protein comprising a modified form of the extracellular domain of the human activin receptor type IIb linked to the human IgG1 Fc domain. Luspatercept works by binding specific ligands of the transforming growth factor β (TGF-β) superfamily, reducing SMAD2 and SMAD3 signaling, which alleviates the inhibitory effect on red blood cell maturation, leading to increased differentiation and proliferation of erythroid precursors (7, 8). Herein, we report a case of transfusion-dependent anemia of unknown etiology even after an extensive workup successfully treated with luspatercept.

Case description

A 34-year-old Caucasian woman with a history of antiphospholipid syndrome on lifelong anticoagulation, chronic Lyme disease, and childhood asthma presented to the hematology clinic for evaluation of transfusion-dependent severe anemia for the past 9 months. The patient did not have any family history of hematological disorders. The patient had initially presented to an outside facility for evaluation of lethargy and fatigue. Her initial complete blood count (CBC) revealed severe macrocytic anemia with hemoglobin levels at 2.6 g/dL and MCV 106.7, while her platelets and white blood cells (WBCs) were within normal limits. She was admitted for further management and received multiple PRBC transfusions.

She had esophagogastroduodenoscopy (EGD) and colonoscopy during this hospitalization, but no significant abnormalities were seen. CT scans of her chest, abdomen, and pelvis were obtained but did not show any abnormalities, including lymphadenopathy, hepatomegaly, and splenomegaly. Although her bone marrow biopsy revealed hypercellular marrow with trilineage hematopoiesis with megaloblastic changes and an increase in bone marrow histiocytes, there was no evidence of any disorder by morphology or flow cytometry. Additionally, there was no clear evidence of myelodysplasia, with no significant dysplasia or increase in blasts, and the cytogenetic profile was also negative. She had repeat bone marrow biopsies performed after her hospitalization discharge that consistently revealed hypercellular bone marrow, but no other abnormalities were detected. All bone marrow biopsies were reviewed by board-certified hematopathologists with expertise in bone marrow failure and myelodysplastic syndromes. Further workup was pursued after her discharge to identify the etiology of her anemia.

Evaluation for nutritional deficiencies showed her vitamin B₁₂ levels were found to be low at 100 ng/L, with her methylmalonic acid and homocysteine levels being elevated at 0.76 mmol/L and 16 mmol/L, respectively, although her iron studies and folate levels were normal. She started parenteral cyanocobalamin supplementation, and although her vitamin B₁₂ levels improved, her anemia did not improve, and the patient remained transfusion-dependent. Her hemoglobin electrophoresis was unremarkable, and flow cytometry for paroxysmal nocturnal hemoglobinuria (PNH) was negative. Viral serologies for parvovirus, cytomegalovirus (CMV), and Epstein–Barr virus (EBV) were also negative. Her inflammatory markers were elevated, with C-reactive protein (CRP) at 45.8 mg/L and erythrocyte sedimentation rate (ESR) being more than 140 mm/h. Evaluation for other autoimmune pathologies was undertaken but returned negative. The patient was evaluated for a hematopoietic stem cell transplant at this juncture but was deemed ineligible as the etiology of her anemia remained inconclusive.

The patient had a repeat bone marrow biopsy, which revealed hypercellular marrow with decreased erythroid precursor maturation and increased granulopoiesis but was negative for myelodysplastic syndrome by morphology and flow cytometry. Cytogenetic testing was unremarkable, and next-generation sequencing (NGS), comprising 141 gene panels, was negative for any characteristic mutations of myelodysplastic or myeloproliferative diseases, although she did have a variant of uncertain significance (VUS) in NF1, exon 13, c.1472A>G; p.Y491C, and NPA, exon 13, c.2407G>A; p.E803K. Further testing with whole-exon sequencing and genetic testing for Diamond–Blackfan anemia and Fanconi anemia were also negative.

The patient was trialed on steroids with prednisone 40 mg, as there were concerns of hemophagocytosis on her repeat bone marrow biopsy, but she was refractory to the steroids. The patient was subsequently initiated on cyclosporine 400 mg twice daily, but the treatment had to be terminated in a few weeks due to adverse events with no improvement in her hemoglobin. She was eventually started on rituximab, but it was ineffective as well, and the patient remained transfusion-dependent. Although the patient’s absolute reticulocyte count was 9,000/μL (reticulocyte index: 0.08), the patient did not seem appropriate for erythropoietin-stimulating agents as her serum erythropoietin levels were elevated at 1,789 mIU/mL.

Four years after her diagnosis, she was initiated on luspatercept. Based on the patient’s bone marrow biopsy showing erythroid maturation arrest, luspatercept was deemed to be suitable. Luspatercept was initiated under compassionate use after multidisciplinary review and institutional approval for off-label administration, with informed consent obtained from the patient. No adverse effects were reported, and her dose was gradually increased from 1 to 1.75 mg/kg. Her hemoglobin levels improved, and she became transfusion-independent 1 year after commencing luspatercept (compared to requiring approximately 1 unit RBC transfusion per week prior to initiation of luspatercept). A repeat bone marrow biopsy performed revealed normocellular trilineage hematopoiesis (Figure 1).

Discussion

Luspatercept has emerged as an effective modality for achieving transfusion independence for multiple hematological conditions. In recent clinical trials involving patients with myelodysplastic syndromes and β-thalassemia, treatment with luspatercept demonstrated notable efficacy.

In the phase 3 BELIEVE trial, luspatercept significantly reduced transfusion burden in adults with transfusion-dependent β-thalassemia, achieving a ≥33% reduction in 21.4% of patients versus 4.5% for placebo (9). In the phase 3 MEDALIST trial, luspatercept led to transfusion independence for 8 weeks or longer in 38% of patients with lower-risk myelodysplastic syndromes compared to 13% for placebo10. Similarly, in the phase 3 COMMANDS trial, 59% of luspatercept patients achieved 12 weeks of transfusion independence, compared to 31% with epoetin alfa for lower-risk myelodysplastic syndromes (11).

Commonly reported adverse effects with luspatercept include headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, dizziness, dyspnea, peripheral edema, nausea, and hypersensitivity reactions. More serious adverse effects, such as cerebrovascular accident, deep vein thrombosis, hypertension, and extramedullary hematopoietic (EMH) masses, have also been reported (9–11). No adverse events were reported in our patient, and luspatercept was well tolerated.

As previously discussed, diagnosing the etiology of transfusion-dependent anemia can be challenging. NGS has emerged as an effective modality for the diagnosis of rare anemias, circumventing these challenges (12). However, in our patient, no relevant alterations were found, and the diagnosis remained obscure.

Currently, luspatercept is approved for transfusion-dependent anemia in patients with β-thalassemia, patients with ESA-naive very low- to intermediate-risk MDS, and patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) failing an ESA and requiring two or more RBC units over 8 weeks (13). Luspatercept has also demonstrated efficacy in improving anemia and reducing transfusion burden in patients with myelofibrosis, particularly in combination with ruxolitinib (14).

Our case presents an instance of successful off-label use of luspatercept for treating transfusion-dependent anemia of unknown etiology, highlighting the potential of this therapeutic agent beyond its approved indications. A few cases have also been reported, highlighting its utility in α-thalassemia and congenital sideroblastic anemia (15–17).

In conclusion, this case emphasizes the need for continued exploration of luspatercept’s therapeutic potential. Further clinical studies are warranted to validate these findings and elucidate the broader applicability of luspatercept, particularly in managing transfusion-dependent anemias of unknown etiology.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/frhem.2025.1714544/full#supplementary-material

Supplementary material Supplementary material at the source

Footnotes

Edited by: Mariasanta Napolitano, University of Palermo, Italy

Reviewed by: Guangsheng He, Nanjing Medical University, China

Sara Tinsley-Vance, Moffitt Cancer Center, United States