Acute splenomegaly, haemolysis, and thrombocytopenia following luspatercept initiation in a patient with transfusion‐dependent thalassaemia: A case report

Summary

Patients with transfusion‐dependent thalassaemia (TDT) require chronic, life‐sustaining red blood cell transfusions, which contribute to iron overload and associated morbidity and mortality. Luspatercept, an inhibitor of the transforming growth factor‐beta pathway, decreases transfusion requirements in a subset of transfusion‐dependent β‐thalassaemia patients and is increasingly prescribed in clinical practice. Subsequent to regulatory approvals, several reports have identified the risk of extra‐medullary haematopoiesis, which resulted in updated safety labelling. In this report, we present a case of a patient with TDT who developed severe splenomegaly, haemolysis and thrombocytopenia necessitating treatment discontinuation.

INTRODUCTION

β‐Thalassaemia is a haemoglobinopathy caused by β‐globin mutations resulting in globin‐chain imbalance that precipitates ineffective erythropoiesis and haemolytic anaemia. Transfusion‐dependent thalassaemia (TDT) is a phenotypic presentation of thalassaemia that describes the disorder in patients who require chronic, life‐sustaining red blood cell (RBC) transfusions. TDT patients also require iron chelation and management of iron overload and other disease complications. ¹

Luspatercept is a first‐in‐class fusion protein that promotes late‐stage erythropoiesis through its action as a ligand trap inhibiting SMAD‐2/3 signalling in the transforming growth factor‐beta pathway. ² The BELIEVE trial and follow‐up studies highlighted reduced transfusion requirements and iron overload in a subset of patients with TDT treated with luspatercept, resulting in regulatory approval. ³ , ⁴

Data have subsequently emerged highlighting the risk of extra‐medullary haematopoiesis (EMH) in patients who receive luspatercept, resulting in its updated safety labelling. ⁵ Long‐term follow‐up studies reported EMH masses in 3.2% of adult patients with TDT and symptomatic spinal cord compression in 1.9% of patients. ⁵ A case of paraspinal EMH causing spinal cord compression following four doses of luspatercept has been described, ⁶ as well as a case series of paraspinal EMH in four of six patients with TDT treated with luspatercept for 14–20 months. ⁷ Three of the four cases of EMH were asymptomatic and detected on screening magnetic resonance imaging (MRI). ⁷

While paraspinal EMH has been reported, no cases of luspatercept‐associated acute symptomatic splenomegaly have been described to our knowledge. In this report, we present a case of a 24‐year‐old male patient with TDT who developed severe splenomegaly, acute thrombocytopenia and worsening haemolysis following treatment initiation with luspatercept.

CASE PRESENTATION

The patient was diagnosed with transfusion‐dependent β‐thalassaemia in early life. Genetic studies demonstrated homozygosity for the IVS‐I‐5 G → C β⁺‐thalassaemia mutation and heterozygosity for the rightward single α‐globin gene deletion (−α^3.7/αα). He was treated with regular RBC transfusions; iron chelation; currently consisting of single‐agent deferasirox at 28 mg/kg; and monitoring and management of related complications.

He typically received 3 units of RBC transfusion every 3 weeks before luspatercept initiation (48 units during the 12 months preceding luspatercept start). There was mild asymptomatic splenomegaly at baseline (long axis measuring 14.2 cm), but no known hepatomegaly or EMH masses. Iron overload was suboptimally controlled and baseline ferritin was 11 613 μg/L with a liver iron concentration of 7.9 mg/g dry weight on Ferriscan® MRI. Notably, he had a history of agranulocytosis with deferiprone and was unwilling to add deferoxamine to his chelation regimen. Luspatercept was initiated at 1 mg/kg every 3 weeks to decrease transfusion requirements and improve iron overload. Subsequent dosing was increased to 1.25 mg/kg to optimize his response.

The patient presented to the emergency department approximately 10.5 weeks after starting luspatercept, 10 days after his fourth dose, with a two‐month history of progressive fatigue and subjective painful enlargement of the spleen in addition to a three‐day history of progressive dyspnoea and presyncope. On examination, he was tachycardic (heart rate 114 bpm), with other vital signs within normal limits. Respiratory, cardiac, and abdominal exams were recorded as unremarkable. Lab work was notable for anaemia and thrombocytopenia (Table 1). No evaluation for haemolysis was completed. A chest computed tomography with pulmonary angiography was negative for pulmonary embolism but incidentally noted worsening splenomegaly of 17.6 cm. The patient was diagnosed with symptomatic anaemia, received 1 unit of RBCs, and was then discharged home in stable condition with no aetiology of dyspnoea identified.

TABLE 1.

Laboratory investigations.

Time relative to luspatercept start or period	Luspatercept dose (mg/kg)	RBC transfusion (RBC units)	Haemoglobin (g/L)	Reticulocyte count (×109/L)	Platelet count (×109/L)	Total bilirubin (direct) (μmol/L)	LDH (U/L)	Nucleated RBCs (×109/L)
Day −2 (0 weeks, −2 days)			85	8	147	24 (8)	207	0.2
Day 0 (0 weeks, 0 days)	1.0	3
Day +19 (+2 weeks, 5 days)			105	23	120	35 (11)		0.4
Day +21 (+3 weeks, 0 days)	1.0	2
Day +40 (+5 weeks, 5 days)			77		110	45		1.9
Day +42 (+6 weeks, 0 days)	1.25	3
Day +61 (+8 weeks, 5 days)			70	45	70	50 (16)		6.5
Day +63 (+9 weeks, 0 days)	1.25	3
Day +68 (+9 weeks, 5 days)			96	44	42			5.6
Day +73 (+10 weeks, 4 days)		1	82		77
Day +82 (+11 weeks, 5 days)			73	30	62		911	4.2
Day +84 (+12 weeks, 0 days)		4	57	30	53	47		3.9
Day +103 (+14 weeks, 5 days)			95	9	168	41 (16)	284	0.2
Day +105 (+15 weeks, 0 days)		3
Day +126 (+18 weeks, 0 days)		3	75		154	38 (17)		0.1
Day +147 (+21 weeks, 0 days)		3	83	8	116	24 (8)		0.3
Day +168 (+24 weeks, 0 days)		3	84	7	95	25 (9)		0.2
∆12‐week average		+5 (total)	−8.8	+27	−86	+19	+704	+3.5
∆12‐month average		+8 (total)	−9.4	+7.7	−69	+13	+295	+1.1

Abbreviations: LDH, lactate dehydrogenase; RBC, red blood cell.

At re‐evaluation 10 days later, he reported minimal interval change in dyspnoea, presyncope, and tender splenomegaly. He recalled having symptoms of an upper respiratory tract infection beginning approximately 2 weeks after his first luspatercept dose that subsequently resolved. On examination, his heart rate was 102 bpm, with other vital signs within normal limits. His spleen was palpable approximately 6 cm below the costal margin and was tender to palpation. Investigations were notable for anaemia, thrombocytopenia and elevated reticulocytes, bilirubin and lactate dehydrogenase (LDH) (Table 1).

Additional investigations were negative for Epstein–Barr virus (EBV) viral load, heterophile antibodies, human immunodeficiency virus (HIV) 1 and 2 antibodies and antigen enzyme immunoassay, and parvovirus B19 immunoglobulin G (IgG) and immunoglobulin M (IgM). No H bodies were detected on the haemoglobin H inclusion body stain. High‐performance liquid chromatography was performed, which showed Haemoglobin F (2.4%), Haemoglobin A (80.4%), Haemoglobin A2 (2.6%), and no abnormal peaks. The peripheral blood film demonstrated a leukoerythroblastic picture with granulocyte left shift to the promyelocyte stage and many nucleated erythroid precursors. No RBC fragments were seen. No circulating malignant cells or reactive lymphocyte morphology was seen to suggest a viral illness. An abdominal ultrasound with Doppler demonstrated splenomegaly (long axis 20.4 cm; estimated volume 1423 cc), without evidence of abdominal thrombosis. A review of bloodwork trends and spleen size following luspatercept initiation revealed worsening anaemia, new thrombocytopenia and increasing haemolytic indices (Figure 1).

FIGURE 1.

Selected laboratory parameters with luspatercept treatment over time. LDH, lactate dehydrogenase; RBC, red blood cell.

The patient was transfused 4 units of RBCs for symptomatic anaemia. Luspatercept was discontinued following the fourth dose. The patient's symptoms, haemolytic parameters and transfusion requirements were closely monitored. As highlighted in Table 1, during the 12‐week luspatercept trial, the patient's average RBC transfusion requirement initially increased but then decreased to pretreatment baseline following treatment cessation. Additionally, the patient developed increasing reticulocytes and new thrombocytopenia with a nadir 5 days after the final luspatercept dose, which also improved after treatment discontinuation.

Similarly, subsequent monitoring ultrasounds demonstrated decreasing splenic size with luspatercept discontinuation: an ultrasound assessment completed 15 weeks after the final dose of luspatercept reported a long axis of 18.6 cm and an estimated volume of 328 cc, and repeat imaging 11 months post‐luspatercept initiation demonstrated stable splenic size, reporting a 17.9 cm long axis and estimated volume of 353 cc.

The patient's worsening anaemia and new thrombocytopenia were attributed to increased haemolysis and splenic sequestration, as supported by imaging and laboratory results. The temporal association with luspatercept initiation and the resolution of symptoms, decreased spleen volume and return to baseline laboratory values following treatment cessation raised strong suspicion of luspatercept as the cause. While the patient did report a history of a coincident upper respiratory tract infection, investigations showed no evidence of HIV, EBV or parvovirus B19 infection, nor any changes on peripheral blood film to support this as an alternate aetiology for the patient's splenomegaly and bicytopenia. However, the aetiological possibility of an infection with a virus not tested for cannot be ruled out. Inflammatory markers were not measured but could have been useful to support or refute an infectious aetiology.

Unfortunately, treatment with luspatercept was counterproductive in our patient, as he required increased transfusions to manage symptomatic anaemia and splenomegaly. Previous studies have demonstrated that luspatercept use is associated with increased bilirubin but not LDH. ⁸ The mechanism by which luspatercept triggered increased haemolysis is unclear but may be related to improved survival of thalassemic erythrocytes predisposed to haemolysis. The aetiology of the splenomegaly is also unclear, and we hypothesize that it resulted from sequelae of haemolysis and possibly splenic EMH. For example, it is possible that the increased erythropoiesis, demonstrated by robust reticulocytosis, led to extravascular haemolysis and resultant splenomegaly. Given the patient's co‐inherited alpha‐globin deletion, we wondered if luspatercept could have triggered a relative excess of β‐globin production resulting in worsening globin‐chain imbalance manifesting with Haemoglobin H or Haemoglobin Barts contributing to haemolysis; however, no evidence of this was found. In addition, next‐generation sequencing panel testing for selected membranopathies and enzymopathies (tested genes listed in Supporting Information) was performed, which excluded these as contributors.

The two main pathophysiological mechanisms of splenomegaly in TDT are EMH and increased destruction of RBCs by the reticuloendothelial system. ⁹ Considering luspatercept's known association with the development of EMH masses, we hypothesize that luspatercept may have contributed to splenic EMH resulting in progressive splenomegaly‐causing platelet and RBC sequestration. ⁵ , ⁶ , ⁷ Unfortunately, we do not have access to soluble transferrin receptor testing, a biomarker of ineffective erythropoiesis, which may have supported this hypothesized contributing mechanism. ¹⁰

Luspatercept's updated safety label lists the following risk factors associated with the development of EMH masses: a history of EMH masses, hepatomegaly, splenomegaly, splenectomy and low baseline haemoglobin (<85 g/L), ⁵ and recommends a review of these risk factors before initiating treatment; however, no guidance is provided on the degree of risk associated with each factor. ⁵ The patient described in our report had only one listed risk factor—a history of mild splenomegaly. Interestingly, thrombocytopenia and reticulocytosis developed within 3 weeks of starting luspatercept and became increasingly severe with subsequent doses before improving with treatment cessation, likely representing the earliest signs of splenomegaly in this patient. Similar to Piga et al.'s findings, increasing reticulocyte levels was one of the earliest changes noted and was inversely proportional to the progression of thrombocytopenia in this patient. ⁸

In conclusion, we suggest increased vigilance for splenomegaly in patients starting luspatercept, especially those with enlarged spleens at baseline. We recommend obtaining a pretreatment ultrasound to assess baseline splenic size and careful monitoring for symptoms and signs of splenomegaly, with close attention to the development of thrombocytopenia and reticulocytosis as early indicators. In addition, at sites with access to testing, monitoring soluble transferrin receptor levels as a biomarker of ineffective erythropoiesis could aid in the early detection of increasing EMH.

AUTHOR CONTRIBUTIONS

Hayley Merkeley and Stephanie Garland were critical in diagnosing and treating this patient, supervised the study and provided critical revision of the paper. Bianca Zaidel analysed the data and wrote the paper. All authors have read and agreed to the final version of the manuscript.

CONFLICT OF INTEREST STATEMENT

HM has received consultant fees from Bristol Myers Squibb (BMS). The authors have no competing interests.

INFORMED CONSENT

Written informed consent was obtained from the patient for his anonymized information to be published in this case report.

Supporting information

Data S1.

Zaidel B, Garland S, Merkeley H. Acute splenomegaly, haemolysis, and thrombocytopenia following luspatercept initiation in a patient with transfusion‐dependent thalassaemia: A case report. Br J Haematol. 2025;206(6):1806–1810. 10.1111/bjh.20131