Use of a novel erythroid maturation agent in transfusion-dependent β-thalassaemia

Case 1: A patient with concomitant liver abscess and AF
History and presentation
A 45-year-old female, diagnosed in infancy with transfusion-dependent β-thalassaemia (TDT) major of β⁰/β⁰ genotype, presented with a liver abscess in December 2019. She was admitted to hospital multiple times for repeated drainage of the abscess, which was caused by Klebsiella, and required several prolonged courses of antibiotic treatment. The patient was on a regular transfusion schedule of 3 red blood cell (RBC) units every 4 weeks in addition to iron chelator therapy with intravenous (IV) deferoxamine and oral deferasirox.

Treatment
As a result of the infectious complication, deferoxamine was switched to oral deferiprone from February 2020 onwards, but the patient continued receiving oral deferasirox. Once the liver abscess was adequately treated, in May 2021, subcutaneous deferoxamine was resumed and oral deferiprone was added. During the following months, her serum ferritin levels gradually increased, and the patient started to complain of heart palpitations.

Monitoring with 24-hour ECG detected atrial fibrillation (AF). The patient’s treatment was then switched to IV deferoxamine, which was administered in a day hospital setting over 8 hours, 5 days per week for about 3–4 months. Furthermore, cardiac MRI performed in August 2021 showed T2* relaxation time of 10 msec, suggestive of moderate myocardial iron overload. Nevertheless, ejection fraction remained normal, implying preserved heart function. In addition, liver MRI T2* value was 1.4 msec, indicating severe iron overload in the liver. At the time, the patient's serum ferritin level was at 17,717 pmol/L. By November 2021, her serum ferritin level had reached its peak and was at 39,382 pmol/L.

In February 2022, the patient started receiving luspatercept subcutaneous injections at the standard dose of 1 mg/kg every 3 weeks. So far, she has tolerated the drug very well. The transfusion burden has reduced from 3 RBC units every 4 weeks to 2 RBC units every 4–5 weeks. (Figure) Her pretransfusion haemoglobin levels remained stable at about 10 g/dL. Additionally, her serum ferritin level decreased dramatically to 3,187 pmol/L, and she no longer complained of heart palpitations or chest discomfort. (Table) Once the ferritin levels dropped <10,000 pmol/L, she was switched from IV back to subcutaneous deferoxamine, which eliminated the need for multiple day admissions at hospital every week. The latest cardiac and liver MRI performed in January 2022 showed longer T2* relaxation times of 11.3 msec and 1.9 msec, respectively.

Overall, the patient, who previously experienced great anxiety because of her health condition, which was further exacerbated by the liver abscess and subsequent AF diagnosis, is much happier after luspatercept initiation, having experienced several positive outcomes, including improvement in iron load, resolution of cardiac symptoms, reduced need for RBC transfusions and the end of prolonged, frequent hospital visits for IV deferoxamine infusions.

Case 2: A patient with concomitant IgA nephropathy, HCV infection and papillary thyroid carcinoma
History and presentation
The patient is a 42-year-old female with β-thalassaemia intermedia. She underwent splenectomy at 5 years of age and became transfusiondependent at the age of 28 years, when her haemoglobin level dropped to 6 g/dL. She was receiving 2 units of RBC every 4 weeks. In addition, she received iron chelation with deferoxamine and deferiprone over several years.

In 2008, she was diagnosed with concomitant immunoglobulin A (IgA) nephropathy, with an estimated glomerular filtration rate (eGFR) of 11 mL/min/1.73 m², which partly contributed to a more severe β-thalassaemia phenotype. The renal disease was treated with corticosteroids. She also has a history of hepatitis C virus (HCV) infection, which was cleared with interferon therapy, and papillary thyroid carcinoma, which was treated with total thyroidectomy.

Treatment
In November 2021, the patient was initiated on luspatercept injections at 1 mg/kg (60 mg) every 3 weeks. Aspirin was given prophylactically to reduce the risk of splenectomy-associated thrombosis. Subsequently, her transfusion burden reduced by 1 RBC unit in alternate transfusions. Her serum ferritin levels improved from 7,600 pmol/L to 5,649 pmol/L. Unfortunately, luspatercept treatment was interrupted in February 2022 as the patient was reluctant to visit the hospital due to the COVID-19 outbreak in Hong Kong. During this period, she reverted to the original transfusion schedule.

The patient resumed luspatercept treatment in June 2022 at a dose of 1 mg/kg (60 mg) every 3 weeks. Her transfusion burden was reduced by 1 unit of RBC in alternate transfusions. In order to further reduce the transfusion requirement, luspatercept dose was escalated to 1.25 mg/kg (80 mg) every 3 weeks. The patient's pretransfusion haemoglobin level improved by 0.5 g/dL, while her eGFR remained at 10 mL/min/1.73 m². To date, no signs of hepatic or cardiac iron overload have been noted.

Discussion
β-thalassaemia is an inherited disorder characterized by ineffective erythropoiesis and anaemia. It is estimated that there are 300–400 TDT patients under the care of Hong Kong’s Hospital Authority.¹ For several decades, the standard of care for patients with this blood disorder has been lifelong regular RBC transfusions and iron chelation therapy.

RBC transfusions help to alleviate anaemia, but represent a considerable burden on the health system and negatively impact patients’ quality of life (QoL). TDT patients undergo screening about 3–7 days prior to the scheduled transfusion to find compatible donor RBCs. Patients typically receive a transfusion every 3–4 weeks, and it takes about 6–9 hours to transfuse 3 units of RBC.²

Iron chelation therapy is aimed at removing excess iron, which can accumulate in and damage various organs – mainly the heart, liver and endocrine glands. Thus, routine monitoring of iron overload is a crucial part of clinical management of β-thalassaemia.² Iron overload has been associated with hepatocellular carcinoma.³

Luspatercept is a first-in-class erythroid maturation agent approved for the treatment of adult patients with transfusion-dependent anaemia associated with β-thalassaemia. It is administered subcutaneously at a starting dose of 1.0 mg/kg once every 3 weeks.⁴

The efficacy and safety of luspatercept in TDT were demonstrated in the randomized, double-blind, placebo-controlled, phase III BELIEVE trial. TDT patients were randomized 2:1 to receive either luspatercept or placebo every 3 weeks for ≥48 weeks. The primary endpoint was a ≥33 percent reduction in RBC transfusion burden from baseline during weeks 13–24. Results showed that 21.4 percent (48/224) of patients in the luspatercept arm vs 4.5 percent (5/112) of patients in the placebo arm (p<0.001) achieved the primary endpoint.⁵

In this primary analysis, the proportion of patients who experienced transfusion burden reduction of ≥33 percent during any 12-week interval was 70.5 percent vs 29.5 percent in the luspatercept vs placebo group.⁵ Notably, at the latest data cutoff (139 weeks after primary data cutoff), an even greater proportion of patients (77.2 percent) had ≥33 percent response during any 12-week interval.⁶ Furthermore, in patients whose transfusion burden reduced by ≥50 percent, the number of RBC units transfused decreased over the course of long-term treatment, while the time between transfusions increased vs baseline.⁶

In addition, recent data from the open-label extension phase of the BELIEVE trial showed that luspatercept responders (defined as patients who achieved the primary endpoint) had a reduced number of transfused RBC units and reduced transfusion visits over 120 weeks, regardless of baseline transfusion burden, vs nonresponders.⁷

Both of our patients experienced transfusion burden reduction. In case 1, the number of RBC units needed per transfusion has reduced from 3 to 2, and the transfusion interval has increased from 4 weeks to 4–5 weeks since commencing luspatercept treatment in February 2022. In case 2, one fewer RBC unit was needed in alternate transfusions, and the dose of luspatercept was increased in order to further reduce the transfusion burden.

Furthermore, case 1 patient’s serum ferritin levels were elevated despite intensive iron chelation therapy with three iron chelators, as opposed to the standard single or dual iron chelator regimens. Initiation of luspatercept has enabled her serum ferritin levels to drop considerably, thus reducing the iron overload. With the observed reduction in serum ferritin, she no longer required IV deferoxamine infusions, which significantly improved her QoL. As observed in the BELIEVE trial, further improvements can be expected in the patient’s transfusion burden, iron levels, and QoL with continued use of luspatercept.

Luspatercept is generally well-tolerated. In the BELIEVE trial, adverse events (AEs) led to treatment discontinuation in 5.4 percent of patients in the luspatercept group vs 0.9 percent in the placebo group. Thromboembolic AEs occurred in 3.6 percent of patients in the luspatercept group (including two grade ≥3 events) and in 0.9 percent of patients in the placebo group. All thromboembolic AEs occurred in splenectomized patients who had at least one other risk factor for thromboembolic disease, including a history of venous thrombosis or thrombocytosis at baseline.⁵ It is recommended that patients receiving luspatercept are assessed and assigned prophylactic intervention according to risk-stratification guidelines for the prevention of thromboembolic events, as was done for our splenectomized patient in case 2, who received aspirin.

In summary, luspatercept, an erythroid maturation agent, is emerging as a promising treatment option for TDT. Findings from the BELIEVE trial have shown that long-term use of luspatercept produces sustained reductions in RBC transfusion units required and frequency of transfusions. Furthermore, as demonstrated in case 1, luspatercept treatment can effectively reduce iron overload. These benefits will likely translate into QoL improvements for patients with TDT.