Luspatercept in β-thalassemia: Who and when. Strengths and weaknesses points of a real-world evidence

The treatment landscape for transfusion-dependent β-thalassemia (TDT) has evolved, with safer transfusion practices and advances in iron overload management.

Nevertheless, limitations of blood supply, and adverse events related to transfusions and iron chelation, can lead to increased morbidity and reduced quality of life [1].

Luspatercept (ACE-536) was recently approved for managing anemia in TDT based on data from the BELIEVE trial [2].

However, management in routine clinical practice is only initial, and clear criteria for treatment prioritization are still lacking.

Here, we report our real-life experience regarding its use in 10 TDT patients followed from March 2023 to June 2024 (Table 1), presenting predicting factors of quality response and the best timing of starting treatment (Tables 2 and 3).

ACE-536 was administered subcutaneously every 21 days at a starting dose of 1 mg/Kg, adjusted up to 1.25 mg/Kg in two patients, without changes in iron chelation therapy.

All our patients were studied by magnetic resonance imaging of the spine and by thrombophilia tests.

Prior evaluation of BetaHcg in female patients was performed to exclude a concomitant pregnancy. We have strongly recommended, regardless of the kind of sex, the use of effective contraceptive methods, due to the unknown effects on embryogenesis.

We have ruled out all patients with a previous medical history of thrombotic events.

Psychological support was provided to all patients.

We performed B vitamins intravenously administration, with folates and cyanocobalamin to support the increased erythropoiesis process.

We have reported  ACE-536 efficacy in terms of transfusional burden reduction, transfusional interval extended, increase of hemoglobin values preblood transfusion and ferritin values decrease, comparing 12 weeks before and after the first drug administration (Table 2 and Figures 1 and 2).

Statistical analysis was performed with an independent two-sample t-test, with values of p < 0.05 considered statistically significant.

Two patients were excluded from the statistical analysis due to short follow-up.

Two patients in our cohort (B0/alpha −3,7 and with B+/HbE) have won until now their transfusional independence of respectively 20 and 18 weeks, without relevant adverse events (respectively, number 1 and 7 of Table 1).

The impact of ACE-536 in patients affected by beta-thalassemia intermedia appeared of particular interest, with a better response when compared to thalassemia major in our experience.

Notably, the magnitude of the effect was influenced by genotype aspects. In our experience, it was higher in patients with non-beta0–beta0 patients as shown by a subanalysis of BELIEVE trial.

Our data herein reported showed significant advantages in the HbE-beta patients are the same as results presented in the last American Society of Hematology Conference 2023 [3].

Two patients discontinued therapy due to loss of response.

Ferritin values have shown a reduction of 34% comparing iron exams before the first ACE-536 administration and after four cycles.

The safety profile was good, with the majority of side effects easily manageable (Figure 3).

Nevertheless, all patients under treatment had shown an increase in platelet count from baseline (Figure 4).

Only two patients have shown severe thrombocytosis with values more than 1 million/mmc of platelets, respectively, after 5 and 6 months of treatments. We have in greater detail reported this event to Italian Regulatory Medicines Agency adverse events schedules.

Myeloproliferative disorders by bone marrow evaluation and molecular markers were excluded.

We have therefore to interrupt this efficient treatment in these two patients.

There is not much data, based on our knowledge, regarding a probable correlation between ACE-536 and thrombocytosis.

Recent studies in myelodysplastic syndromes (MDS) have shown an influence of ACE-536 on bone marrow niche, modulating activity and function of mesenchymal stromal cells and enhancing the clonogenic potential of hematopoietic progenitors [4]. This evidence in vitro could explain the increase of platelet and neutrophil counts reported in low-risk MDS (secondary endpoints of the MEDALIST trials) [5]. Also, a recent EHA European Hematology Association 2022 poster has shown the same results in Greek TDT patients [6].

It is not fully understood until now if ACE536 shares the same mechanism of induced thrombocytosis in MDS and in thalassemia, as well as in neoplastic clones versus progenitor hematopoietic clones affected by genetic and not oncological disease.

We therefore strongly suggest a closed monitoring of platelet count in this field.

We have not reported any effects on lactate dehydrogenase, white cell counts, uric acids, spleen volume, and body mass index analyzed in our cohort.

We have also tried to select the best time to start properly new therapy (Table 3C). For instance, we had waited about 2 months after splenectomy in two patients due to significant thrombocytosis after surgery (numbers 1 and 3, Table 1).

Finally, HbF baseline values could be another important positive predictor of response because two patients winning transfusion independence have higher levels compared to the other (medium 35% vs. 18%).

In conclusion, to the best of our knowledge, this is the first report assessing thrombocytosis related to ACE-536 and excellent results in HbE-beta-thalassemia in a real-world setting.

Our results support the effectiveness of transfusion burden and iron parameters previously reported [7-9].

A longer follow-up together with multicentric prospective studies is warranted.

Experience with using ACE-536 is only meant to grow over the next few years and real-world data are very important to corroborate its clinical use [9].

Lorenza Torti designed the study, collected clinical data, and wrote the manuscript. Nicolina Ardu collected clinical data, performed statistical analysis, and reviewed the manuscript. Laura Maffei, Francesco Sorrentino, and Paolo De Fabritiis reviewed the manuscript. All the authors read and approved the final manuscript.

The authors declare no conflicts of interest.

The authors received no specific funding for this work.

The authors have confirmed ethical approval statement is not needed for this submission.

We obtained before submission of this manuscript, patient's written consent to publication of image in Figure 3 and of all other patients to share information about them in your journal.

The authors have confirmed clinical trial registration is not needed for this submission.