Treating Thalassemia Patients with Luspatercept: An Expert Opinion Based on Current Evidence
- From week 13 to week 24, 21.4% of patients in the luspatercept arm responded vs. 4.5% in the placebo arm (p < 0.001);
- From week 37 to week 48, 19.6% of patients in the luspatercept arm responded vs. 3.6% in the placebo arm (p < 0.001);
- In any 12-week interval, 76.3% of patients in the luspatercept arm responded vs. 34.8% in the placebo arm (p < 0.0001).
- From week 13 to week 24, 7.6% of the luspatercept arm responded vs. 1.8% of placebo (p = 0.03);
- From week 37 to week 48, 10.3% of the luspatercept arm responded vs. 0.9% of placebo (p = 0.002).
2. Patient Selection
- Question 1: Is luspatercept contraindicated for specific reasons in subjects under 18?
- Question 2: Is there an upper age limit for prescribing luspatercept?
- Question 3: Is it necessary to analyze the patient’s genotype before starting therapy?
If not already available, it is suggested that the thalassemic genotype be analyzed for diagnostic confirmation and a better characterization of the treated population. However, it is not strictly required for prescription.
- Question 4: Can patients with HbE/beta-thalassemia access luspatercept therapy?
- Question 5: Can patients with Hb Lepore (delta–beta fusion) access luspatercept therapy?
- Question 6: Can patients who are heterozygous for a beta-globin mutation associated with the presence of supernumerary alpha genes access luspatercept therapy?
- Question 7: Can previously non-transfusion-dependent (NTDT) patients who afterwards became TDT access luspatercept therapy?
- IRON OVERLOAD
- Question 8: Are there limits related to the values of ferritin, liver iron concentration (LIC), or myocardial iron concentration (MIC) for the administration of luspatercept?
- Question 9: Could luspatercept have a positive effect on iron overload?
- HISTORY OF NEOPLASIA
- Question 10: Is malignancy an exclusion criterion?
Caution is advised when starting treatment with luspatercept in patients with a history of malignancy.
- HISTORY OF THROMBOSIS
- Question 11: Patients treated with luspatercept in the BELIEVE study who developed thrombosis were all splenectomized. Is splenectomy an exclusion criterion?
It is recommended that a thorough history of thrombotic risk factors is taken, and any possible correcting measure considered, particularly in splenectomized patients (i.e., to evaluate the opportunity to start acetylsalicylic acid in the function of platelet numbers as recommended by international guidelines).
- Question 12: Is thrombophilic screening required in all luspatercept candidate patients?
- Question 13: Can the splenectomized patient who has already been identified as a carrier of a mutation associated with a thrombophilic status access luspatercept therapy?
As for the non-splenectomized patients, the decision to start luspatercept therapy or not should be evaluated on a case-by-case basis, taking the risk/benefit ratio into account.
- Question 14: If the patient had a thromboembolic event shortly before the possible start of luspatercept, is the degree of contraindication to the drug considered greater?
Regardless of the temporal relationship with the previous thrombotic event, the panel suggests carefully evaluating subjects with previous thrombosis, considering modifiable and non-modifiable risk factors.
- ANTICOAGULANT THERAPY
- Question 15: Is anticoagulant or antiplatelet prophylaxis advisable for patients during therapy?
Initiating luspatercept therapy is not ‘per se’ an indication to start anticoagulant or antiplatelet therapy.
- WOMEN OF CHILDBEARING AGE
- Question 16: Is luspatercept teratogenic?
- Question 17: Do women of childbearing age have to take a pregnancy test before each administration?
Maintaining a particularly high focus on preventing pregnancy and promptly investigating any menstrual delay during treatment is advisable.
- Question 18: What if a woman being treated with luspatercept becomes pregnant?
- Question 19: Are there contraindications to the use of luspatercept in male subjects with a desire for offspring?
- MASSES OF EXTRAMEDULLARY ERYTHROPOIESIS
- Question 20: Can luspatercept be prescribed in patients with masses of extramedullary erythropoiesis?
- Question 21: Is it necessary to look for possible EMH in all patients before proposing luspatercept therapy?
The panel suggests, whenever possible, to search for any EMH using magnetic resonance imaging before starting luspatercept therapy.
- Question 22: Do patients with EMH require specific monitoring?
Based on clinical experience, periodic instrumental monitoring with MRI and clinical evaluation in patients with masses of extramedullary erythropoiesis are suggested for the early detection of any volumetric changes.
- Question 23: Should luspatercept treatment be discontinued if EMH volume increases?
- Question 24: Can hydroxyurea therapy in patients with EMH also be continued in patients treated with luspatercept?
The panel suggests continuing the administration of hydroxyurea in cases where the efficacy in controlling erythropoiesis masses has already been verified, as the effect of luspatercept alone is not known.
3. Modulation of Transfusion Therapy during Luspatercept Treatment
- PRE-TRANSFUSION HEMOGLOBIN
The accurate recording of pre-transfusion Hb values is recommended.
- Question 25: Is there an ideal value of pre-transfusion Hb to be maintained during luspatercept therapy?
The target for pre-transfusional Hb is the average of pre-transfusional Hb in the 24 weeks before treatment initiation if it is within the range recommended by the international guidelines.
- TIMING OF LUSPATERCEPT ADMINISTRATION IN RELATION TO THE TRANSFUSION CYCLE
- Question 26: At what point in the transfusion cycle should luspatercept be administered?
There are no medical contraindications to the administration of luspatercept on the same day as transfusion.
- Question 27: In cases of administration on the same day of transfusion, is it preferable to administer luspatercept before, during, or at the end of the transfusion session?
It is believed that luspatercept can be administered approximately half an hour before transfusion so that any drug-related reactions can be identified. Post-transfusion administration, if any, should be performed at the end of the post-transfusion monitoring period. It is not recommended to administer luspatercept during transfusion because it would be challenging to differentiate the cause of a possible reaction.
- Question 28: During luspatercept therapy, is it preferable to increase the transfusion interval or to keep it unchanged by reducing the amount of blood transfused?
- Question 29: What should be done if, 21 days after the administration of luspatercept, Hb is higher than the target pre-transfusion Hb value?
In the case of Hb values being higher than the pre-transfusion Hb target, as far as is possible, it is recommended that the transfusion be postponed while abiding by the transfusion guidelines. It is also recommended that the transfusion parameters be carefully recorded.
- Question 30: What should be done if, 21 days after the administration of luspatercept, the Hb value is lower than expected?
In these cases, it is recommended to evaluate alternative causes (immunization, hemolysis, bleeding, infection, or other conditions) as in patients not treated with luspatercept.
4. Evaluation of the Response/Timing
Before starting luspatercept therapy, it is necessary to collect a detailed history of pre-transfusion Hb, number of transfused red blood cells units, transfused volume, and transfusion-free interval. The same parameters should be recorded during treatment. These data could be integrated with erythropoiesis markers.
- Question 31: Which parameter/s can be used to evaluate the response?
The reduction in the transfusion burden could be due to an extension of the transfusion interval or a reduction in the number of transfused units per session when the interval remains the same. If the pre-transfusion Hb is higher than the threshold value of that patient, the transfusion can be postponed.
- Question 32: Is the reduction in serum ferritin during treatment an indication of a positive response to luspatercept?
- Question 33: Which reduction value of the transfusion burden defines the response to luspatercept?
It is believed that the timing of the reduction in transfused units may differ from patient to patient. Therefore, the assessment of the response to luspatercept and the decision to continue the therapy should be evaluated on a case-by-case basis (for example, considering factors such as the presence of severe iron accumulation, immunizations, and other conditions).
- Question 34: When is it appropriate to verify the response to luspatercept?
It is believed that the response of each patient to luspatercept should be assessed by calculating the change in the number of units of red blood cells transfused in the period between the last two treatment cycles compared to the period of equal duration before the beginning of treatment. For the purpose of a more accurate evaluation, it is suggested that the variation is calculated, also considering the volumes of the units of transfused red blood cells.
In patients defined as non-responders according to the criteria of the BELIEVE protocol, in particular those with a β0/β0 genotype and despite the dose increase, the variability of the interpersonal and intra-personal response to luspatercept over time should be considered.
5. Adverse Events
- Question 35: How frequent is bone pain?
- Question 36: How long after the injection can the patient experience pain?
- Question 37: Does luspatercept-related bone pain represent a limitation for the patient?
- Question 38: What is the most effective treatment for luspatercept-related pain?
- Question 39: Is it advisable to administer paracetamol before luspatercept to prevent the pain?
- Question 40: For how long is pain present?
- Question 41: How frequent is the risk of hypertension in thalassemic patients treated with luspatercept?
- Question 42: If a patient develops hypertension, is it advisable to interrupt treatment?
If the patient develops hypertension, the panel recommends the prescription of a therapy for the management of hypertension and to consider postponing the administration of the drug in the case of an adverse event.
- GENERAL CONSIDERATIONS, SECTION IV—ADVERSE EVENTS
- Question 43: Can an already hypertensive patient be a candidate for luspatercept therapy?
It is recommended that uric acid levels be periodically monitored and current indications for the management of hyperuricemia be followed.
- NEOPLASTIC RISK
- Question 44: Is there an increased risk of cancer in those receiving luspatercept treatment?
- GENERAL CONSIDERATIONS
- Question 45: Are there any precautions to be observed when first administering luspatercept?
It is recommended that the patient’s state of health is assessed, monitoring vital signs and hematological parameters before each administration.
- Question 46: How long should the patient be observed for possible adverse reactions after luspatercept administration?
It is prudentially suggested to keep the patient in the clinic for about 15 min after the injection.
- Question 47: If a patient experiences a side effect during therapy, should the treatment be stopped?
- Postpone the administration of the drug until the reaction has improved and then restart treatment, according to the clinician’s judgment, at the same previous dose or at a reduced dose (for example, 1 mg/Kg if the event occurred at a dosage of 1.25 mg/Kg or 0.8 mg/Kg if the event occurred at a dosage of 1 mg/Kg).
- Discontinue treatment if the adverse event is considered unacceptable.
At the time of therapy proposal, it is recommended that the patient be informed of the possible expected adverse events and to discuss the treatment management, including dose reduction or delays.
6. Concurrent Therapies
- Question 48: Are there known drug interactions between luspatercept and other compounds?
- Question 49: Are any therapies to be modified, discontinued, or combined when a patient starts receiving luspatercept?
- Question 50: Are there any therapies that contraindicate the use of luspatercept?
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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Longo, F.; Motta, I.; Pinto, V.; Piolatto, A.; Ricchi, P.; Tartaglione, I.; Origa, R. Treating Thalassemia Patients with Luspatercept: An Expert Opinion Based on Current Evidence. J. Clin. Med. 2023, 12, 2584. https://doi.org/10.3390/jcm12072584
Longo F, Motta I, Pinto V, Piolatto A, Ricchi P, Tartaglione I, Origa R. Treating Thalassemia Patients with Luspatercept: An Expert Opinion Based on Current Evidence. Journal of Clinical Medicine. 2023; 12(7):2584. https://doi.org/10.3390/jcm12072584Chicago/Turabian Style
Longo, Filomena, Irene Motta, Valeria Pinto, Andrea Piolatto, Paolo Ricchi, Immacolata Tartaglione, and Raffaella Origa. 2023. "Treating Thalassemia Patients with Luspatercept: An Expert Opinion Based on Current Evidence" Journal of Clinical Medicine 12, no. 7: 2584. https://doi.org/10.3390/jcm12072584