Taher, Ali T., Maria Domenica Cappellini, Antonis Kattamis, Ersi Voskaridou, Silverio Perrotta, Antonio G. Piga, Aldo Filosa et al. “Luspatercept for the treatment of anaemia in non-transfusion-dependent β-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial.” The Lancet Haematology 9, no. 10 (2022): e733-e744.
Clinical Question
In patients with non-transfusion dependent beta thalassemia with Hb<10, does the use of luspatercept result in a meaningful increase in Hb concentration, improvement in health-related quality of life and is its use safe?
Background
Anemia in non-transfusion dependent thalassemia (NTDT) patients can result in serious long term health complications related to chronic hemolytic anemia and ineffective erythropoiesis and resultant hypercoagulable state and iron overload. NTDT patients often experience reduced functional status, poor health related quality of life and increased risk of mental health consequences. Prior studies suggest that an increase in Hb by even 1g/dL in patients with beta thalassemia can result in improvement in these outcomes. Despite this burden there are no FDA approved agents beyond supportive care for increasing the Hb in this patient population.
The non-transfusion dependent beta thalassemia patient reported outcome (NTDT- PRO) instrument was developed to evaluate symptom burden, specifically assessing tiredness, weakness and dyspnea in this patient population. Scores range from 0 (absent) to 10 (extreme) and scores of 3 or higher are indicative of symptomatic non-transfusion dependent beta thalassemia. This therefore serves as a clinically relevant tool for evaluating treatment benefit from a patient perspective.
The SMAD2-SMAD3 pathway is activated in the bone marrow of patients with MDS and in models of ineffective erythropoiesis such as patients with beta thalassemia. Luspatercept is a recombinant fusion protein that acts as a ligand trap for the TGF beta superfamily ligands, reducing signaling and thereby promoting late stage erythroid maturation. Luspatercept has been found to result in decreased red cell transfusion burden in patients with transfusion dependent beta thalassemia and preliminary studies have indicated that it may also result in improvement in quality of life metrics all while having a manageable side effect profile.
Guidelines
“Patients with any degree of anaemia combined with ineffective erythropoiesis/anaemia-related symptoms or complications may also be considered for short/limited-term intervention to raise haemoglobin levels and alleviate their symptoms, especially in instances where evidence of benefit is established.”
Study Design
- Multicenter, randomized double-blind, placebo-controlled phase 2 trial
- Setting: Thailand, Italy, United Kingdom, the United States, Lebanon and Greece
- N= 145
- 96 in luspatercept group
- 49 in placebo group
- Enrollment period- Feb 5, 2018- Oct 14, 2019
- Double blind treatment period lasted 48 weeks
- Analysis: Intention to treat
- Primary outcomes: increase in Hb by 1g/dL or higher from baseline over a continuous 12 week interval (weeks 13-24) in the absence of red blood cell transfusion.
- Key secondary outcomes:
- Mean change in NTDT-PRO tool tiredness/weakness domain score over a continuous 12 week period (weeks 13-24)
- Mean change from baseline in Hb concentration over a continuous 12 week interval (weeks 13-24)
- Proportion of patients with a mean Hb increase of 1g/dL or higher from baseline over a continuous 12 week period (weeks 37-48)
- Key safety outcomes were graded according to the common terminology criteria for adverse events report system version 4.03. Events of particular interest included thromboembolic events and malignancies.
- Additional analyses included post-hoc analysis of the correlation between the change in NTDT-PRO tool T/W domain score and hemoglobin response and the NTDT-PRO tired/weakness domain score improvement by clinical response status and by visit.
Populations
- Inclusion Criteria
- 18 years or older
- Confirmed diagnosis of beta thalassemia or HbE/beta thalassemia (noting that concomitant alpha globin deletions, mutations or duplications were allowed)
- Baseline Hb<10 at screening
- Non-transfusion dependent- defined as receiving <5 transfusions of red blood cells over a 24 week period
- Free from red blood cell transfusion for >8 weeks prior to randomization
- Key exclusion criteria:
- Diagnosis of HbS/beta thalassemia or alpha thalassemia
- Active hepatitis B or C infection
- HIV infection
- Any other medical or laboratory condition that could have put them at risk if they were to participate in the study or may have confounded the interpretation of study data
- Uncontrolled HTN
- Major organ damage
- Prior malignancies
- Psychiatric illness
- Severe allergies or anaphylactic reactions to recombinant proteins
- Receiving anticoagulant therapy
- Use of hydroxyurea or ESA < 24 weeks prior to randomization
- Pregnant or lactating females
- Previous treatment with luspatercept or sotaracept
- Baseline characteristics
- 160 patients assessed for eligibility
- 145 randomized. Median age of randomized patients was 40 (range 29-47) with 57% of participants being female.
- Of the 96 patients assigned to the lupatercerpt group 37% were younger than 32 yrs, 43% between the ages of 33 and 50 and 21% older than 50.
- Of the 49 patients assigned to the placebo group, 25% were younger than 32, 53% between the ages of 33 and 50 and 22% older than 50.
- The 2 groups were relatively well matched on race, BMI, ECOG performance status, beta-thalassemia diagnosis and genotype, baseline Hb concentration, transfusion burden and NTDT-PRO T/W domain score.
- Proportionally speaking, more patients in the placebo group had baseline serum ferritin >800.
Intervention
- Patients were randomized 2:1 to luspatercept or placebo
- Luspatercept was given SC 1mg/kg every 3 weeks for 48 weeks with some patients having dose escalation to 1.25mg/kg if no response.
- After unblinding, there was an open-label extension. Some patients who benefited were then continued on luspatercept for an additional 15 months
- Luspatercept was given SC 1mg/kg every 3 weeks for 48 weeks with some patients having dose escalation to 1.25mg/kg if no response.
- Patients in both groups continued to receive best supportive care inclusive of iron chelation and blood transfusions as needed
Outcomes
- Primary efficacy endpoint:
- 77% of patients assigned to luspatercept vs 0% assigned to placebo achieved an increase from baseline of >1g/dL in mean hemoglobin values over a continuous 12-week interval in the absence of transfusion. Result was statistically significant with p<0.001.
- Secondary efficacy endpoints:
- The mean change from baseline in the NTDT-PRO T/W domain scoreover a continuous 12 week interval in patients assigned to the lupatercept group was -0.68 and -0.20 in the placebo group. These results were not statistically significant with a p value of 0.092 obtained.
- The mean change in Hb from baseline over a continuous 12-week interval in the absence of transfusions was 1.48 in the luspatercept group and 0.07 in the placebo group. Results were statistically significant with a p value of <0.0001 obtained.
- 71% of individuals assigned to the luspatercept group had an increase in Hb > 1g/dl from baseline over a continuous 12 week interval in the absence of transfusion compared to 2% assigned to the placebo group. Results were statistically significant with a p value of <0.0001 obtained
- Safety:
- 99% of patients experienced one or more treatment emergent adverse events. With 27% experiencing one or more grade 3-4 events.
- Most common adverse event reported in the luspatercept group were bone pain, headache, arthralgia, back pain, prehypertension and hypertension with the highest incidence occurring during cycles 1-4 of treatment, decreasing thereafter.
- There were no thromboembolic events, no malignancies or deaths occurring in the luspatercept group during the trial period.
- Reported post-hoc analysis:
- Luspatercept responders (patients who had the mean Hb increase of >1g/dL during weeks 13-24) had a greater magnitude of improvement of NTDT-PRO tool T/W domain score during weeks 13-24 (mean difference of -0.70) and weeks 37-48 (mean difference of -1.28) than did patients receiving placebo who were all non-responders.
- As Hb concentrations increased the NTDT-PRO tool T/W domain scores decreased.
Commentary and Intepretation:
In this trial by Taher et al, in patients with non-transfusion dependent beta thalassemia with a baseline hemoglobin of <10 g/dL, the use of luspatercept results in a significant increase in Hb concentration by more than 1g/dL over a 12 week period of continuous use in the absence of transfusion. The drug did not result in a statistically significant improvement in NTDT-PRO weakness/tiredness domain scores but there was a trend towards improved scores as Hb concentration increased, implying that longer term follow up or larger sample size may be required.
In addition to being efficacious the drug was well tolerated with the most common reported adverse events being bone pain, headaches and arthralgia with events decreasing after cycle 4 of treatment.
The major limitations of the study include the fact that there were issues with enrollment, with one site in Italy not enrolling any patients. Initially it was calculated that 150 patients were needed in order for the study to be adequately powered to detect the difference between the treatment and placebo groups, however only 145 patients were enrolled. It was however ultimately concluded that this did not compromise the assumptions of the planned statistical analyses and that it still retained 99% power to detect the difference between the two groups for the primary endpoint and 89% power to detect the difference between the two groups for the key secondary efficacy endpoints. Challenges with recruitment may also have introduced selection bias and may limit the generalizability of the findings to the broader NTDT patient community.
While it was a multicenter international trial many patients were treated in highly resourced centers. A significant proportion of beta thalassemia patients worldwide hail from developing/middle and lower income nations, additionally the geographic distribution of enrolled patients may have some bearing on the baseline genetic characteristics and specific beta globin mutations observed. Therefore, the observed efficacy and tolerability of luspatercept may not be generalizable to a broader global NTDT population.
In summary luspatercept use in patients with non-transfusion dependent beta thalassemia with a baseline Hb<10g/dL results in an Hb increase of ³1g/dL. The drug is well tolerated. Further study is needed to determine whether the rise in Hb translates to sustained improvement in functional status, quality of life and long-term clinical outcomes.
Jason Lofters MBBS completed medical school at the University of the West Indies, Mona (Jamaica) and then internal medicine residency at Englewood Hospital/Hackensack University Medical Center in New Jersey, where he also served as chief resident. He is a current chief fellow at Boston University Medical Center. His clinical and research interests focus on classical hematology with particular emphasis on red blood cell disorders.
