-
1.
Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial
van de Loosdrecht, A. A., Cremers, E. M. P., Alhan, C., Duetz, C., In 't Hout, F. E. M., Visser-Wisselaar, H. A., Chitu, D. A., Verbrugge, A., Cunha, S. M., Ossenkoppele, G. J., et al
Leukemia. 2024
Abstract
A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).
-
2.
Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency
van Beers, E. J., Al-Samkari, H., Grace, R. F., Barcellini, W., Glenthøj, A., DiBacco, M., Wind-Rotolo, M., Xu, R., Beynon, V., Patel, P., et al
Blood advances. 2024
-
-
-
-
Editor's Choice
Abstract
Pyruvate kinase (PK) deficiency is a rare, hereditary disease characterized by chronic hemolytic anemia. Iron overload is a common complication regardless of age, genotype, or transfusion history. Mitapivat, an oral, allosteric PK activator, improves anemia and hemolysis in adult patients with PK deficiency. Mitapivat's impact on iron overload and ineffective erythropoiesis was evaluated in adults with PK deficiency who were not regularly transfused in the phase 3 ACTIVATE trial and long-term extension (LTE) (NCT03548220/NCT03853798). Patients in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to Week [W] 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to W24) to mitapivat (W24 to 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to W96. Improvements in hepcidin (mean [95% confidence interval ⟨CI ⟩] 4770.0 ng/L [-1532.3, 11,072.3], erythroferrone (-9834.9 ng/L [-14,328.4, -5341.3]), soluble transferrin receptor (-56.0 nmol/L [-84.8, -27.2]), and erythropoietin (-32.85 IU/L [-54.65, -11.06]) were observed in the M/M arm (n=40) from baseline to W24, sustained to W96. No improvements were observed in the P/M arm (n=40) to W24; however, upon transitioning to mitapivat, improvements similar to the M/M arm were seen. Mean (95% CI) changes from baseline in liver iron concentration (LIC) by magnetic resonance imaging (MRI) at W96 were -2.0 mg Fe/g dry weight (dw) (-4.8, -0.8; M/M arm) and -1.8 mg Fe/g dw (-4.4, 0.80; P/M arm). Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency.
PICO Summary
Population
Adults with pyruvate kinase deficiency not regularly transfused, enrolled in the phase 3 ACTIVATE clinical trial and long term extension (LTE) (n= 80).
Intervention
Mitapivat throughout ACTIVATE/LTE baseline to week (W) 96 (mitapivat-to-mitapivat M/M arm, n= 40).
Comparison
Switched from placebo (baseline to W24) to mitapivat W24 to 96 (placebo-to-mitapivat P/M arm, n= 40).
Outcome
Changes from baseline in markers of iron overload and erythropoiesis were assessed to W96. Improvements in hepcidin (mean [95% confidence interval (CI)] 4770.0 ng/L [-1532.3, 11,072.3]), erythroferrone (-9834.9 ng/L [-14,328.4, -5341.3]), soluble transferrin receptor (-56.0 nmol/L [-84.8, -27.2]), and erythropoietin (-32.85 IU/L [-54.65, -11.06]) were observed in the M/M arm from baseline to W24, sustained to W96. No improvements were observed in the P/M arm to W24; however, upon transitioning to mitapivat, improvements similar to the M/M arm were seen. Mean (95% CI) changes from baseline in liver iron concentration by magnetic resonance imaging at W96 were -2.0 mg Fe/g dry weight (dw) (-4.8, -0.8; M/M arm) and -1.8 mg Fe/g dw (-4.4, 0.80; P/M arm).
-
3.
Ferric carboxymaltose effects on restless legs syndrome and on brain iron in patients with iron deficiency anemia
Bae, H., Cho, Y. W., Kim, K. T., Li, X., Earley, C. J.
Sleep medicine. 2023;109:128-131
Abstract
OBJECTIVE Brain iron status is fundamental in RLS pathogenesis. The aim of this study was to determine the clinical efficacy and brain iron concentration improvement in RLS patients with IDA, using 1500 mg FCM. METHODS This is a randomized, double-blinded, placebo-controlled study. RLS patients with IDA were grouped into either 1500 mg FCM or placebo. The primary outcomes were the change from baseline on the International Restless Legs Syndrome Study Group scale (IRLS) and brain iron measured by QSM and R2∗. RESULTS A total of 18 RLS patients with IDA were enrolled, 10 in the FCM group and 8 in the placebo. At the week 6 endpoint, the FCM group showed significant improvement in both IRLS (-13.60 ± 9.47 vs. -3.63 ± 5.40, p = 0.011) and VAS (-40.50 ± 28.81 vs. -0.63 ± 28.28, p = 0.004) from baseline. Change from baseline with R2∗ techniques showed a treatment effect for the thalamus and QSM technique for both the substantia nigra and pulvinar. A correlation was proved between the IRLS difference and the difference of QSM in thalamus (p = 0.028). CONCLUSION This study demonstrates that 1500 mg FCM effectively treats RLS symptoms in IDA patients over six weeks, with MRI measurements of improved brain iron content serving as a potential biomarker for RLS patients.
-
4.
Health-related quality of life in patients with β-thalassemia: Data from the phase 3 BELIEVE trial of luspatercept
Cappellini MD, Taher AT, Piga A, Shah F, Voskaridou E, Viprakasit V, Porter JB, Hermine O, Neufeld EJ, Thompson AA, et al
European journal of haematology. 2023
Abstract
BACKGROUND Patients with transfusion-dependent (TD) β-thalassemia require long-term red blood cell transfusions (RBCTs) that lead to iron overload, impacting health-related quality of life (HRQoL). METHODS The impact of luspatercept, a first-in-class erythroid maturation agent, versus placebo on HRQoL of patients with TD β-thalassemia was evaluated in the phase 3 BELIEVE trial. HRQoL was assessed at baseline and every 12 weeks using the 36-item Short Form Health Survey (SF-36) and Transfusion-dependent Quality of Life questionnaire (TranQol). Mean change in HRQoL was evaluated from baseline to week 48 for patients receiving luspatercept + best supportive care (BSC) and placebo + BSC and between luspatercept responders and non-responders. RESULTS Through week 48, for both groups, mean scores on SF-36 and TranQol domains were stable over time and did not have a clinically meaningful change. At week 48, more patients who achieved clinical response (≥50% reduction in RBCT burden over 24 weeks) in the luspatercept + BSC group had improvement in SF-36 Physical Function compared with placebo + BSC (27.1% vs. 11.5%; p = .019). CONCLUSIONS Luspatercept + BSC reduced transfusion burden while maintaining patients' HRQoL. HRQoL domain improvements from baseline through 48 weeks were also enhanced for luspatercept responders.
-
5.
Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial
Platzbecker, U., Della Porta, M. G., Santini, V., Zeidan, A. M., Komrokji, R. S., Shortt, J., Valcarcel, D., Jonasova, A., Dimicoli-Salazar, S., Tiong, I. S., et al
Lancet (London, England). 2023
-
-
-
Full text
-
Editor's Choice
Abstract
BACKGROUND Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial. METHODS The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting). FINDINGS Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment). INTERPRETATION In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups. FUNDING Celgene and Acceleron Pharma.
PICO Summary
Population
Patients who were erythropoiesis-stimulating agent naive, transfusion-dependent, and diagnosed with lower-risk myelodysplastic syndromes, enrolled in the COMMANDS trial in 26 countries (n= 356).
Intervention
Luspatercept (n= 178).
Comparison
Epoetin alfa (n= 178).
Outcome
The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1.5 g/dL (weeks 1-24), assessed in the intention-to-treat population. The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26.6; 95% CI [15.8, 37.4]). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) vs. epoetin alfa (27 weeks [19-55]).
-
6.
Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study
Germing, U., Fenaux, P., Platzbecker, U., Buckstein, R., Santini, V., Díez-Campelo, M., Yucel, A., Tang, D., Fabre, S., Zhang, G., et al
Annals of Hematology. 2023;102(2):311-321
Abstract
Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients' baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25-48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.
-
7.
A Phase 2 Randomized Controlled Trial of Single-Agent Hydroxyurea Versus Thalidomide Among Adult Transfusion Dependent β Thalassemia Patients
Bhattacharjee U, Khadwal A, Shafiq N, Lad D, Sharma P, Das R, Shukla P, Jain A, Prakash G, Malhotra P
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2023;:1-10
Abstract
Hydroxyurea and low dose thalidomide are low-cost, easily accessible Hb F inducing agents that have been found to decrease transfusion dependency among transfusion-dependent thalassemia patients. However, these drugs have not much been explored in a randomized controlled setting. The objective of this study was to determine the efficacy and safety of hydroxyurea and low dose thalidomide in adult transfusion dependent β thalassemia. A total of 39 transfusion dependent β thalassemia patients were randomized into three arms: Arm A (Hydroxyurea 500 mg/day), Arm B (thalidomide 50 mg/day), and Control Arm. The primary outcome was rise in haemoglobin at 24-weeks from the baseline levels. The mean age of the cohort was 26.9 ± 4.7 years. Total 13 patients (33.3%) were splenectomised. The mean rise of haemoglobin at the end of 24 weeks was 0.18 ± 0.645 g/dl, 0.56 ± 1.343 g/dl, and - 0.31 ± 0.942 g/dl in Arm A, Arm B and control arm, respectively, p = 0.127. The mean volume of blood transfused per unit body weight in 24 weeks was significantly less in the thalidomide arm compared with the control arm (p = 0.035). Abdominal pain (Grade 1-2, 23.1%) and pruritus (Grade 1, 15.4%) were the main adverse events in hydroxyurea arm, whereas somnolence was the main side effect noted in the thalidomide arm (Grade 1-2, 78.3%). Single agent hydroxyurea or thalidomide is ineffective in increasing haemoglobin and decreasing transfusion burden among majority of the adult transfusion dependent thalassemia patients. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s12288-022-01620-3.
-
8.
A randomized controlled trial of thrice-weekly versus thrice-daily oral ferrous fumarate treatment in adult patients with iron-deficiency anemia
Jongkraijakra S, Doungngern T, Sripakdee W, Lekhakula A
Annals of hematology. 2023;102(6):1333-1340
Abstract
Iron deficiency anemia (IDA) is a common health problem in developing countries. Many studies have shown that low-dose oral iron could have similar efficacy and less gastrointestinal effects in iron deficiency without anemia. This prospective open-labeled randomized controlled study was designed to compare the response of 200 mg ferrous fumarate thrice-weekly (TIW) as not inferior to the thrice-daily (TID) regimen and to assess the incidence of adverse events (AEs) between two regimens in treating adult patients with IDA. The primary endpoint was either an increase in Hb ≥ 3 g/dL, having Hb of 12 g/dL in females or 13 g/dL in males at the 12th week of treatment. Secondary outcomes included adverse events (AEs), red blood cell indices, iron profiles, and patient compliance. Sixty-four patients were randomized: 32 in the TIW arm and the other 32 in the TID arm. The response rates were not different between two arms either with intention to treat analysis (72.0%, 95%CI 56.6-88.5 vs. 71.9%, 95%CI 53.3-86.3, p = 0.777); or per-protocol analysis (88.9%, 95%CI 70.8-97.6 vs. 88.5%, 95%CI 69.8-97.6, p = 1.0), respectively. The trial demonstrated non-inferiority at a margin of 23%. Although the iron profile response of the TID arm was earlier than the TIW arm, almost all patients recovered from anemic symptoms at week 4, and hematologic responses were not different at week 12. There were more gastrointestinal AEs in the TID arm. In conclusion, this study showed that the TIW was non-inferior to the TID iron treatment of IDA patients but less AEs and costs.
-
9.
Biomarkers of erythropoiesis response to intravenous iron in a crossover pilot study in unexplained anemia of the elderly
Yoo JJ, Cohen HJ, Artz AS, Price E, Fill JA, Prchal J, Sapp S, Barnhart H
Hematology (Amsterdam, Netherlands). 2023;28(1):1-8
Abstract
Anemia is common in older adults, but often unexplained. Previously, we conducted a randomized, controlled trial of intravenous (IV) iron sucrose to study its impact on the 6-minute walk test and hemoglobin in older adults with unexplained anemia and ferritin levels of 20-200 ng/mL. In this report, we present for the first time the response of hemoglobin, as well as the dynamic response of biomarkers of erythropoiesis and iron indices, in a pooled analysis of the initially IV iron-treated group of 9 subjects and the subsequently IV iron treated 10 subjects from the delayed treatment group. We hypothesized that there would be a reproducible hemoglobin response from IV iron, and that iron indices and erythropoietic markers would reflect appropriate iron loading and reduced erythropoietic stress. To investigate the biochemical response of anemia to IV iron, we studied the dynamics of soluble transferrin receptor (STfR), hepcidin, erythropoietin (EPO), and iron indices over 12 weeks after treatment. In total, all 19 treated subjects were evaluable: 9 from initial treatment and 10 after cross-over. Hemoglobin rose from 11.0 to 11.7 g/dL, 12 weeks after initiating IV iron treatment of 1000 mg divided weekly over 5 weeks. We found early changes of iron loading after 1-2 IV iron dose: serum iron increased by 184 mcg/dL from a baseline of 66 mcg/dL, ferritin by 184 ng/mL from 68 ng/mL, and hepcidin by 7.49 ng/mL from 19.2 ng/mL, while STfR and serum EPO declined by 0.55 mg/L and 3.5 mU/mL from 19.2 ng/mL and 14 mU/mL, respectively. The erythroid response and evidence of enhanced iron trafficking are consistent with the hypothesis that IV iron overcomes iron deficient or iron-restricted erythropoiesis. These data provide new insight that iron-restricted erythropoiesis is a potential and targetable mechanism for patients diagnosed with unexplained anemia of the elderly and offers support for larger prospective trials of IV iron among anemic older adults of low to normal ferritin.
-
10.
A randomized, controlled, open label non-inferiority trial of intravenous ferric carboxymaltose versus iron sucrose in patients with iron deficiency anemia in China
Jin, J., Ran, Z., Noseda, E., Roubert, B., Marty, M., Mezzacasa, A., Göring, U. M.
Frontiers of medicine. 2023
Abstract
Iron deficiency (ID) and ID anemia (IDA) pose significant public health concerns in China. Although iron sucrose (IS) treatment is well-established in the country, ferric carboxymaltose (FCM) offers the advantage of higher doses and fewer infusions. This open label, randomized, controlled, non-inferiority trial was conducted at multiple sites in China to compare the outcomes of FCM (maximum of 2 doses, 500 or 1000 mg iron) and IS (up to 11 infusions, 200 mg iron) treatments in subjects with IDA. The primary endpoint was the achievement of hemoglobin (Hb) response (an increase of ⩾2 g/dL from baseline) within 8 weeks, whereas secondary endpoints included changes in Hb, transferrin saturation, and serum ferritin levels. Among the 371 randomized subjects, a similar percentage of subjects treated with FCM and IS achieved Hb-response (FCM 99.4%, IS 98.3%), thereby confirming the non-inferiority of FCM compared with IS (difference 1.12 (-2.15, 4.71; 95% confidence interval (CI))). Furthermore, a significantly higher proportion of FCM-treated subjects achieved early Hb-response at Week 2 (FCM 85.2%, IS 73.2%; difference 12.1 (3.31, 20.65; 95% CI)). Additionally, the increase in TSAT and serum ferritin levels from baseline was significantly greater at all time points for FCM-treated subjects. The safety profiles of FCM and IS were comparable, with the exception of transient hypophosphatemia and pyrexia, which are consistent with FCM's known safety profile. In conclusion, FCM proves to be an efficacious treatment for IDA, providing faster Hb-response and correction of ID with fewer administrations than IS.