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Editor's Choice
  • van Beers EJ
  • Al-Samkari H
  • Grace RF
  • Barcellini W
  • Glenthøj A
  • et al.
Blood Adv. 2024 May 28;8(10):2433-2441 doi: 10.1182/bloodadvances.2023011743.
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).

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 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to week 24) to mitapivat (week 24 to week 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to week 96. Improvements in hepcidin (mean, 4770.0 ng/L; 95% confidence interval [CI], -1532.3 to 11 072.3), erythroferrone (mean, -9834.9 ng/L; 95% CI, -14 328.4 to -5341.3), soluble transferrin receptor (mean, -56.0 nmol/L; 95% CI, -84.8 to -27.2), and erythropoietin (mean, -32.85 IU/L; 95% CI, -54.65 to -11.06) were observed in the M/M arm (n = 40) from baseline to week 24, sustained to week 96. No improvements were observed in the P/M arm (n = 40) to week 24; however, upon transitioning to mitapivat, improvements similar to those observed in the M/M arm were seen. Mean changes from baseline in liver iron concentration by magnetic resonance imaging at week 96 in the M/M arm and the P/M arm were -2.0 mg Fe/g dry weight (dw; 95% CI, -4.8 to -0.8) and -1.8 mg Fe/g dw (95% CI, -4.4 to 0.80), respectively. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency. This trial was registered at www.ClinicalTrials.gov as #NCT03548220 (ACTIVATE) and #NCT03853798 (LTE).

Editor's Choice
  • Saraf SL
  • Hagar RW
  • Idowu M
  • Osunkwo I
  • Cruz K
  • et al.
Blood Adv. 2024 Apr 19; doi: 10.1182/bloodadvances.2023012467.
POPULATION:

Patients with sickle cell disease (SCD) (n= 36).

INTERVENTION:

Single dose cohort: etavopivat 700mg (n= 5); placebo (n= 2). Multiple ascending doses (MAD) cohort: etavopivat 300mg (MAD1, n= 8); etavopivat 600mg (MAD2, n= 8); placebo (n= 4). Open label (OL) cohort: etavopitat 400mg (n= 15).

COMPARISON:

OUTCOME:

The single dose portion of the study was conducted to confirm the safety and pharmacokinetic/pharmacodynamic response to 700-mg. All patients in the single dose and MAD cohorts completed the study. Fourteen of 15 patients in the OL cohort (including 6 patients from the MAD cohorts who elected to roll over) completed the study; 1 withdrew due to an adverse event (AE). Increases in ATP and decreases in 2, 3 diphosphoglycerate were observed and sustained over 12 weeks' treatment. This translated clinically to an increase in haemoglobin (mean maximal increase 1.6 [range= 0.8, 2.8] g/dL), with >1 g/dL increase in 11 (73%) patients during treatment. Additionally, oxygen tension at which haemoglobin is 50% saturated was reduced with concomitant shift in point-of-sickling to lower oxygen tension in oxygen-gradient ektacytometry. Haemolysis markers decreased from baseline, along with matrix metalloproteinase-9 and erythropoietin. In the OL cohort, adverse events were mostly grade 1/2, consistent with underlying SCD; 5 patients had serious AEs. Vaso-occlusive pain episode was the most common treatment-emergent AE (n= 7) in the OL cohort.

Etavopivat is an investigational, once-daily, oral, selective erythrocyte pyruvate kinase (PKR) activator. A multicenter, randomized, placebo-controlled, double-blind, 3-part, phase 1 study (https://clinicaltrials.gov/study/NCT03815695) was conducted to characterize the safety and clinical activity of etavopivat. Thirty-six patients with sickle cell disease (SCD) were enrolled into 4 cohorts: one single-dose; two multiple ascending doses; one open-label [OL]. In the OL cohort, 15 patients (median age 33.0 [range, 17‒55] years received 400-mg etavopivat once daily for 12 weeks; 14 completed treatment. Consistent with the mechanism of PKR activation, increases in ATP and decreases in 2,3 diphosphoglycerate were observed and sustained over 12 weeks' treatment. This translated clinically to an increase in hemoglobin (mean maximal increase 1.6 [range, 0.8‒2.8] g/dL), with >1 g/dL increase in 11 (73%) patients during treatment. Additionally, oxygen tension at which hemoglobin is 50% saturated was reduced (P=.0007) with concomitant shift in point-of-sickling (P=.0034) to lower oxygen tension in oxygen-gradient ektacytometry. Hemolysis markers (absolute reticulocyte count, indirect bilirubin, lactate dehydrogenase) decreased from baseline, along with matrix metalloproteinase-9 and erythropoietin. In the OL cohort, adverse events (AEs) were mostly grade 1/2, consistent with underlying SCD; 5 patients had serious AEs. Vaso-occlusive pain episode was the most common treatment-emergent AE (n=7) in the OL cohort. In this first study of etavopivat in SCD, 400 mg once daily for 12 weeks was well-tolerated, resulting in rapid and sustained increases in hemoglobin, improved RBC physiology, and decreased hemolysis.

Editor's Choice
  • Zhang Y
  • Li J
  • Li X
  • Geng Q
  • Xie Y
  • et al.
Syst Rev. 2024 Apr 4;13(1):101 doi: 10.1186/s13643-024-02515-2.
POPULATION:

Patients with severe aplastic anaemia (16 studies, n= 2,148).

INTERVENTION:

Immunosuppressive therapy (IST) combined with eltrombopag (EPAG).

COMPARISON:

Immunosuppressive therapy.

OUTCOME:

The IST combined with the EPAG group had higher overall response rate (ORR) than the IST group at 3 months (pooled OR 2.10; 95% CI [1.58, 2.79]) and 6 months (pooled OR 2.13; 95% CI [1.60, 2.83]), but the difference between the two groups became statistically insignificant at 12 months (pooled OR 1.13; 95% CI [0.75, 1.72]). The results of complete response rate (pooled OR at 3 months 2.73; 95% CI [1.83, 4.09], 6 months 2.76; 95% CI [2.08, 3.67] and 12 months 1.38; 95% CI [0.85, 2.23]) were similar to ORR. Compared with the IST group, the IST combined with the EPAG group had better overall survival rate (pooled OR 1.70; 95% CI [1.15, 2.51]), but there were no statistically significant differences in event-free survival rate (pooled OR 1.40; 95% CI [0.93, 2.13]), clonal evolution rate (pooled OR 0.68; 95% CI [0.46, 1.00]) and other adverse events between the two groups.

BACKGROUND AND OBJECTIVE:

Immunosuppressive therapy (IST) is the first choice for severe aplastic anemia (SAA) patients with hematopoietic stem cell transplantation (HSCT) limitation, and the main factor limiting its efficacy is too few residual hematopoietic stem/progenitor cells (HSPC). Eltrombopag (EPAG), as a small molecule thrombopoietin receptor agonist, can stimulate the proliferation of residual HSPC and restore the bone marrow hematopoietic function of patients. In recent years, many studies have observed the efficacy and safety of IST combined with EPAG in the treatment of SAA, but the results are still controversial. The aim of this study is to systematically evaluate the efficacy and safety of IST combined with or without EPGA in the treatment of SAA.

METHODS:

We conducted a systematic review of all relevant literature published up to January 19, 2024. Pooled odds ratio (OR) was calculated to compare the rates, along with 95% confidence intervals (CI) and p value to assess whether the results were statistically significant by Review Manager 5.4.1. The p values for the interactions between each subgroup were calculated by Stata 15.1. The Newcastle-Ottawa Scale and the Cochrane bias risk assessment tools were respectively used to evaluate the quality of the literature with cohort studies and randomized controlled trials. The Review Manager 5.4.1 and Stata 15.1 were used to assess bias risk and perform the meta-analysis.

RESULTS:

A total of 16 studies involving 2148 patients were included. The IST combined with the EPAG group had higher overall response rate (ORR) than the IST group at 3 months (pooled OR = 2.10, 95% CI 1.58-2.79, p < 0.00001) and 6 months (pooled OR = 2.13, 95% CI 1.60-2.83, p < 0.00001), but the difference between the two groups became statistically insignificant at 12 months (pooled OR = 1.13, 95% CI 0.75-1.72, p = 0.55). The results of complete response rate (CRR) (pooled OR at 3 months = 2.73, 95% CI 1.83-4.09, p < 0.00001, 6 months = 2.76, 95% CI 2.08-3.67, p < 0.00001 and 12 months = 1.38, 95% CI 0.85-2.23, p = 0.19) were similar to ORR. Compared with the IST group, the IST combined with the EPAG group had better overall survival rate (OSR) (pooled OR = 1.70, 95% CI 1.15-2.51, p = 0.008), but there were no statistically significant differences in event-free survival rate (EFSR) (pooled OR = 1.40, 95% CI 0.93-2.13, p = 0.11), clonal evolution rate (pooled OR = 0.68, 95% CI 0.46-1.00, p = 0.05) and other adverse events between the two groups. The results of subgroup analysis showed that different ages were a source of heterogeneity, but different study types and different follow-up times were not. Moreover, all p-values for the interactions were greater than 0.05, suggesting that the treatment effect was not influenced by subgroup characteristics.

CONCLUSION:

EPAG added to IST enables patients to achieve earlier and faster hematologic responses with a higher rate of complete response. Although it had no effect on overall EFSR, it improved OSR and did not increase the incidence of clonal evolution and other adverse events.

Editor's Choice
  • Poston JN
  • Brown SP
  • Ilich A
  • Ginsburg AS
  • Herren H
  • et al.
Res Pract Thromb Haemost. 2024 Mar 1;8(2):102358 doi: 10.1016/j.rpth.2024.102358.
POPULATION:

Adult patients with a haematologic malignancy or aplasia undergoing chemotherapy, immunotherapy, or haematopoietic stem cell transplant, enrolled in the A-TREAT trial (n= 326).

INTERVENTION:

Tranexamic acid (TXA) (n= 163).

COMPARISON:

Placebo (n= 163).

OUTCOME:

This study was a post hoc analysis of the A-TREAT clinical trial data. TXA did not change the overall rate of infections, but the rate of severe infections (Common Toxicology Criteria for Adverse Events grade 3+) was lower in patients who received TXA compared with the placebo group. Patients who experienced grade 3+ infections had higher rates of World Health Organization grade 2+ bleeding and red blood cell transfusion requirements than patients who did not experience a grade 3+ infection, irrespective of treatment group. TXA did not impact other inflammatory outcomes such as mucositis, rash, or graft vs. host disease.

BACKGROUND:

Tranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding in a multitude of clinical settings from postpartum hemorrhage to trauma. TXA may have clinical effects unrelated to bleeding; plasminogen, the target of TXA, alters immune responses, and TXA appears to decrease the risk of infection in patients undergoing cardiac surgery, as well as joint arthroplasty.

OBJECTIVES:

To address whether TXA alters rates of infection and inflammatory outcomes in patients with hematologic malignancies.

METHODS:

We performed a post hoc analysis of outcomes of patients randomized to receive either TXA or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (Clinicaltrials.gov identifier: NCT02578901).

RESULTS:

TXA did not change the overall rate of infections, but the rate of severe infections (Common Toxicology Criteria for Adverse Events grade 3+) was lower in patients who received TXA compared with the placebo group. Patients who experienced grade 3+ infections had higher rates of World Health Organization grade 2+ bleeding and red blood cell transfusion requirements than patients who did not experience a grade 3+ infection, irrespective of treatment group. TXA did not impact other inflammatory outcomes such as mucositis, rash, or graft vs host disease.

CONCLUSION:

Patients with hematologic malignancies who received TXA had less severe infections than those who received placebo with no difference in overall rate of infection or other inflammatory outcomes. Further investigation is needed on the impact of TXA on infections in this population.