法国圣路易斯医院Pierre Fenaux联合德国莱比锡大学医院Uwe Platzbecker团队取得一项新突破。他们研究出luspatecept可有效治疗低风险骨髓增生异常综合征患者。相关论文发表在2020年1月9日出版的《新英格兰医学杂志》上。

贫血和低风险骨髓增生异常综合征患者采用促红细胞生成素治疗无效，往往依赖于红细胞输注。luspatecept是一种重组融合蛋白，可结合转化生长因子-β超家族配体，减少SMAD2和SMAD3信号传导，在临床2期的研究中疗效显著。

在一项双盲、安慰剂对照的临床3期试验中，研究组招募了229名患有极低风险、低风险或中等风险骨髓增生异常综合征伴有环状铁幼粒细胞的患者，均曾接受常规红细胞输注，将其分为两组，其中153名接受每3周皮下注射luspatecept，76名接受安慰剂治疗，两组患者一般资料无显著差异。

从治疗第1周至第24周，luspatecept组有38%的患者获得8周及以上的输血独立，显著高于安慰剂组（13%）；luspatecept组有28%的患者获得12周及以上的输血独立，显著高于安慰剂组（8%）。至第48周，luspatecept组共有33%的患者获得12周及以上的输血独立，显著高于安慰剂组（12%）。Luspatecept组中最常见的不良反应为疲劳、腹泻、乏力、恶心和头晕。但不良事件的发生率随治疗时间的推移而逐渐降低。

总之，luspatecept降低了低风险骨髓增生异常综合征伴环状铁幼粒细胞患者贫血的严重程度，这些患者曾接受常规红细胞输注，对促红细胞生成素不敏感或应答不足，或对促红细胞生成素有不良反应而停止服用。

附：英文原文

Title: Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes

Author: Pierre Fenaux, M.D., Ph.D.,, Uwe Platzbecker, M.D.,, Ghulam J. Mufti, F.R.C.P.,, Guillermo Garcia-Manero, M.D.,, Rena Buckstein, M.D.,, Valeria Santini, M.D.,, María Díez-Campelo, M.D., Ph.D.,, Carlo Finelli, M.D.,, Mario Cazzola, M.D.,, Osman Ilhan, M.D.,, Mikkael A. Sekeres, M.D.,, José F. Falantes, M.D.,, Beatriz Arrizabalaga, M.D.,, Flavia Salvi, M.D.,, Valentina Giai, M.D., Ph.D.,, Paresh Vyas, B.Ch., B.M.,, David Bowen, M.D.,, Dominik Selleslag, M.D.,, Amy E. DeZern, M.D.,, Joseph G. Jurcic, M.D.,, Ulrich Germing, M.D.,, Katharina S. Gtze, M.D.,, Bruno Quesnel, M.D., Ph.D.,, Odile Beyne-Rauzy, M.D.,, Thomas Cluzeau, M.D.,, Maria-Teresa Voso, M.D.,, Dominiek Mazure, M.D.,, Edo Vellenga, M.D., Ph.D.,, Peter L. Greenberg, M.D.,, Eva Hellstrm-Lindberg, M.D.,, Amer M. Zeidan, M.B., B.S., M.H.S.,, Lionel Adès, M.D.,, Amit Verma, M.D.,, Michael R. Savona, M.D.,, Abderrahmane Laadem, M.D.,, Aziz Benzohra, M.D.,, Jennie Zhang, M.S.,, Anita Rampersad, B.A.,, Diana R. Dunshee, Ph.D.,, Peter G. Linde, M.D.,, Matthew L. Sherman, M.D.,, Rami S. Komrokji, M.D.,, and Alan F. List, M.D.

Issue&Volume: 2020-01-08

Abstract: 

BACKGROUND
Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study.

METHODS
In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48.

RESULTS
Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time.

CONCLUSIONS
Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. 

DOI: 10.1056/NEJMoa1908892

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1908892