DeZern Amy E, Thepot Sylvain, de Botton Stephane, Patriarca Andrea, Deeren Dries, Torregrossa-Diaz Jose-Miguel, Marconi Giovanni, Bernal Teresa, Bergua Burgues Juan, Xicoy Blanca, Jonášová Anna, Zeidan Amer M, Dimicoli-Salazar Sophie, Simand Célestine, Valcarcel David, Diez Campelo Maria, Chai-Ho Wanxing, Saini Lalit, Garnier Alice, Geissler Klaus, Ofran Yishai, Nagy Zsolt, Krishnamurthy Pramila, Lübbert Michael, Basak Grzegorz, Carraway Hetty E, Sallman David A, Borate Uma, Santini Valeria, Campbell Victoria, Fenaux Pierre, Braun Thorsten, Lanza Francesco, Zaucha Jan Maciej, Roth David A, Paul Sofia, Roy Pourab, Kelly Michael J, Volkert Angela, Chisholm Jaime, Malak Tanya Abdul, Klimek Virginia M, Cluzeau Thomas
Johns Hopkins University, Hematologic Malignancies, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.
Centre Hospitalier Universitaire, Hematology, Angers, France.
Blood Adv. 2025 Aug 26;9(16):4090-4099. doi: 10.1182/bloodadvances.2025016229.
Higher-risk myelodysplastic syndrome (HR-MDS) with RARA gene overexpression is a subset of patients (pts) with an actionable target for tamibarotene, an oral and a selective retinoic acid receptor-α (RAR-α) agonist. Tamibarotene with azacitidine (AZA) showed complete remission (CR) rates in myeloid leukemia. SELECT-MDS-1 was a phase 3 study comparing the activity of tamibarotene + AZA to placebo + AZA in these pts with newly diagnosed HR-MDS with RARA overexpression. Eligible pts had confirmed RARA overexpression, untreated MDS with higher-risk features by revised International Prognostic Scoring System (IPSS-R), and marrow blast count >5%. Pts were randomized 2:1 to receive tamibarotene + AZA or placebo + AZA, respectively. A total of 246 participants were randomized with 164 and 82 in the tamibarotene + AZA and placebo + AZA groups, respectively. Baseline characteristics included: 69.9% male; median age 75 years (range, 38-93); primary MDS, 89.8%; MDS-excess blasts-1, 48% and MDS-excess blasts-2, 52%; and IPSS-R risk category intermediate (25.5%), high (35.7%), and very high (38.9%). The study did not meet the primary end point of CR, with a P value of .2084 for the treatment effect in the tamibarotene + AZA group. The CR rates were 23.81% and 18.75% in the tamibarotene + AZA and placebo + AZA groups, respectively. The use of tamibarotene-based therapy to target RAR-α as a novel approach in pts with HR-MDS with RARA gene overexpression is not a paradigm, which can augment response rates beyond AZA monotherapy. Further explorations of alternative approaches, including those with a biomarker, to alter the natural history of this disease are warranted. This trial was registered at www.clinicaltrials.gov as #NCT04797780.
伴有RARA基因过表达的高危骨髓增生异常综合征（HR-MDS）是一组患者，他米巴罗汀是一种口服选择性维甲酸受体-α（RAR-α）激动剂，对这组患者有可操作的治疗靶点。他米巴罗汀联合阿扎胞苷（AZA）在髓系白血病中显示出完全缓解（CR）率。SELECT-MDS-1是一项3期研究，比较他米巴罗汀+AZA与安慰剂+AZA在这些新诊断的伴有RARA过表达的HR-MDS患者中的活性。符合条件的患者确诊RARA过表达，根据修订的国际预后评分系统（IPSS-R）诊断为具有高危特征的未治疗MDS，且骨髓原始细胞计数>5%。患者按2:1随机分组，分别接受他米巴罗汀+AZA或安慰剂+AZA。共有246名参与者被随机分组，他米巴罗汀+AZA组和安慰剂+AZA组分别有164名和82名。基线特征包括：男性占69.9%；中位年龄75岁（范围38-93岁）；原发性MDS占89.8%；MDS伴过多原始细胞-1占48%，MDS伴过多原始细胞-2占52%；IPSS-R风险类别为中危（25.5%）、高危（35.7%）和极高危（38.9%）。该研究未达到CR的主要终点，他米巴罗汀+AZA组治疗效果P值为0.2084。他米巴罗汀+AZA组和安慰剂+AZA组的CR率分别为23.81%和18.75%。在伴有RARA基因过表达的HR-MDS患者中，以RAR-α为靶点使用基于他米巴罗汀的疗法作为一种新方法，并非一种能提高缓解率超过AZA单药治疗的模式。有必要进一步探索包括基于生物标志物的替代方法，以改变这种疾病的自然病程。该试验已在www.clinicaltrials.gov上注册，注册号为#NCT04797780。
