Sekeres Mikkael A, Maciejewski Jaroslaw P, Giagounidis Aristotle A N, Wride Kenton, Knight Robert, Raza Azra, List Alan F
Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Desk R35, 9500 Euclid Ave, Cleveland, OH 44195, USA.
J Clin Oncol. 2008 Dec 20;26(36):5943-9. doi: 10.1200/JCO.2007.15.5770. Epub 2008 Nov 17.
Patients with myelodysplastic syndromes (MDS) often require treatment with growth factors (GFs) or non-GF therapies. One non-GF drug, lenalidomide, is particularly effective at achieving transfusion independence (TI) in patients with lower-risk MDS with the del(5q) cytogenetic abnormality. However, approximately half of del(5q) patients and one quarter of non-del(5q) patients treated with lenalidomide experience significant cytopenias. Lenalidomide-induced cytopenias occurring early in treatment may serve as a surrogate marker of clonal suppression and, therefore, may be predictive of a TI response.
We analyzed 362 low-risk, transfusion-dependent patients with MDS, with or without the del(5q) abnormality, enrolled in two phase II studies (MDS-003 and MDS-002) to determine whether treatment-related cytopenias are correlated with lenalidomide response. Cytopenias were assessed during the first 8 weeks of therapy, and response was defined as TI; response predictors were explored in univariate and multivariate analyses.
Among patients with del(5q), 70% of those whose platelet count decreased by > or = 50% achieved TI, as compared with 42% of those whose platelet count remained stable or declined by less than 50% (P = .01). Among patients without baseline neutropenia, 82% of those whose absolute neutrophil count (ANC) decreased by > or = 75% achieved TI, as compared with 51% whose ANC remained stable or decreased by less than 75% (P = .02). These relationships were consistent in multivariate analyses. No relationship between the development of cytopenias and response could be established for lower-risk patients with MDS without del(5q).
These findings support the hypothesis that a direct cytotoxic effect of lenalidomide specific to the del(5q) clone may be indicative of a TI response.
骨髓增生异常综合征（MDS）患者常需接受生长因子（GFs）治疗或非GF治疗。一种非GF药物来那度胺，对于具有del(5q)细胞遗传学异常的低危MDS患者实现脱离输血（TI）特别有效。然而，接受来那度胺治疗的del(5q)患者中约一半以及非del(5q)患者中四分之一会出现显著血细胞减少。治疗早期出现的来那度胺诱导的血细胞减少可能作为克隆抑制的替代标志物，因此可能预测TI反应。
我们分析了362例低危、依赖输血的MDS患者，这些患者有或无del(5q)异常，入组了两项II期研究（MDS - 003和MDS - 002），以确定治疗相关的血细胞减少是否与来那度胺反应相关。在治疗的前8周评估血细胞减少情况，反应定义为TI；在单变量和多变量分析中探索反应预测因素。
在del(5q)患者中，血小板计数下降≥50%的患者中有70%实现了TI，而血小板计数保持稳定或下降少于50%的患者中这一比例为42%（P = 0.01）。在无基线中性粒细胞减少的患者中，绝对中性粒细胞计数（ANC）下降≥75%的患者中有82%实现了TI，而ANC保持稳定或下降少于75%的患者中这一比例为51%（P = 0.02）。这些关系在多变量分析中是一致的。对于无del(5q)的低危MDS患者，无法确定血细胞减少的发生与反应之间的关系。
这些发现支持这样的假设，即来那度胺对del(5q)克隆的直接细胞毒性作用可能预示着TI反应。
