Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA.
Cancer. 2012 Aug 15;118(16):3968-76. doi: 10.1002/cncr.26741. Epub 2011 Dec 16.
Primary myelofibrosis (PMF) and overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal hematopoietic disorders that share similar clinical features and molecular abnormalities, such as the Janus kinase 2 (JAK2) valine to phenylalanine mutation at codon 617 (V617F) and the tet methylcytosine dioxygenase 2 (TET2) mutation. There are limited therapeutic options available for these diseases, and single agents have only modest efficacy. In this phase 2 study, the authors combined multiple active agents (thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid [TADA]) to treat patients with these disorders.
This multicenter trial was conducted from January 2005 to July 2007. The primary endpoint was to evaluate the efficacy of TADA therapy. Patients received the combination for one 12-week cycle followed by maintenance thalidomide for an additional 3 months. Response was assessed using International Working Group criteria.
Among 28 enrolled patients, the median age was 66.5 years; 15 patients had MDS/MPN-unclassifiable, 8 patients had chronic myelomonocytic leukemia type 1, and 5 patients had PMF. Approximately 60% of the patients had normal cytogenetics. The JAK2V617F mutation was detected in 5 of 14 tested patients, and TET2 mutations were detected in 2 of 8 tested patients. Almost half of the patients had splenomegaly. With a median on-study follow-up of 5.7 months, 21 patients (75%) completed the entire 12-week course of therapy, and 6 patients (29%) responded to TADA. With a median extended follow-up of 24.1 months for 15 evaluable patients, the median progression-free survival was 14.4 months, and the median overall survival was 21.4 months.
The TADA regimen yielded clinical responses in patients with PMF and MDS/MPN. To the authors' knowledge, this study represents the first trial targeting this patient population. The results indicated that it is reasonable to incorporate multiple novel agents in the treatment of these rare diseases.
原发性骨髓纤维化（PMF）和重叠骨髓增生异常/骨髓增殖性肿瘤（MDS/MPN）是具有相似临床特征和分子异常的克隆性造血疾病，例如 Janus 激酶 2（JAK2）缬氨酸到苯丙氨酸突变（V617F）和四甲基环化二氧酶 2（TET2）突变。这些疾病的治疗选择有限，单一药物的疗效也只有适度。在这项 2 期研究中，作者联合使用多种活性药物（沙利度胺、三氧化二砷、地塞米松和抗坏血酸[TADA]）来治疗这些疾病的患者。
这项多中心试验于 2005 年 1 月至 2007 年 7 月进行。主要终点是评估 TADA 治疗的疗效。患者接受该联合方案治疗 1 个 12 周的周期，随后再接受 3 个月的维持性沙利度胺治疗。使用国际工作组标准评估反应。
在 28 名入组患者中，中位年龄为 66.5 岁；15 名患者患有 MDS/MPN 无法分类，8 名患者患有慢性粒单核细胞白血病 1 型，5 名患者患有 PMF。大约 60%的患者具有正常的细胞遗传学。在 14 名接受检测的患者中，有 5 名检测到 JAK2V617F 突变，在 8 名接受检测的患者中有 2 名检测到 TET2 突变。近一半的患者有脾肿大。在中位研究随访时间为 5.7 个月时，21 名患者（75%）完成了整个 12 周的治疗过程，6 名患者（29%）对 TADA 有反应。在 15 名可评估患者的中位扩展随访 24.1 个月时，中位无进展生存期为 14.4 个月，中位总生存期为 21.4 个月。
TADA 方案在 PMF 和 MDS/MPN 患者中产生了临床反应。据作者所知，这项研究代表了针对这一患者群体的首次试验。结果表明，在治疗这些罕见疾病时，将多种新型药物联合使用是合理的。
