Beran M, Kantarjian H
M.D. Anderson Cancer Center, Houston, TX, USA.
Semin Hematol. 1998 Jul;35(3 Suppl 4):26-31.
Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are heterogeneous disorders for which there exist few active therapies and where the standard of care is still considered supportive. Identification of new effective therapies in MDS and CMML is a high priority for hematologic oncologists. We have evaluated the efficacy of single-agent topotecan, a topoisomerase I inhibitor, in patients with MDS (refractory anemia with excess blasts [RAEB] and refractory anemia with excess blasts in transformation [RAEB-T]) and CMML. Sixty patients (MDS = 30; CMML = 30) with a median age of 66 years were treated. Chromosomal abnormalities were present in half of the patients, as was thrombocytopenia. Topotecan was administered at 2 mg/m2 by continuous intravenous infusion over 24 hours daily for 5 days every 4 to 6 weeks until remission, followed by one course every 4 to 8 weeks for a maximum of 10 courses. Nineteen patients (32%) achieved a complete response (CR); seven had hematologic improvement. CRs were observed in 11 of 30 patients with MDS (37%) and eight of 30 patients with CMML (27%). Conversion to diploid karyotype was observed in eight patients with karyotypic abnormalities at diagnosis who later achieved a CR. History of prior chemotherapy and monocytosis was associated with poor prognosis. Mutation of the RAS oncogene was found in six CMML patients (20%), and none responded to topotecan therapy. The estimated 12-month survival rate was 33%, the median survival time was 9.3 months, and the median remission duration was 7 months. The most significant toxicities were gastrointestinal, including mucositis (67%; severe 23%) and diarrhea (38%; severe 17%). Febrile episodes were noted in 85% of the patients, while documented infection occurred in 47%. Topotecan has demonstrated significant single-agent activity in MDS and CMML with generally manageable side effects. Future studies will evaluate topotecan-based combination therapies with topoisomerase II reactive agents, cytarabine, alkylating agents, and hypomethylating agents.
骨髓增生异常综合征（MDS）和慢性粒单核细胞白血病（CMML）是异质性疾病，针对它们的有效治疗方法很少，目前的标准治疗仍被认为是支持性治疗。确定MDS和CMML的新有效治疗方法是血液肿瘤学家的当务之急。我们评估了拓扑替康（一种拓扑异构酶I抑制剂）单药治疗MDS（伴有过多原始细胞的难治性贫血[RAEB]和转化中的伴有过多原始细胞的难治性贫血[RAEB-T]）和CMML患者的疗效。对60例患者（MDS = 30例；CMML = 30例）进行了治疗，患者的中位年龄为66岁。一半患者存在染色体异常，血小板减少的情况也很常见。拓扑替康以2 mg/m²的剂量通过持续静脉输注，每天24小时给药，共5天，每4至6周重复一次，直至缓解，随后每4至8周进行一个疗程，最多进行10个疗程。19例患者（32%）达到完全缓解（CR）；7例有血液学改善。30例MDS患者中有11例（37%）达到CR，30例CMML患者中有8例（27%）达到CR。在诊断时存在核型异常且后来达到CR的8例患者中观察到核型转变为二倍体。既往化疗史和单核细胞增多与预后不良相关。在6例CMML患者（20%）中发现RAS癌基因突变，这些患者对拓扑替康治疗均无反应。估计12个月生存率为33%，中位生存时间为9.3个月，中位缓解持续时间为7个月。最显著的毒性反应是胃肠道反应，包括黏膜炎（67%；严重程度为23%）和腹泻（38%；严重程度为17%）。85%的患者出现发热，47%的患者有记录的感染。拓扑替康在MDS和CMML中显示出显著的单药活性，且副作用总体上易于控制。未来的研究将评估拓扑替康与拓扑异构酶II反应剂、阿糖胞苷、烷化剂和去甲基化剂联合治疗的效果。
